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Edison KOL Call

Acne

The seventh in our KOL series, Edison sponsors an interview with Dr. Nanette Silverberg, Chief of Pediatric Dermatology at the Mount Sinai Health System. The conversation featured a discussion on emerging Acne and dermatologic treatments.

Call Leader: Great. Thank you, Dr. Silverberg for taking the time for the call. Maybe you can just start by discussing your practice, and your background treating patients with acne.

Doctor: So yes, I am a pediatric and adolescent practitioner, so number one in the pediatric population is eczema. Number two is acne because they’re just volume wise the kids are ... That’s usually how things sort of assess when you look at the studies assessing our intake practice usually. So certainly something that I see on a frequent regular basis, like every day.

Call Leader: Yeah, yeah. I’m in on ... Yeah, I’m sure.

Doctor: Three or four per day would be pretty standard.

Call Leader: Great. And so just to give some background on acne, I know there’s like a gazillion different potential treatments that you can use with your patients, so just how do you decide which treatment to use, or do you have any ones that you like better than others?

Doctor: Well I mean, I participated in acne guidelines developments. It’s standard. Standardly we tend to focus on using as a basis of treatment a retinoid, and a topical retinoid, and benzoyl peroxide. That’s supposed to be the core. But also we have backup options. So we have people who fail those, or people who let’s say are too irritated by the combinations, so we add in maybe a combo antibiotic or Clindamycin in that particular setting. And then we end up adding in other stuff if we have a woman with inflammatory acne who really haven’t responded well to that regimen.

We have a lot of women, older. I have adults too in my practice. The adult women are often have an overlap with rosacea, so those particular individuals have some significant problems responding to the acne regimen we just described because it’s our retinoids are increase irritants, increase penetration of secondary agents, we’re really looking in that particular situation at a self refuting regimen if that’s what you use consistent with as we move onto other agents that per setting which like topical Dapsone which is wonderful on chin acne. We might use topical Metronidazole especially if there’s overlap situation. If it would come to the usage of oral antibiotics at the second tier or oral contraceptives as a second trial to save the latter in females and kind of move on from there.

Call Leader: That was helpful. When you’ve gone through your first line and then the regimens you usually use in failures, how many people after all that are still not responding to treatment and really are clamoring for a new treatment? Do you have a sense of that?

Doctor: I would have to say that teenagers, a lot of them are first coming to me and they’ve had a minimal intervention from the pediatrician. There I can really promote a traditional regimen and it’ll be the first time that they’re using it and I would probably say that two thirds of teenagers are like that.

When it comes to adults, it’s a little bit different. It’s very often the opposite, so I very often have a variation of a 23 or 24 year old woman who doesn’t necessarily desire to go on Accutane and is looking for an alternative. They’ve maybe been offered that standard regimen in the past.
I see a lot of girls who are straight out of college. First, they tell me that they’re looking for something different. That’s a very common entry point into healthcare usage. Some of those women have been undertreated and it’s been very problematic for them in that setting.

Call Leader: One question that I have on getting new treatments for acne. There are a lot of acne trial failures. Do you have any thoughts on why that is?

Doctor: Failures in acne trials?

Call Leader: Yeah, failures in pivotal face Pimtrea, clinical trials for different agents.

Doctor: Looks as though we’ve always had people behind in these particular trials. I consider Epiduo, an excellent drug, 60, 70, 65% maybe of meaning in point, statistically skilled I think. We have drugs that are wonderful but we don’t have our model of acne treatment is not really to use things as monotherapy. That’s the issue. We get these products that are tested as mono therapies. Very often, they’re much more effective in practice because we don’t use them as monotherapy. We use them for combination therapy with other agents and that allows us to achieve a better result. It’s the way that it’s used in the trial. It’s not necessarily real life usage.

Call Leader: I see. Would you suggest to companies that they run combo trials instead?

Doctor: Absolutely. There are trials that have combination therapies. Post marketing combination therapy, so it’s a dearth of trials looking at step therapy. Some of those trials are traditionally incredibly helpful.

I remember a specific trial where there was a usage of Tazarotene. I think it’s the original brand with Minocycline and then at the end of a certain time period, they stopped. They had people randomized to receive Tazarotene alone or Tazarotene with the Min ... long term with the Minocycline like it said. It was really beautiful in the way the study was done, which was really obvious you could maintain yourself without being on oral long term. These kinds of trials are very important for us. It depends on what it is but they’re important for development. We have issues. We really need to develop a better antibiotic stewardship now in all skin care. Any trials that look at ways for us to specifically avoid usage of antibiotics or look at strategies too. Combination strategies are helpful.

None of these drugs hit the market like ... you look at these trials ... I think the original Aczone trial, there was a large enough number that they could separate the effect of the vehicle, but the effective vehicle was actually fairly strong in the original trial. The drug hit the market at a very ... it was a closely how to direct the drugs and we had a lot of people… that want to keep trying alternative products without going on orals. The other thing that hit the market is topical, you will find a user and dermatologist are typically smart about how they incorporate them. You see a lot of people developing really interesting rationales and ultimately that’ll resolve them in a lot of usage long term.

Call Leader: Ok great. The main topic of the call is DRM01 from Dermira, what do you think about them generally or the product generally? What do you think it might fit in the treatment paradigm?

Doctor: I think that issue ... Some people want to go on Accutane to dry their skin out. We have very little to offer people and say they want to dry their skin out. You know, they’re oily, and they want to do something topical. We can do retinoids. Retin-A Micro might have some drying effect because of the long activity and slow release, but generally we don’t have that much to offer people in that respect, and I think that it will have other sort of [inaudible 00:13:01] from OCH. It just absorbs. It’s like makeup in a sense. It absorbs some of the oil production but not necessarily affecting the actual skin and the path we take with it.

We definitely have all kinds of options but not necessarily ... That particular issue is poorly addressed currently in our pharmaceutical options. I think someone like that could really find a strong place in the market. The other thing is there’s clearly ... Let me give you enough background control that when combined with another agent, secondary agents may become more effective. There’s clearly some basis to believe that would be the case because there are four pathogenic mechanisms for acne. One of them happens to be sebaceous gland hyperactivity and overproduction. It’s a conceptual hyperactivity. It’s not really as normal for the age but it’s still hyperactivity and that’s where production contributes to dandruff. It contributes to acne. It contributes for all this. It’s an important feature.

Call Leader: Do you think there’s any safety issues with going out for sebum production or sebaceous gland activity?

Doctor: Do you know what the pregnancy category will be on the drug?

Call Leader: No, not yet.

Doctor: Has the maker given you any fetal rat studies? Is there anything like that in publication? Or any fetal animal studies?

Call Leader: I’m not aware of any but they could exist. Are there any other safety issues besides the sebaceous glands production? I know that ...

Doctor: The four pathogenic mechanisms of acne are excess sebum production, sebum production nourishes the bacteria in the skin causing a bacterial overgrowth and there is a hormonally induced inflammatory blockage of pores. The hormonally induced inflammatory blockage of pores, some of that may have some contributions for ... It may be that one of the sebaceous glands have shrunken and that it may be less of an issue.

It’s possible that this will ... Plus if there’s less oil production, there’ll be less bacteria. It may actually be a feeder mechanism because we consider Accutane the perfect drug and one of it’s main things is that it travels down the sebaceous gland.

Call Leader: In the previous data for DRM01, there was an imbalance. There was actually a lot more colds in the drug arm in the phase two compared to the placebo. There’s theoretically an immune suppression issue. Do you think just in practice, that that would be an issue?

Doctor: What kind of issue? I didn’t understand…

Call Leader: They had more common colds in the drug arm than in the placebo arm. I think it was close to 25 percent, which is relatively high rate.

Doctor: As opposed to what was in the placebo?

Call Leader: I think it was maybe 10 or 12 in the placebo.

Doctor: Interesting, okay. First of all, the company has to have a secondary study on that because it could just be a fluke. You would have just done that one or maybe they decided it wasn’t adequately powered. I could see why that could be potentially the case because we certainly know that these particular products are absorbed into the region, locally. It could be that we’re unaware.
I’ve always felt that sebum production .... When you hit puberty, when you stop…. You have a different activity level. Running through playgrounds and sharing people’s drinks mostly, you have less URI’s in general in that age period. It may be that the application of certain drugs if you’re reducing bacteria on the skin or reducing biotin, all of that may potentially contribute to a change in the flora locally. I do think it’s possible. I just don’t ... It’s hard for me to believe that that’s something that’s concerning in larger series. It’s hard to believe that.

Call Leader: That was helpful. Going back to something you said previously, which was the difference between your adult patients versus your pediatric patients. In the Phase three trial includes adolescents? They weren’t studied previously in the phase two. Do you think that could impact the results?

Doctor: So the adolescents weren’t in the initial trial?

Call Leader: Yeah. Do you think that could impact these results?

Doctor: Could it impact the results? Yeah. The younger you are the more you ... Even the act of touching your face as a teenager is one of the ways that people get you or I. This could impact the results, yeah.

What I would say to a company like that, if they were smart, would produce an age match as opposed to if you’re focused only on global data and there’s not an adequate age matching they have trouble.

Call Leader: That’s very helpful. In the phase two results, they were testing once a day versus twice a day and so they had once a day or twice a day vehicle. Do you think a twice a day vehicle, which is what they have in the Phase three trial, might increase the placebo response?

Doctor: Yes, clearly. Clearly, that would do so but as long as you make a statistical difference in the usage, it really means nothing to us. If the background lies, just as long as it achieves statistical significance because even just a great vehicle ... If it works. If it reduces these so what, we’re going to be happy practitioners using them.

Call Leader: What do you consider a clinically significant benefit in acne both in terms of percent reductions and inflammatory and non?

Doctor: I usually ascribe to the data, the guidelines from the FDA. In clinical practice, the patients will be fairly happy with a 30 to 40 percent reduction in acne if they’re not too severe to start with. If they’re severe, they really need to get more. If they’re moderate to severe, then a 60 to 70 percent reduction to feel satisfied, from our perspective.
That’s just from my clinical experience. I’m not going to say that’s true, globally. I don’t think there’s enough data actually published on that to say that’s the case, but what the actual mark off is. It’s actually a good thought for study.

Call Leader: Just in terms of percentage, you have a two point reduction in IGA scores?

Doctor: I like that the FDA created that. For me, that’s been something that’s very helpful because it’s hard otherwise to figure out how to benchmark acne. I like these acne scores related to counting lesions and then they give these actual numbers. I think that’s a very clever way to put it together because it’s not easy to categorize.

Call Leader: What percent would have to hit that two point reduction in IGA for you to think that’s clinically meaningful?

Doctor: It depends on what the enrollment is. If it’s mild to moderate disease, I personally ... it has to be statistically significant. I don’t really care with the numbers. Virtually, no one reads those numbers, I don’t think. I might be wrong. From my perspective, most of the way people adopt usage of acne skin care products is that companies bring the new product. They explain the mechanism. Maybe people go to a roundtable dinner. They get samples in the office. Somebody comes in and they give him samples and then the patient can decide if it’s working or not.
Sometimes the drugs, they’ll say that if you just happen to give the first couple of patients the drug and it didn’t do a thing in your office. People are going to say I don’t think this thing works.
Sometimes it seems to work great and people will continue their mention of the practice. Some of that has to do with where you practice, who you practice with and whether your patients are fussy about the elegance of the product. In the end, a lot of treatment of acne is an art and we do get people picking things based on their initial rounds of experience or because they need to get something new.

Sometimes drugs are given to individuals who failed many other drugs initially because they may need something new. Sometimes that really does work well and sometimes not as well as you’d wish. Everybody is going to end up using this as long as it’s not a category X. The category X would be harder to sell.

Call Leader: In terms of inflammatory versus non-inflammatory lesions, if they show efficacy against one and not the other. Is that still going to be used? Is that important at all?

Doctor: For us, it’s nicer to have something that works for both but you typically ... When you look at a retinoid and a benzoyl peroxide regimen. The retinoid works largely on non-inflammatory ... It works long term on inflammatory but in the short term, non-inflammatory. The other one works mostly on the inflammatory because of the antibacterial. We are typically mixer and matchers. That shouldn’t be concerning to a dermatologist with experience.

Call Leader: The Dermira trials are relatively small. People are thinking that they’re underpowered. They’re about 350 patients per arm. Some of the other trials ...

Doctor: I don’t think that’s so small.

Call Leader: It’s lower than what some of the other people like Allergen and Galderma have had.

Doctor: For which drugs?

Call Leader: Like the Aczone trials were about a little more than a thousand in each arm.

Doctor: Well, that would concede that there’s high background co-effect on the drug. It needed it. As long as it reached statistical significance, it really doesn’t matter what the size of the trial is.

Call Leader: The size might hurt your ability to hit the statistical significance.

Doctor: If you don’t hit statistical significance, then you have to do a second version of the same trial and combine the two trials. You’ll see that with some of the atopic dermatitis trials.
I like that actually. What’s interesting is that some of the data will vary from site to site in trials because there is statistical variation in response. Sometimes they get things from different ends of the spectrum which still statistically saying. For that particular kind of situation, they have to add more. They have to apply to the FDA to get more. They start smaller because they’re costly trials. I can’t blame people for saying how smaller they are because they’re costly trials. There’s no question but if they reach statistical significance it’s of no account. If they don’t, that’s their issue. They’re stuck. They’ll have to figure out a strategy that the FDA will agree to allow in order to make that reach a statistical level.

Call Leader: In the Phase two trials there was a bit of a complex dose response in that the 4% gel once a day did better than the 7.5% once a day. Do you think that’s an issue or do you think it’s an anomaly of a smaller trial?

Doctor: No, it may be that the efficacy of the product is at a lower level. Conceptually, we always think more is better but it may be that the study status achieved ... Is no different whether you’re at 3% or 10%. Probably the side effects with the irritation lies with the percentages. If one is for a drug company, then that’s actually pretty reasonable because the FDA will look at that and pick the 4%.

I don’t find it that hard. Later on, a lot of times, they look at the higher percentages. It’s a cheaper product to make if you’re using the 4% versus the 7.5%. You do much better off with the drug company.

Call Leader: That’s where it gets a little confusing because in the Phase three they decided to go forward with 5%, which they didn’t have in the Phase two. 5% twice a day. I don’t know if you have any thoughts on that?

Doctor: That is unusual. They have to provide a different concept to the FDA. They’re developing the strike or fail. They have to apply a group of concepts to the FDA. You have to have something quite critical than the 5% twice a day.

I think they’re probably matching Axiom’s percentages. Axiom is either 5% twice a day or 7.5% once a day. They probably made a mistake in the initial trial with the 4%. It’s hard to say. I don’t know what they were thinking on that but they must have the data to support it.

Call Leader: When it comes to the market, do people pay for branded drugs, given that there’s a plethora of generic drugs?

Doctor: Every drug company has to provide coupons and some kind of help and the development of prior authorization. The companies have to work on that when a drug comes to market.

Call Leader: Do you have any thoughts on what price they can charge to get through payers without too much problem?

Doctor: That is a good question. I don’t know. I couldn’t say. I think that if you can make it as a monotherapy and you can show some cost efficacy. You might get a “tier two”. The aim for the drug companies is to get their products into a lower tier. The lower tier of cost because usually tier one, tier two, tier three. Sometimes they’ll go up to tier 8.

Call Leader: Tier 8, that sounds bad.

Doctor: Usually, tier one is going to be a generic. Tier two is going to be a less costly topical. Typically, acne drugs are on tier 3, with a fifty to seventy-five dollar copay. Then the drug company will give a coupon and then they’ll be thirty-five dollar copay.

Call Leader: One question about what is important for you to make treatment decisions. The company didn’t release any before or after pictures from the Phase two. Is that important to you at all? Or are you more interested in numbers and then sampling?

Doctor: You should ask them if they should have at some of the trials, some pictures of before and after because they’re usually included in the marketing. It should be something that they plan to have for marketing purposes even if they haven’t presented them to you.

Call Leader: Do you inject any Botox? Do you use Botox in your practice?

Doctor: I do, actually. I see a lot of adults so I have to. I do a lot actually, if I had to include that. I have a lot of young women. That goes along with the whole process.

Call Leader: There’s a company called Revance that has a long acting Botox. They recently have some data on that. Do you think that’s important to have a long acting Botox? I believe it’s supposed to work for around six months.

Doctor: I think it’s a really nice product, conceptually but they have to come to the market and say what’s distinctive about them. What’s distinctive about them that they should be used as opposed to other drugs?

Call Leader: If they’re longer acting than traditional Botox. I think Botox is supposed to work for two to three months and they’re supposed to work for six months.

Doctor: No, Botox is four to six. The longer you’ve used it, the longer the advocacy persists.

Call Leader: So you don’t think a six month Botox is particularly game changing or distinctive?

Doctor: It could be. It depends. If the results at six months are identical to the results at three months, then I would say that the product has more like a twelve month activity. It’s a longer shelf life. In that setting, you might save yourself with that. It’s my drug of choice because I want to spend less in terms of coming in less frequently. It depends on how it’s positioned.
I’m not totally sure what the plan is with that. I don’t get in touch with the marketing agents much.

Call Leader: Do you have any thoughts on why previous competitors failed. There was Dysport, The Xeomin, that never really made the headway because Allergan has a stranglehold. Do you have any thoughts?

Doctor: Some of it is cost. They price fixed pretty well and it’s very hard for people to figure out what to do with something like Dysport. It was very hard to figure out what the actual conversion rate was. How many units of Botox equals how many units of Dysport? Conceptually, Dysport was a lovely product. But it sort of became….I just don’t think it…It wasn’t…

When you come to market with that kind of stuff, people have a dose in their mind for or a volume in their mind that they use to achieve the effects that they want. If you start shifting that, people are concerned with the markers and ask how to make that equivalent. I can’t say that that’s wrong. I think it’s hard as a physician to start adjusting that all.

Call Leader: Do you also treat psoriasis patients?

Doctor: Yes.

Call Leader: There’s a lot of psoriasis drugs on the market now. There’s always other players in the pipeline. Are there any areas within psoriasis that you would consider to be an unmet need?

Doctor: Yeah. The development of pediatric drugs. Pediatric and adolescents is still unmet. The development of adequate scalp preparations is an unmet need. Development of preparations for sensitive skin areas may be an unmet need. There’s always a unmet need for somebody that’s not ... not so much a biologic. I don’t know that everybody in the universe wants injection.

Call Leader: I see that. One last question. If you include all parts of your practice, what’s making you most excited today?

Doctor: What makes me most excited today? Completing my paperwork. That’s a joke. I love my patients. I love to help them but at the end of the day, when I can close out the list, my stack of col vacs and prior authorizations. There’s something exceptionally gratifying about that.

Call Leader: That’s funny. Is there anything in the pipeline or something that just came out that’s really exciting?

Doctor: It’s clear that the atopic market is going to just take off like crazy in the next five to ten years. There’s a lot of pipelines. It’ll be interesting to see how that sets out.

Call Leader: Great. Thank you so much for your time Dr. Silverberg. This is very helpful.

Doctor: My pleasure. Thanks. Sorry about the phone issues.

Call Leader: No problem at all. Have a great day.

Doctor: Thanks, you too.

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Edison KOL call

Major Depression Disorder

The sixth in our KOL series, Edison sponsors an interview with Dr. Michael Thase of the Perelman School of Medicine of the University of Pennsylvania.  The conversation featured a discussion on emerging depression treatments.

Call Leader: Great. Thank you so much Dr. Thase for joining the call today. Can you please start off by describing your background and clinical practice?

Doctor: I’m a professor of psychiatry at the University of Pennsylvania’s Perelman School of Medicine. I’ve been a psychiatrist since the early 1980’s when I completed residency. My practice has always been academically based, although it’s always included some private practice. Typically on the order of eight to ten hours a week. Currently, in addition to that, I also supervise a residents clinic one afternoon a week. That basically provides, let’s see, exposure to about 20 additional patients a week.

Call Leader: Okay great. Then, just kind of briefly, what’s your preferred treatment algorithm for patients with MDD, Major Depressive Disorder?
Doctor: The first distinction is based on severity and degree of incapacity and also modified by patient preference. If the illness is not too severe and not too incapacitating and the person would prefer to see a psychotherapist, we may opt to do nonpharmacologic treatment instead. The more severe, the more incapacitating the illness, the more I am biased towards prescribing medication with or without concomitant psychotherapy. I think of ECT when available pharmacol therapies have failed or if the patient is just grossly incapacitated by the illness. I think of TMS the other neuromodulation option we use these days for people who are intolerant to multiple medications, but not severe enough to think about ECT. I do occasionally send patients to Ketamine clinics and I am conducting research with both Ketamine and Esketamine for people who aren’t responsive to antidepressants, but for whom we’re not thinking of ECT on urgency grounds.

Call Leader: What percentage don’t respond to standard therapy such as SSRIs?

Doctor: The best you can do, I mean if you take good care of people, you use psychotherapy in addition to pharmacotherapy, and you’ve got patients with decent prognostic indicators, the best you can do is about a six out of ten rate with the first course of treatment and then about a five out of ten or two out of the four remaining with the second course of treatment. Things go south unless you move on to Ketamine or ECT past that. So, by the time you get through four lines of treatment, you’ve probably treated eight out of ten people and maybe 50% of the remaining patients you can get better with more intensive strategies. I would say that even under ideal circumstances, at least 10% of people will remain ill at the end of one year of continuous treatment.

Call Leader: Okay, great. That was very helpful. Just on the reimbursement front, how hard is it to get reimbursement for branded therapies for depression?

Doctor: Oh, it’s impossible basically. The people who make branded therapies, essentially give them away through various coupons and incentive kinds of things that you typically can’t use a branded therapy for beyond, until you get to third or fourth line use.

Call Leader: That was helpful. I’m just trying to think, is there a pricing ceiling where if branded therapy was cheap enough, would it be easier to get reimbursement or is that have nothing to do with it if it’s branded it’s [inaudible 00:06:29].

Doctor: It’s the Rockefeller test. I just apply a different version. I say, what would be the price tag where I would start to become annoyed, and I’m no Rockefeller but ... the price point where people won’t pay out of pocket even if they’re incredibly wealthy, somewhere north of 200 dollars for a prescription. The real point when people start getting squeamish, maybe around the 50 dollar line. Something like that.

Call Leader: Mm-hmm (affirmative).
Doctor: Typically, branded antidepressants are at about three to five dollars a day. So that’s about 150 a month. So they’re below that line, but they’re above what most people feel okay about paying.

Call Leader: Yeah, I would definitely think that’s the case. Kind of moving on to clinical data, what level of HAM-D or MADRS improvement do you need to see in order to view the results as clinically meaningful?

Doctor: This is just nonsense because these are research tools and practicing clinicians don’t even use them. This is stuff that people will opine and pontificate about, but honestly you need a treatment that reliably works and is at least as good or nearly as good as other things that reliably work, but offers some kind of advantage.

In order to beat placebo in properly done, randomized clinical trials, you need to have about a two or three point advantage on Hamilton’s scale. That translates to about a three or four point advantage on the Montgomery-Asberg. Those mean differences really are explained by about a 15% response or remission rate advantage for the active treatment, versus the placebo. In this kind of scenario the active drug does 50% response and the placebo does 35, and low and behold the average difference in the HAM-D is three points or something like that. So, the average difference only is important because it’s tied to the probability of a statistically significant finding, which is tied to the approval of the FDA which gets the drug to market.

Call Leader: Are there any types of scales that you do use with your patients or is it more you just look at the symptoms, ask them how they are, etc.

Doctor: The easiest scale to do in your practice is called the Clinical Global Impressions Scale, where a 1 is very much improved, basically remitted. A 2 is much improved and this would correspond to a 50% reduction on one of those more extensive scales. Then every number below that, three, four, five is a worse outcome. Meaning, not acceptable. Not a meaningful benefit for your patient. The numeric scales that are now in wider use can be back fit to apply to this kind of clinical global impressions, but the two that are the most commonly used and most widely available and don’t cost anything are the PHQ9 and the quick inventory of depressive symptoms, self report version. Your patients can fill those out in the waiting room and generally a 50% reduction in the symptom burden or more goes along with responding and 70-75% or better goes along with remitting. There are exceptions to these rules. Somebody with mild depression can get 40% improvement and be a responder. Somebody with life threatening terrible depression can have a 60% improvement and still be too sick to be a responder, but these general convictions work reasonably well.
Call Leader: That’s very helpful. Now, let’s jump into some of the emerging therapies. Can you tell me, what do you think about the potential for Ketamine and Esketamine for patients with MDD and can you just compare and contrast the two?

Doctor: Everybody who receives Ketamine is receiving half Esketamine and half R-Ketamine. So, Esketamine is simply a purified variant of the Ketamine molecule that only has one of the two stereoisomers. It’s a tiny bit stronger and the manufacturer picked the Esk in aptamer because they knew that they would lose some potency when they went from intravenous infusion to intranasal delivery. Ketamine is generically available, it’s inexpensive but the therapeutic use is being pushed through an IV so you need to get the IV started and you need to have a medically safe place for the person to receive the IV therapy. At the least, an infusion center perhaps a place with a recovery room, not unlike what’s done for ECT, for example.

There are hundreds of dollars of cost associated with intravenous delivery of Ketamine. So, the drug’s not the problem, it’s the delivery of the drug. So that’s why J&J chose to go with intranasal delivery of Esketamine, because psychiatrists don’t have to start the IV. There’s not nearly the same kind of worry that the person will keel over or be out of it for an hour and a half that you might have with an IV delivery. It’s just much better suited for the ambulatory world where psychiatrist practice.

Call Leader: Is it possible to get reimbursement for Ketamine?

Doctor: No, because it’s not an approved therapy.

Call Leader: Mm-hmm (affirmative). Okay.

Doctor: I’ve heard stories where some people get reimbursed for it, but I just don’t know which insurers have decided to do that. Maybe it’s Kaiser? The Kaiser system in the west coast is doing that.

Call Leader: Mm-hmm (affirmative).

Doctor: Because they’ve determined that treatment resistant depression cost them so much, that it costs them less to set up their own Ketamine program. Ketamine is really inexpensive and again you can control the cost of delivery. You get 50% of these horribly ill service consuming people better and suddenly you’ve got a value proposition there. I don’t think my insurance would cover it for me if I needed it. I think I would have to pay out of pocket for it.

Call Leader: Mm-hmm (affirmative),

Doctor: That’s the trump card that will be there for Esketamine. It both, doesn’t require an IV and it will be reimbursed.
Call Leader: Mm-hmm (affirmative). In terms of the dissociative side effects for Esketamine, is it much shorter?
Doctor: Shorter and less intense. You’re only getting about 80-90% of the drug exposure. Not quite as dramatic and there’s not much of it. People will have, I’d say 30-40% of people have some dissociative or psychotomimetic kind of experiences, but for the most part these aren’t ... if you were an experienced recreational Ketamine user, you’d be disappointed. These are not good high intensity trips. They’re below that threshold.

Call Leader: Oh, okay. On repeated dosing, do the dissociative effects go down or do they stay with the treatment?

Doctor: They tend to go down, but it’s not always like clock work. They don’t always go down. We sometimes see someone have a stronger experience three weeks out than they had originally. There is some fluctuation to it. Maybe it has to do with how much of the drug got absorbed from the intranasal delivery, but there is a tendency. This is why abusers, over the course of a long weekend of heavy use will use more and more and start to get themselves into trouble.

Call Leader: Mm-hmm (affirmative).

Doctor: There is some tolerance that develops to the intoxicating effects.

Call Leader: Are the dissociative effects at a level where there could be wide spread use in severely depressed patients?

Doctor: Yes. This is the least of our worries. The worry about bad trips and too strong dissociative effects, that will get rubbed out pretty quickly once the drug is widely available. The real worry is, first of all, it won’t work, which is a 40 or 50% proposition that it just won’t work for this patient. Even though it’s being presented as the great white hope, it honestly will only work about half the time. Maybe a little less and then if it works, is this the only thing that will ever work or can you segue back to a more conventional treatment over time? That’s completely unknown. It’s possible if the treatment is priced too high, and only it works, that you now have a treatment that the patient knows will help them but they can’t afford.

Call Leader: What do you think about the cardiac side effects? Do you think that’s going to be any sort of barrier?

Doctor: A little barrier, but I mean it’s some high blood pressure. That’s mostly it. It’s mostly transient, it mostly passes within an hour, hour and a half. It’s not a big deal. I know it sounds like I drank the Kool-Aid, but we’ve done 30 or 40 of these at this point, there’s just not much there.

Call Leader: Sounds like the side effects might be manageable enough for your regular community psychiatrist to be able to handle the administration. They probably just need to have a place for the employees.

Doctor: The side effects and the medical seriousness of this will be such that the upper quarter of prescribing docs who are tougher minded and know how to take blood pressures and do things like that, those will be the doctors that are actually using it. The other docs who aren’t so tough minded, don’t like doing the regular medical stuff, they’ll refer.

Call Leader: Okay.

Doctor: I don’t think it’ll ever have the Prozac kind of impact.

Call Leader: Yeah, do you think they would have to perhaps hire an additional staff member just to handle Esketamine administration or anything like that?

Doctor: You’ll need babysit ... not babysitters, you’ll need somebody in the caretaker responsibility because you’re not going to have the psychiatrist sitting in the room, or sitting in the room next door making sure the person’s okay.

Call Leader: Mm-hmm (affirmative).

Doctor: More akin to a group practice or a service TMS clinic where you got some support staff around to help make sure that everything is going smoothly.

Call Leader: Great, that was very helpful. Do you have any thoughts on Rapastinel from Allergan?
Doctor: Sure, I’ve got lots of thoughts. It’s everything I said good about Esketamine is also true about Rapastinel except it’s less of a sure thing because we know Esketamine is half the active ingredient of Ketamine so if you doubled the dose, you have the same thing. Rapastinel looks like it works. There’s animal data that suggests that it will work,  but it’s a completely novel compound. It may not address the NMDA glutamate system exactly the same way that Ketamine does. There’s some oddities in the data that makes them less than slam dunk interpretable. There are 12 good placebo controlled studies of Ketamine now; there are none yet on Rapastinel. Bring it on, I hope it works great, but it’s just three years too early to have that same confidence.

Call Leader: Yeah, no I understand that. Can you describe what oddities in the data and what you meant by that?

Doctor: In the first study only one of the four doses worked. The fact that the one dose that worked was right in the middle of the dose response range was interesting to everybody because that’s sort of like Ketamine, but the fact remains that there’s not a replication of the working dose. There’s just this one study. The second study used an odd design in which they identified people who responded at various doses and then continued them on, some on active, some not on active. Most of the patients who appeared to respond, stayed better and so they didn’t demonstrate the same reliable loss of effect following short term administration that’s routinely seen for Ketamine. Then people began to say, “oh well this might have much longer lasting effects.” Maybe it didn’t work in the first place. Maybe this is an elaborate placebo intervention and they got some people better and sure enough they stayed better when they continued it.

Call Leader: Mm-hmm (affirmative), great.

Doctor: The people at Allergan took these things very seriously. They looked at it very closely, they thought that the risk that maybe it didn’t work, although it was there, the chances that it really did work and they just needed to do better studies, and they invested heavily in that. If I had to wager, I would wager that it really worked. I’m just telling you it’s three years behind.

Call Leader: Do you think that ... let’s say that it has less of a therapeutic effect than Esketamine, but it doesn’t have the dissociative effects. Would it generally be used more?

Doctor: Well, no. If it’s given intravenously you still pushed yourself into that most difficult to treat group of patients that needs to go someplace that a doctor will put an IV and push a drug. For the son of Rapastinel if there is indeed really a son, it might be given orally. The fact that there may be less of an effect if given orally is still potentially meaningful because it’s a new mechanism. An oral medicine of a new mechanism is going to fit in a treatment hierarchy and the fact that it’s safer and doesn’t have the blood pressure effect and doesn’t appear to have the dissociative effects kind of taps in to an orally administered medication. There’s a future here if it works. Even if it doesn’t work as well as Ketamine because of its novel mechanism of action.
Call Leader: Mm-hmm (affirmative). I think there was some evidence in rat models in enhanced memory and learning?

Doctor: Well, yeah that would be exciting, and there’s this whole interesting thing about pairing this up with say cognitive therapy or something that you could ... maybe patients would the most difficult depressions can’t benefit so much from these learning based psychotherapies because they’ve lost the plasticity effects to modifying neural systems with experience, but now you restore that with the medication and wham, you can do therapy coincident with the treatments. This is a very exciting possibility.

Call Leader: Have we seen any of that with Esketamine as well or is it just with Rapastinel?

Doctor: No, no it’s true for Esketamine also. It’s at the animal model level. No one has done a therapy facilitation yet in this area, but there are other studies using other compounds like dicyclomine would suggest that you can facilitate the learning of therapy or the benefit of therapy with pharmacologic enhancement.

Call Leader: Great, yeah that’s very helpful. Let’s move on to SAGE-217. What are your thoughts on that one? I know the data is relativity ... there’s not that much of it.

Doctor: It’s the first drug that’s called a neurosteroid that’s being studied in humans. The potential value in postpartum depression was interesting. The little preliminary study that was done, very nice effect. That was all exciting although the potential market for this is tiny. Postpartum depression’s common, but pregnancy is not so common so the fact that ... this was an interesting but somewhat obscure finding, until they decided to take a chance and give it to regular depressed people including some men. It seemed to show, admittedly it’s a very low sophistication design, it’s open label. They seem to show a large benefit for men and women and this indeed, because it’s a novel mechanism of action, suddenly makes this more commercially interesting because you’ve got no dissociative potential, no intoxicating kind of worries, no controlled substance alerts and a novel mechanism of action. It could have it’s own complimentary life, in other words.

Call Leader: Now, I know that the HAM-D treats was something like 20 points in 15 day trial. Is it possible for a placebo to go down that much or is it obviously doing something?

Doctor: There are studies of people who have torn menisci, who have had placebo surgery, and in the weeks convalescing from their placebo therapy they’re walking without a limp. Under some special circumstances of interesting exciting novel developments and so forth, it’s possible to see a time, one time, of kind of miraculous effect. This is why people go to Lourdes and get cured of all sorts of things. It’s not possible for this to happen over and over again. If indeed, this effect is seen a second time or a third time then it becomes much more interesting, much more likely or possible that this is the real thing.

Call Leader: Just given the mechanism, what side effects do you expect to be concerned about?

Doctor: I haven’t thought about this. I’m obviously not bashful about giving opinions, but this is not one that I’ve thought through carefully. The only one that would come to the tips of my finger would be, I would worry about the potential for sedation and because the delivery is done by infusion, you really need to see about whether there’s another way of delivering this medication for it to be commercially viable on a larger scale, but I don’t have any knowledgeable reservations about the tolerability.

Call Leader: Well, the SAGE-547 that’s the one that was in postpartum depression, that was IV, but the SAGE-217 which they had for major depressive disorder in the open label trial, that actually was oral so they ...

Doctor: I read that and I completely had forgotten that.

Call Leader: No problem, but I was wondering, there’s a bit of an argument about these drugs. I know you haven’t necessarily researched them too deeply. Some people think they are neuroactive steroids and others just think of them as maybe even better Benzodiazepines.

Doctor: That is possible, but we’ll learn about that if that’s true and there’s nothing wrong if that’s the case. We just have to sort this out and work around it. If they are Benzodiazepine-like, but they’re non habit forming, there’s no problem with that.

Call Leader: Aren’t there are long term cognitive decline issues with benzos?

Doctor: No. No, there are long term ... there’s an epidemiologic association between long term Benzo use and cognitive decline, but it may well be that people who take Benzos longterm have chronic, significant anxiety and that there’s cognitive decline associated with chronic significant anxiety. Benzos do increase your falling risk and they’re not good to take into late life for several different reasons. We’re not talking about something that you go on at age 36 and you take for the next 50 years. We’re talking about something that would be used in a step model as a treatment for people who have not responded to easier, simpler treatments that would only be continued if it was highly effective, and if it was highly effective, then we’d get to work on figuring out the benefits and the risk for longer term use.

Call Leader: Mm-hmm (affirmative). If you assume a world where the open label data is verified in a large Phase 3, and then knowing what you know about Rapastinel and Esketamine, where would this go in the treatment algorithm?
Doctor: This is a year or two behind Rapastinel, and because it mechanistically appears to be separate or distinct or at least not closely overlapping with Rapastinel, and let’s assume the son or cousin of Rapastinel, the orally delivered one becomes available, we now have two new non-closely overlapping, o one can’t be called a “me too” of the other,  alternatives that have mechanistically unique therapies. I think Esketamine is the loser in the long run, but would probably be focused on the induction of getting these difficult to treat patients better, if they can get better. Then these alternate therapies would be looked at as the longer term options.

Call Leader: Thank you, that was very helpful. I know that you mentioned that it’s a really small market, but on postpartum depression, what’s the typical treatment regimen for those patients?

Doctor:There are two kinds of postpartum depression. One is regular depression that just so happens to happen in postpartum period. They generally treat this either with focused psychotherapy or SSRIs or both. Then there’s this horrible life threatening, terrible psychotic depression. The one that causes mothers to sometimes kill their babies; that is a psychiatric emergency. To my knowledge, this medication, this SAGE medication has been studied in the regular postpartum depression, not the horrible life threatening one. Is that your understanding also?

Call Leader: Yes, that’s my understanding as well. How many of the patients have the horrible?

Doctor: The horrible one is like one per thousand live births or something. It’s not the 5-10%. That would make it one in one hundred, right?

Call Leader: Yeah.

Doctor: One in a hundred who get depressed have the horrible one.

Call Leader: Okay. So you kind of have two types of postpartum depression. The horrible one and the miserable?

Doctor: Yeah, miserable. Just normally miserable.

Call Leader: Yeah. In terms of the treatment, I would think a lot of women would be hesitant to take a therapy because they might want to breastfeed. What percentage go untreated?

Doctor: More than half because treatment takes time and it’s inconvenient and you have to schlep the baby with you. If it’s medication then you can’t breastfeed and mothers are sort of conditioned, and society goes along with this, to take the hit
and make sure that the baby’s cared for. I think it’s more than 50% go untreated. There is a great unmet need out there for having a more acceptable mother friendly kind of treatment.

Call Leader: Although a 60 hour infusion is probably not that.

Doctor: That doesn’t count.

Call Leader: That would probably, I mean the only market would probably be in the horrible category for that one.

Doctor: If indeed it works for the horrible one.

Call Leader: Yeah, and are those people usually admitted into clinical institutions?

Doctor: Yeah, the horrible ones either die or kill somebody or get usually court committed, emergency psychiatric hospitalization.

Call Leader: Wow, that sounds pretty serious.

Doctor: Well, yeah. You know a women in Texas that killed her kids? You remember that one? She drove the car into the lake.

Call Leader: Yeah, I remember that story.

Doctor: This was like her third kid and it was the third time and the first two kids managed not to be killed, but then she killed all three of them with the third one.

Call Leader: Moving on to a brighter subject, do you have any familiarity with NSI-189 from Neuralstem? There’s just a little bit of data from Dr. Fava I believe he’s at MGH.

Doctor: Yeah. Yeah, I don’t really know much about that. I saw the press release I think. Was there a press release about this?

Call Leader: Yeah, it was a couple years back and there is a paper. I think some of the doses were significant, others weren’t. The data was like a positive signal, but not necessarily outstanding.

Doctor: Yeah, it looked like it had antidepressant effects.

Call Leader: Yeah, exactly. If you’re not too aware of it, we can just move on. In terms of, first lets start with depression, out of all the drugs that we talked about and some that we haven’t talked about, what’s really exciting you?

Doctor: There’s nothing out there that’s exciting me that we haven’t talked about.

Call Leader: Okay.

Doctor: There could be some things at a level of development that I don’t know about yet or haven’t heard enough about, but Rapastinel I am excited about and cautiously optimistic. I really do hope it’s the real thing. The whole notion that Ketamine and its descendants can help repair the brain’s ability to learn and be resilient to stress and that we can take learning based interventions that aren’t strong enough to help people in their current brain injured state. That’s metaphoric, brain injured when I say that, but with this reparative effect they can progress. These are the things that I think make the next decade the most interesting.

Call Leader: Mm-hmm (affirmative). Do you think there’s potential for these products and other disorders like bipolar disorder?

Doctor: Oh, yeah. The depression of bipolar disorder it would likely be responsive to everything that we’ve talked about. You have another level of complexity because you have to determine whether these interventions will promote mania or cause cycling. We know that was true about the re-uptake inhibitors and the MAOI’s, but we don’t know if that will be true for these medicines.

Call Leader: Do you know if they’re planning on doing any work in bipolar depression?

Doctor: Generally these guys stay away from bipolar depression because the studies are harder and more complicated until they start to get ready to come to market. Then they think about ways to have a competitive advantage or do something new and interesting. If indeed the Rapastinel studies or the Esketamine studies start to read out positive then you will see at least one bipolar study done with each of these compounds.

Call Leader: Mm-hmm (affirmative). Great. That’s all for my questions. Thank you so much Dr. Thase. This was extremely helpful.

Doctor: Yeah, good. Good luck with your project.

Call Leader: Great, thank you.

Doctor: Okay, bye bye.

Call Leader: Have a great day.

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Edison KOL call

Edison KOL Call: AML

The fifth in our KOL series, Edison sponsors an interview with Dr. Douglas Smith of the Johns Hopkins University School of Medicine.  The conversation featured a discussion on emerging AML treatment.

Call Leader: Great. Thank you so much for joining us Dr. Smith. I was wondering if you could just start by describing your practice?
Doctor: Yes, I’m at an academic medical center. We have a leukemia program within the academic center, so we have a fairly large volume of leukemia patients. My research interests are in drug development and novel therapeutics so that’s where I spend most of my research time. I’m one of the senior folks in our program having been here for 22 or so years in this leukemia world.

Call Leader: Great. I was wondering if you could walk us through ... What’s the usual course of therapy when you get a patient with AML into your practice?
Doctor: Yeah, sure. The approach to really diagnose patients with AML is to, number one, determine whether or not they’re a candidate for intensive therapy versus less intensive therapy mostly based on their medical comorbidities and age. Number two, we determine the prognosis associated with the type leukemia that they have.
Doctor: We use the markers of leukemia. Molecular markers, surface markers, cytogenetic markers to ... and the patient’s history of course, to try to determine the likelihood of whether that leukemia’s ... would respond to traditional approaches with infusional chemotherapy. So those are the two big things that we do when people first arrive. The majority of our patients are treated with ARC plus an anthracycline combination, so sort of a standard approach.
We’re lucky that we’ve had clinical trials for people that are newly diagnosed or recently relapsed or refractory so, putting patients on a clinical trial is a very high likelihood in our institution and it’s something that we do a lot of. But our standard approach would be an ARC-based, plus anthracycline chemotherapy.
Call Leader: What percentage of your patients end up going on clinical trials?
Doctor: Probably close to 80% of our patients our treated on a clinical trial. Most of those clinical trials are therapeutic. Some of them are donation of blood and bone marrow and those types of things but for the most part the majority of our patients are put on clinical trials.
Call Leader: Okay, great. Do you see that changing any in the next few years? I’m probably skipping ahead a little bit, but just with ... I mean, Vyxeos is going to be coming online, Venetoclax probably, it can be used off-label now and will be on-label in a few years, and then you have Midostaurin from Novartis and the Agios IDH inhibitors. You might have a lot more on the market. Will that take away from the clinical trials that are still ongoing?
Doctor: Well, my hope is that we’ll still have clinical trials looking at other drugs, and that we will continually refine the approach. So just like I said in a very big global we look at somebody who’s old and frail and say, “You’re not a good candidate,” or somebody who’s young and robust and say, “You are a good candidate for the therapy.”
In addition, moving forward when we have these other drugs to play with, I think we’ll be able to say, “Okay, your molecular markers show you have an IDH1 mutation. You’re going to get chemo plus an IDH1 inhibitor because it’s available off the shelf, it’s approved, and we can use it.” Many of those patients will get that as their standard of care and the people that don’t have an identifiable marker or whatever, those people would still be potentially eligible for clinical trials moving forward, with new agents and new targets, etc.
It may become more personalized sooner than many people would have thought of.
Call Leader: Okay great. Which subgroups within AML would you say are underserved by current practice?
Doctor: I always hate the word “most” but there’s no really great group where things work that well for. The exception being patients with APL where we’re likely to cure the majority of those patients and we can get away without using lots of cytotoxic chemotherapy. It’s not that the treatment isn’t hard, but it’s a lot different than with cytotoxic chemotherapy.
Outside of that, I think every way you want to slice it to me I think that we can probably do better. We always talk about the holy grail of drug development as elderly leukemia. A low-toxicity drug but with high efficacy, it can be taken by pill and those types of things are sort of ... always been the challenge in drug development, can we find these drugs where we can treat older patients noting the median age is pushing 70 for patients newly diagnosed with AML, so I think that group is the one we all talk about but I think that a young healthy person even with a favorable cytogenetics, with a 40-plus percent chance of relapsing over the course of their lifetime, I think that group’s underserved as well.
Even if you think they’re going to do pretty well, there’s most people with leukemia in the end don’t get cured, have to go through intensive cytotoxic chemotherapy, and it’s a challenge, so I think we can do probably better in all the groups that we talk about.
Call Leader: Okay, great. Now, why has AML just always been so difficult? I feel like there’s always dozens of pipeline candidates that are trying and then generally until recently most of them fail.
Doctor: If you were on the east coast, I’d invite you the Grand Rounds on Friday. I’m actually doing a talk on this, if you can believe it or not, talk about the serendipity of a call.
We don’t really know the answer. I think the biggest drug development problem in leukemia is that the FDA has wanted survival data, and survival data are challenging in AML, because there’s other treatments that we can use and sometimes people get salvaged with a cure like a bone marrow transplant, so when we look at salvage options for folks, it tends to mitigate some of the data from response, so even though most of the people that have refractory leukemia will die with their leukemia and die relatively quickly, one of the challenges we’ve had is showing a survival advantage of a novel agent.
The second challenge is that all meaningful therapies to date for AML have included multiple drugs, so it turns out that it’s hard for the FDA to approve a drug, a novel drug, when it’s in combination because they always make the argument, “Well, we don’t know how much of the success of this combination is due to the novel drug.”
Again, leukemia is a multi-mutation, multi-stem cell, multi-clonal problem and so it’s hard to show that you can ... a single drug can have a big impact, on its own, and it’s hard to show survival, because when people don’t do well, there are other things that we try that helps sustain them and makes so that the survival advantage is hard to assess in a lot of our trials.
Call Leader: Okay, that makes a lot of sense. Now, when you’re assessing something like survival, is there a hazard ratio that you have in your head that you think, “Okay, this is the delta I need to see.”
Doctor: It depends on the group, so the answer is no. I think the common language that’s thrown around by my colleagues and myself when we’re talking with companies or developing trials is, when you’ve got a predictive response rate of 20-30%, you’re going to want to move that up to 40-50%. You’re going to want to almost double that if you’re looking at a response rate where you can look and say, “In this small study the response rate was 45%. We definitely need to look into this drug more,” versus a response rate of 33%, which is marginal at best and you say, “Hey, that’s not such a good benefit. Maybe this drug isn’t such a great drug.”
When you’re looking at response rates of 50 or 60%, then for example if you use induction chemotherapy and you expect 60-70% of people to get a remission, and you say, “I want to add a FLT3 inhibitor, in IDH1 inhibitor, to that regimen, I want to make it better,” I think in that situation, where we’re probably not trying to make it a 90% CR rate. We’d like that, but I think we’re really looking at, can we make a more meaningful CR so that people survive longer or have leukemia-free survival, relapse-free survival, in that circumstance. It’s slightly different depending on the patient population that we were thinking about.
Call Leader: Okay, that’s very helpful. Just going to ... getting your thoughts on some of these individual drugs. In terms of Vyxeos, the improved 7 plus 3 regimen, how will that change practice?
Doctor: I’m waiting to see. My bias is that I think this is a step forward and I think my hangup is that it’s an expensive step forward, so in the end I worry that science and clinical trials outcomes will only play a minor role in deciding what happens with this drug, and insurance companies and third party payers and P&T committees will make it more of a challenge. I think that’s a real legitimate worry when we talk about expensive therapies.
Even ones that seem to show a benefit that we’ve been ... We’re a desperate community looking to approve a drug in this space, and it’s probably the one. A lot of people think it’s likely to move forward so I think in our practice I’m hoping that my colleagues and I will all agree in a population, secondary leukemias for example, older patients, that this will be our standard of care. I think we’ll develop an algorithm to try to do that.
I think the next step in our job and what we really should be doing then is looking at, are there other groups that might benefit from this drug? Should we look at younger people with the same type of secondary leukemias, then younger people with more standard leukemias? Our job is to really assess what are we missing, what else can we offer? How can we do this so that it benefits more and more patients.
So I do think that ... my hope would be that if it’s an effective drug for other populations, that its indications will eventually expand over time. But we have to do those studies. I don’t necessarily think your P&T committee’s going to let you give a really expensive drug in a situation where it’s not been proven to be better than the standard drugs you can pull off the shelf.
Call Leader: Okay, so, just to expand on that a little bit, are you now pretty limited in terms of your ability to use off-label drugs, especially if they’re branded and expensive?
Doctor: Yeah, we are. Certainly, big centers don’t want to absorb the cost of an insurance company that’s not going to pay for a drug. We’re limited if an insurance company comes back and says, “We’re not going to pay for that because it’s not an indicated therapy for that problem.” So our P&T committee would restrict us the availability of that to the indications for super expensive drugs. That does happen.
Call Leader: Have insurance companies gotten much more difficult with regards to off-label usage in the last few years?
Doctor: Yep. I think they’ve become more sophisticated and ... The answer is yes.
Call Leader: So, just extrapolating the Vyxeos data from secondary AML with the primary AML, even that might be too big of a jump for them?
Doctor: My answer would be yes. I think it will be a challenge to substitute a very expensive agent for a ... expensive but not as expensive treatment. My guess is that they will not want to do that outside of the context of a clinical trial or not without clinical trial as data.
Call Leader: Okay. How expensive is it to treat a moderate AML patient, just generally? I know for standard 7 plus 3 therapies they need to be in the hospital for a long time, so it gets kind of expensive. How much of the total expense is from the drug?
Doctor:  Relatively small, but I think the ... I don’t know what the Vyxeos drug will come out as, cost wise, but it can’t be cheap, so I think it will contribute a significant amount to the hospital stay. Again, there’s sort of ... we compartmentalize these things but, insurance company will pay for your bed in the hospital and a different part of your insurance pays for your drug, and different part of your insurance might pay for your CAT scans, so there is an important component of how your insurance company pays for this stuff that will be important.
Call Leader:  Okay, great. That was helpful. What do you think at least theoretically, is there any reason why Vyxeos wouldn’t work in a primary AML population?
Doctor: No. Absolutely not. There’s no obvious reason why it would or wouldn’t work. People that study this for a long time say, “Why does it work at all?” Nobody really knows. I would agree with your supposition that there’s no reason to think it wouldn’t, but whether it’s better or not we just don’t know.
Call Leader: Is there any toxicity concerns with Vyxeos compared to 7 plus 3 that you have?
Doctor: The answer is not really. Obviously any studies that are done with this moving forward will certainly look at the death rate from infections, and the red flags that people may have seen with the studies that have been done, but for the most part I don’t think ... that there’s nothing that really stands out that I would expect in a younger healthier population to cause trouble right off the bat.
Call Leader: Okay, great. Now moving on, what do you think about Venetoclax in AML?
Doctor:  Well, I’m a big fan of Venetoclax in AML. What I would tell you is that I think everybody ... a lot of us have been impressed with the clinical outcomes data in tough to treat populations.
Now again, I’m specifically referring to the combinations of Venetoclax, both either low-dose chemo, ARC, or demethylating drug. But the early data that have been presented at meetings so far suggests that there’s a pretty interesting response rate. Again, toxicity profile, there’s work to be done to sort out if the safety profile of it, but I think that this feels like a drug that’s contributing ... There’s been a ton of small studies. Just look at demethylating agents, there’s been a ton of small studies looking at other epigenetic modifiers to throw in there with azacytidine or decitabine for example, and all of these in small studies show they look pretty good combos, and in big studies they kind of pan out a little bit.
This looks good in the early studies, so you never really know when you do the huge big deal cooperative group study. There are data coming forth, I suspect we’ll hear about it at ASH this year. There are big data coming forward that suggest that we’re going to learn more about in a bigger study, a randomized study what kind of benefit we’re getting but the benefit that we’ve seen in the published reports so far with the combination suggests that it’s ... the responses are very interesting and very provocative.
Call Leader: Great. So, just assuming that the bigger studies end up being consistent with the earlier smaller studies, where do you see using Venetoclax within the treatment paradigm?
Doctor: I mean, I think that where we’re ... Elderly patients, AML patients you’re going to give a DNA methyltransferase drug a hypomethylator to is, you sort of say to yourself, “Why not use the hypomethylating drug in combination with Venetoclax?” So, probably get a better response rate, maybe a more durable response. Those things are very provocative so for sure in our mind, I would broaden it to say that ... I know that they’re looking at other populations like high-risk MDF and other populations like that.
I would say, “Jeez, I’d want to put this almost any time I was using a demethylating drug, I might want to try and see if I can get more bang for my buck with a drug like Venetoclax blocking the anti-apoptotic hit.” So, again it would be what will my insurance company let me do, and what will the patient do, but I think those are types of places where we would want to be using a drug like Venetoclax in combination.

Call Leader: Great. Is there any particular toxicities of Venetoclax that you are worried about?
Doctor: Again, I haven’t been. The company is very diligent and watching very carefully that we don’t see Tumor Lysis, or where people know how to manage it. That has been well-described as a concern. I think that prescribers of the drug will need to be thoughtful and educated about it, so I would only mention that as to say that is one of the things that people talk about and the company’s been diligent about making such people understand.
Call Leader: Okay great. Now just moving onto Midostaurin from Novartis, they showed a survival advantage in FLT3 mutated patients. What do you think about that one? The median survival, I thought there was a big delta, but because the curves were flattening out and the hazard ratio was only a 0.77.
Doctor: We’ve done a lot of FLT3 work here through the years so we know a lot of the FLT3 targeted agents, so they’ve been of great interest for the lab researchers here in Baltimore. The truth is that this is a very interesting ... We’ve waited a long time for a drug to show that it’s improving things.
Our institutional bias is that a FLT3 inhibitor is really changing the way FLT3 leukemia outcomes happened and successful induction, a bone marrow transplant and a FLT3 inhibitor, that combination may really move this into, from a really incurable, tough to cure form of leukemia, into a moderate or even better more easily cured form of AML. So, we think that having a FLT3 inhibitor and applying it to patients during their primary therapy and then as a maintenance strategy following transplant, makes a lot of sense and I think that is a step forward in the FLT3 space.
Call Leader: Great. What percentage of your patients would you say are FLT3?
Doctor: We probably have a disproportionately high, a few percentage points higher just because we see a lot of FLT3, but I think we’re probably in that 20-30%, 20-25% of patients will have a mutation.
The criticism of the presentation with the Midostaurin was that the drug seemed to be equally effective in the patients with high allelic ratio FLT3 versus low, and the suggestion has always been that the high allelic ratios do the worse, and why would it be equally effective in a low allelic ratio scenario where the FLT3 may not be playing a role.
So one of the really interesting questions that’s out there that we wrestle with is, “Is this a general effect of the drug or it is really a FLT3 specific effect of the drug?” I’m not sure we all know the answer to that fully yet and I think that that’s one of the reasons there’ll be probably more studies, the FLT3 agents that will, I think, mirror the studies that have been done and a real effort will be to move even more effective single-agent FLT3 inhibitors into that space.
Call Leader: Okay great. Just moving on to the IDH inhibitors. What do you think about the Agios and Celgene products?

Doctor: I was never quite as enamored with the responses that early people, and that’s just as a personal bias. I looked at the data and for those drugs, IDH1 and 2 inhibitors, I was looking at the glass as partially empty, not that it’s partially full. I wasn’t jumping like crazy when other people were. I think the response rates have come a little closer to Earth than they were early on. I think that there’s cool stories that get us all excited about someone near death and then revived back to life and having six months playing golf. Those are exciting and fun so you realize that the drug has some activity for sure.
I think its utility may end up being in strategies like in combinations where it’s being studied now, again with this idea of a people you’re going to give 7 and 3 to, and they got a mutation, you give them the drug. Somebody you’re going to give azacytidine to, they have an IDH mutation, why not do the combination of the drug. So there may be ways, again, just to begin to peel off people and really individualize our treatments differently, I think they’re good drugs, don’t get me wrong. I just thought they were really good drugs, not super-duper life changing fixing everything type drugs, which they sort of had a little buzz about them early on, that they were these incredible compounds.
The coolest part is that it’s another mechanism that we can begin to exploit to try to make better therapies, because combinations, better so-called cocktails, and that’s the part that I’ve found very interesting.
Call Leader: The way you’d probably use them is in combination with what you would give already to the patient? You wouldn’t necessarily switch out something else?
Doctor: I think you can use them as single agents where you ... they have activity for sure but I think where they’re probably going to make the biggest impact long term is by using these drugs in combination with some chemotherapy based regimen. That’d be the first thing.
If we can prove that then we can say, “Maybe let’s just give an 80 year old a FLT3 positive leukemia.” Maybe an IDH1 inhibitor plus a FLT3 inhibitor would make it so you wouldn’t have to give that patient chemo. I’m making up little scenarios but you could begin to envision where people have a couple of different mutations and you give them a ... we’ll call it a cocktail, literally where you have, you pull the bourbon from here, you pull the ginger ale from there and you make a drink. You could pull an IDH1 inhibitor, plus a FLT3 inhibitor, or an IDH1 inhibitor plus an epigenetics modifier, maybe we’ll have a real impact on cancers that have been harder to treat and were pretty resistant to traditional chemotherapy drugs alone.
Call Leader: Okay great. Looking a little broader, just with all these new drugs that are probably going to be on the market in the next one two or three years, like when Vyxeos and Venetoclax and Midostaurin and the IDHes are there, my sense is that there’s going to be a lot of mixing and matching kind of like being like a baker with different patients trying to figure out which is the best combo for their case. Is that accurate?
Doctor: Well, I think so, and I think a secondary group that’s going to benefit from all this hot action in AML finally are the people who provide the testing, right? So the molecular-based testing.
It’s going to be really imperative if you have all these things that you get molecular testing, get it quickly, have drugs available, move drugs forward. The cool thing from my perspective as a drug develop person or a clinical trial person is I think we really need to study these pretty carefully and I think we need to develop smart clinical trials that gets us answer quickly, where we utilize 30 or 40 patients to get a real answer. We need to do that better so that we can have access to these drugs and these combinations where we can learn if we get any crazy toxicities, and we can learn what’s expected as far as response rates.
We’re not there yet. We’ve got to study it more, we’ve got to have the resources in place to know what the mutations are in real time. We’ve got to understand whether those mutations are really the ones driving the leukemia or are they just riding along, are they passengers? So there’s a ton, a ton of work for people in my space and ways to think about this so that we can effectively and efficiently move drugs forward and have the best chance of impacting patients with these terrible diseases.
Call Leader: Great. That’s very helpful.
Doctor: That may be pie in the sky, but I think it’s not unrealistic that we’re going to be able to do some of these things for some forms of our leukemia.
Call Leader: Yeah, I know, I think ... Yeah, it might take a few years, but it seems like we’re going in the right direction. So, I was just wondering what do you think of the prospects for CAR-T for AML. I know there’s been difficulty in finding the right target for CAR-T.
Doctor: Yeah, yeah. I think that’s the problem. You said it. There are some markers that seem to be on stem cells and not so many other cells are not ... Sorry, cancer cells are not regular hemopoietic stem cells.
One of the ones that people talk a lot about is CD123. What I envision with CAR-T cells is if there would be a way to deliver the CAR-T cell and then have it die, so not produce the memory of ... You certainly want a memory to prevent people from relapse, but if you can develop a CAR-T cell as a cytotoxic, to hit those targets, you wonder if you could give somebody a therapy and then if they weren’t recovering their counts because it was hitting off target effect causing trouble or if they were getting into side effect trouble, that you could quote-unquote kill the T-cells, that is an interesting concept to me. I’m not sure we know how to do that yet, but it’s just something in the back of my mind, like if you had a maintenance drug and you said every six months I’m going to give this, let it work in the patient’s body for three weeks.
It might cause some cytopenias, because it might ding their regular stem cells, their hemopoietic stem cells, but then I just put in the suicide gene and after three replicates it dies.
You wonder if something like that could be created in a very innovative space. I don’t know, but certainly if you have a target that’s of interest for a leukemia, but could have secondary problems on other tissues, there may be a way to do that that could help patients.
Call Leader: Yeah, the funny thing is even though we’re ... I think we’re relative close to a CAR-T approval. It’s still really early days for the space, so you know, it’ll probably be ... CAR-Ts in ten years will probably be very different than today.
Doctor: And they’re toxic. They’re pretty toxic right now, so some programs are put on hold or slowing down because of the toxicity that people aren’t quite ready to manage, so we need more work in that space for sure.
Call Leader: Just moving onto another, a little more off the beaten path therapy. Did you have any thoughts on Iomab-B? It’s basically a beta-emitter for use as a conditioning agent for HSCT.
Doctor: I do. My stuff’s not so super-duper meaningful, my comments. But efforts to radio-label and deliver hopefully lower-toxic drugs for prep regimens or for anti-tumor part of the prep regimen is certainly something of interest to folks.
The downside is that these are a little bit complicated to give they’re complicated to make, they’re complicated to deliver. There’s a big timing factor, I mean big timing part of this, so an institution has to be pretty aggressively geared up to want to study these types of compounds because there’s a whole process of getting the drug and getting it labeled and having ... it to have effectiveness.
There’s a big timing component to it, so a program really has to be geared up, or it has to have the resources allocated to really take care of the patients, to get these radio-labeled antibody type conjugates so, I think they’re interesting. Maybe they’re not as [inaudible 00:39:29] as may be. I’m not sure I’m as bullish on them as I’ve been on other things in the past, but certainly they may find a role for the patient with active leukemia that has a good donor for a transplant, and you really want get them [inaudible 00:39:46] immunomodulatory type approach. I think that that could happen. I think that that would help a lot of patients who are trying to get to a transplant but can’t get there. Where these drugs sort of step in, is they might be able to allow people like that to get to transplant.
Call Leader: What percentage of the market would you estimate that is?
Doctor: I’ll make this up, but let’s say 30%. What I mean by that is, if you could show that you can cure people with less toxicity and transplant works in that setting, whatever percentage of primary refractory patients, 30% right off the top, you might say, “20 or 30% of people don’t go into remission with induction therapy, I don’t have to worry about these other salvage treatments, I’ll just give them this and transplant them.”
So, that’s not even accounting the relapsed patients, or the ... that’s just counting the refractory patients, so it’s a long way to go ‘til we prove that, but if it really worked and if 50% of those patients did well following the transplant and were cured, you’d be hard-pressed to say, “You’re better off giving some other salvage chemotherapy and then doing a traditional transplant.”
I think that there’s a potential large chunk of the marketplace out there depending on the indication that’s available to them and depending on the ability to deliver the drug in the transplant setting, I think it’s real, but there’s no data to tell me it’s going to work.
Call Leader: Just in terms of the ... some of the practical aspects you mentioned, do you think that this is something that a community hospital would be able to deliver?
Doctor: Community hospitals don’t do a lot of transplants. If you said to me, “Could any place that does a transplant, does allogeneic stem cell transplants, would they have the capability of doing something like this?” I would say probably yes.
There’s going to be bigger centers that do have department of radiation and oncology, and they’re going to have access to probably the right things, isolation, etc, etc. But would community practices use it? I’m not thinking, off the top of my head, they would, but that would be a large resource allocation issue for them.
I may not be thinking about that fully and clearly, but off the top of my head I would say I wouldn’t think so unless I’m missing something.
Call Leader: Okay, great. Just thoughts on one more drug, and that’s the Seattle Genetics has that anti-CD33, recently had a clinical hold related to hepatotoxicity. It’s been lifted, but any thoughts on the drug and is that toxicity a concern for you?
Doctor: Any time there’s a clinical hold for a drug that’s got real activity it makes you a little bit anxious, and we know that there have been other drugs that have had liver toxicity, that have thought to be pretty exciting and then they ... we ended up having them taken off the market like the [inaudible 00:43:38] drug years ago, so I think that it’s certainly a concern.
I think that the stuff that came out of ASH last year suggests that they have some good clinical activity, and again we’re just going to have to figure out which patients benefit from it, which patients get hurt by it, and how we can give it in a safer manner. Maybe it’s a scheduling thing, maybe it’s a ... there may be other issues involved, so I think more sorting out, it seems like there’s some level of clinical activity with this and we know that other drugs in the 33 space have activity, so I’m not surprised or shocked that there’s some activity, but I think that we need to be very careful moving drugs with toxicity signals early. We just have to thoughtful about that.
Call Leader: Great. Just wanted to wrap up with one final question that’s just outside of anything we’ve talked about, what’s really exciting you out there?
Doctor:  I’m excited that we seem to have a good paradigm pathway that’s worked out, meaning targeted therapies in combination with traditional therapies. There seems to be a reasonable strategy to look at these drugs. I’m excited by that.
I’m not saying it’s the best drug of all the world, but I think the Venetoclax stuff is pretty cool. We’ve wanted to figure that out, that BCL2 paradigm, and I think that that lends itself to more investigation of anti-apoptotic signals and how to manage them, so I think that’s pretty exciting from that standpoint.
I like the idea that if we can get molecular testing, we can figure out the mutations quickly that we might be able to build more effective therapies by adding the right inhibitor to the right combination to the right cocktail. I think that feels like it’s pretty exciting. And I think that there’s lots of work for most of us to do to really explore these in a little bit more detail. To optimize and to build on the responses that we see, so all of those things together make me feel like it’s a relatively fun ... For years it’s not been that great to be in the AML drug development space. We haven’t had that much success, but the next couple years, we may have a few drugs that are approved that we can begin to integrate into our standard approaches, and that might really help our patients.
Call Leader: Alright, great. I’ve actually had a couple of questions sent to me from the Slingshot community. What percentage of patients with AML receive 7 plus 3 or another aggressive regimen and how many receive HMA or a low-dose therapy?
Doctor: I don’t know if I know that data. I can sort of extrapolate a little bit from our group. The median age of close to 70 would suggest that half the patients would be given a demethylating drug, but it really doesn’t work that way. I think there’s plenty of early 70-ish patients that we’d want to give. My guess is that if you look at all of AML, ARC-based regimens probably in the U.S. be 60% and demethylating drug approaches maybe 40%.
I’m sort of guessing and hedging that one but I still think ARC probably is used more frequently, and I fail to say that most people don’t even treat, they just sort of say” “We’re not even going to treat you with anything because you’re too sick and too old,” so that certainly happens as well, so maybe it’s 10% don’t get anything, and 40% get a demethylating drug, mostly the older folks that are pretty frail, and 50% get ARC-based something or other.
I’m not sure you should rely too much on what I’m saying, but that’s sort of what I when I think about it, because even some 72 and 73 and 74 year olds do get 7 and 3 at lots of institutions. It’s probably pretty close, but it may be in favor of ARC based regimens.
Call Leader: Okay. Just one final question is, how do you see MRD evolving in AML and what roles do you anticipate it will play in the next three to five years.
Doctor: MRD is interesting because MRD may give you a closer view of the mutations driving the stem cell population, so I think that we want to study MRD at both the phenotypic, cell-surface markers identifying them and the genotypic if you will or molecularly to see whether or not these sub-clones that may give rise to leukemia in the future.
I do think that we are wanting to incorporate MRD and study of MRD into our trials and into our research. It’s hard to do it’s a small population, so it’s easier said than done but I think that that is something that will be important. Help us the biology of the disease, and help us think more aloud about what ... Should we be adding something ... Something [inaudible 00:49:57] MRD. Most MRDs data would show they’re going to relapse, so is there something we can add at that point to improve that, to minimize it, to stop it from progressing. Again, if we understood what those cells were, what mutations they harbored, maybe we would be able to do something low toxicity with high efficacy.
Call Leader: Okay, great. That’s all my questions for today thank you so much. This is extremely helpful.
Doctor: I’m glad it worked. I appreciate your time and let me know if there are other questions that come up you can certainly probably reach me through Joe or any of his team, okay?
Call Leader: Wonderful. Thank you so much.
Doctor: Yeah, be well.
Slingshot Admin: Thank you gentlemen.
Call Leader: Yeah, you too.
Slingshot Admin: Thank you gentlemen, I appreciate the time today. Have a good afternoon everyone.
Call Leader: Thank you Joe.

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Edison KOL call

PNH

The fourth in our KOL series, Edison sponsors an interview between Dr. Jaroslaw Maciejewski, Chairman of the Department of Translational Hematology and Oncology Research at the Cleveland Clinic.  The conversation featured a discussion on current and emerging PNH treatments. 

 

Call Leader: Okay, great. Thank you Doctor for taking the time out of your schedule to be on the call today. I was just wondering, maybe you could start by describing your practice?
Doctor: We are a coordinated referral center, big volume, big hospital. I come from the background of NIH whereas NIH was a big referral center for a sort of second opinion and also a lot of indigent people, people from other countries. My hospital is more in the trenches of a real live health delivery, but because we are 27 hematologists as a volume, if you wish, and the area we cover is much bigger. This is not my source of patients, it’s just by word of mouth. Because I see so many patients they have all this on website, online chat cabinets of PNH patients. I see a lot of consult from far away, from places like Florida, California, New York and so on. These are usually consults with recommendation, rather than local patients who are being managed by us by daily basis.
Call Leader: Great. How many patients with PNH do you have and how many of those are on Soliris right now?
Doctor: Okay. What I have is chewy because if I have a patient who we recommend it to, and start it on Soliris and the patient is in Traverse City, Michigan and I see this patient three times a year, do I have this patient? I would concede that I have this patient. They are patient whom I really have by being a primary healthcare deliverer, if you wish, with resource that I am an expert supporting a local hematologist in important decisions. So, among those we have 29, I believe, currently patients on eculizumab. I see since 2002 our database it’s like 180 patients, but many of those patients have smaller clone and might not be necessarily classified as PNH. If you go to a sort of hard core PNH with large clone, it’s a typical hemolytic PNH, his number is going to be around, since 2002 around 80 and currently I have probably like 40 patients.
Call Leader: Great. That was very helpful. Maybe you can just explain also what’s the underlying mechanism of Soliris in preventing thrombotic events in PNH patients?
Doctor: In preventing thrombosis?
Call Leader: Yeah.
Doctor: Prevention in hemolysis?
Call Leader: Yeah, hemolysis.
Doctor: It was a question already on the original trial if PNH cells actually are thrombogenic or whether it’s a hemolysis that is prothrombogenic. The trial showed that by decreasing the hemolysis, of course the number of cells that carry PNH phenotype increases, the overall risk of thrombosis decreases. It was sort of proven to me that the propensity to thrombosis is related to the process of hemolysis. Right? Of course process hemolysis is related to the size of PNH clones. The more PNH cells [divide inaudible 00:06:25] the more hemolysis you have and stuff. By itself, complement cascade starting good classical automate activation pathway goes via C3 and eventually via some other steps, hits C3 and C3 undergoes activation and some [inaudible 00:06:49] cleavage and forms membrane at that complex, which causes susceptible cells to die from the influx of water by osmotic means. White cells, unlike red cells, are protected by additional mechanist from it and normally normal cells are protected from action of complement by having CD55 and CD59 on the fourth phase, which essentially counterbalance activation at the C3 and C5 level.
Call Leader: Mm-hmm (affirmative). Do you think if there was a drug that was targeting C3, do you see advantages to that?
Doctor: It makes sense to target the complement cascade at the earlier stage. The big question in the room is whether there are some inputs into C5 rather than via C3 that could activate C5 directly without C3? Theoretically speaking, one could easily conclude that the C3 activation is indeed proximal and therefore will prevent C5 activation.
Call Leader: Mm-hmm (affirmative). Do you think like a factor D inhibitor would also have kind of the same potential issues as a C3?
Doctor: Factor D would be just even earlier than this. The question would be whether both was factor D classical and alternate complement activation [inaudible 00:08:50] would be both inhibited?
Call Leader: Okay great. Just go into your, the general population PNH, just based on your experience, like what percent of patients are refractory to Soliris?
Doctor: Usually it’s a gray zone because it depends on the definition of refractory. If we stringently define refractory patients who are transfusion dependent and remain transfusion dependent, versus patients who did not experience sufficient elevation of hemoglobin, or whether these are patients and it of course depends on the input. The input would be if I have transfusion independent patient with hemoglobin is eight, I mean this patient cannot be made transfusion independent, he is already transfusion independent. However, the most dramatic example would be a patient who receives transfusions, gets on Soliris and still has a need for occasional transfusion. Or whose rising hemoglobin is inadequate to what we would expect. If we are less stringent, probably 10 to 15% of patients might have values decrease of incomplete response ranging from the refractoriness to a sort of insufficient response or less than perfect response.
Call Leader: Would you consider that 10 to 15% to really also include not just the refractory but the suboptimally treated?
Doctor: Yeah.
Call Leader: Okay.
Doctor: Maybe it would go then if you are not as stringent and it’s to 20%.
Call Leader: Okay. Great. In terms of kind of the mechanism for either the suboptimal treatment or being refractory, is there like a mechanism for that or is there maybe another underlying disorder that’s causing it?
Doctor: I mean essentially you can [inaudible 00:11:25] three different possibilities that I can think of easily, there are probably more. One would be that anemia is not completely a function of hemolysis but a function of the breast production. These with the patients who have low reticulocyte count and whose hemoglobin level depend on both the production and extraction. Second, patient has adequate production, however, it’s under those so he is susceptible to break through hemolysis or either episodic or at the end of each treatment cycle with an endogenous level of Soliris are the lowest.
Finally, the third possibility has been involved as an extravascular hemolysis, which is related to opsonization of erythrocytes with C3 and phagocytosis of opsonized red cells by retical endothelial system in the liver and spleen. As such, this process is not associated necessarily with elevated LDH and is C5 independent. If you wish, this can happen in a fraction of patients. Normally the C3 mediated the extraction of red cells has very little physiologic significance due to the circumstance that this process is much slower than pushing through the cascade of and formation of membrane at that complex. In the situation that there is no inhibition of C5, C5 kills the cell by much faster mechanism and they can accumulate and become targets for phagocytosis via a complement receptor two.
Call Leader: What percentage of your patients would you say discontinue Soliris in any given year and generally what’s the reason for that?
Doctor: Very few. Bone marrow transplant would be one. I stopped Soliris in a couple of patients who were inappropriately started, as they did not have really PNH or the PNH was so minuscule that it was crazy to administer this expensive drug. Yeah. These are these two major. Finally, I had in the last 20 years two patients, one and a half, but two patients whose clone disappeared and was not any longer detectable so that the continuation of Soliris was not justified.
Call Leader: That’s interesting. The route of administration of Soliris, being an IV, has that proven to be a difficult burden for patients?
Doctor: I mean, different scenarios. One scenario is of course that the patient lives across of the hospital and can come over, do that and it’s not a major disruption of life. Verus other patient who have to drive 150 miles every two weeks or 200 miles every two weeks, it just makes it more difficult in terms of by itself administration, it’s a very good drug, but this is a caveat that one is bound to follow calendar and sort of plan ahead with many of the travel, ideas that people who have.
Call Leader: What percentage of your patients do [crosstalk 00:16:16] for another route?
Doctor: For example, patient go on vacation and then you have to sort of dance around how to schedule it that the infusion does not come middle this vacation because they are away. Conversely, the patient that’s across of clinic or patient has to drive for two hours to the clinic.
Call Leader: What percentage of patients do you think would prefer to have another route of administration like subq or even oral?
Doctor: It depends how often is subq. Oral is no brainer, it would be hard to believe that there is anybody who has access to an oral drug would not want oral. Subq might be tricky depending of the volume injected, the frequency injected. Do you have to inject it twice a day, once a day, twice a week? Of course, you measure it against benchmark of every two weeks IV infusion over half an hour versus a benchmark of every two months infusion over whatever, four hours. These would be changes in the demographics of patients who have something wrong “with complement.”
Call Leader: Do you think every four hours every two months, is that preferable to once every couple of weeks for a half an hour?
Doctor: To do what?
Call Leader: Just in terms of convenience for the patients, assuming they’re not 200 miles away from the clinic. Like let’s say they can go, it’s a relatively local clinic that they get the infusion. Do you think there’ll be a lot of people who prefer like a four hour infusion every eight weeks to once every two weeks for thirty minutes?
Doctor: I mean, forget that majority of the patients with private insurance will get it at home by home health nurse. So this is another factor. Overall, it’s difficult to compare weekly subq injection to big infusion every four weeks and it might not necessarily be safe or work. In the end of the day we need to measure the frequency, you know the one that is more efficacious. It’s comparison issue to what would be identically available. If you compare this to a pill versus compare it to injection, versus compare I have to go to the clinic every two weeks it’s two hours drive, versus I have a friendly and pretty home health nurse coming with whom I have a nice discussion, drink coffee and she infuses it to me every two weeks. There’s a spectrum of sort of circumstances.
Call Leader: Sure. Would some of these competitor products have to be actually superior to Soliris in order for you to switch if you’re not considering convenience?
Doctor: I’m sorry, I lost train of thought.
Call Leader: Sure.
Doctor: Somebody was in my room. Can you repeat the question?
Call Leader: Yeah, sure. A lot of doctors don’t like to switch patients from drugs unless there’s a reason. Would some of these competitors have to actually have better efficacy than Soliris for you to consider switching to them?
Doctor: Again, are they single agent or do they have to give a companion with Soliris? Are the correct response achieved with Soliris or isn’t? If correct responses achieved with Soliris and there is some sort of habit issue versus switching to new, this new should be at least good or have some convenience factor to it, doing it every two months or being able to self administer or this type of thing. I think one has to see it in the context how the patient is doing on the current drug.
Call Leader: Just going back to kind of the convenience issue, if someone that had a subcutaneous version, do you think a two times a day version would be viable?
Doctor: Hard to say. Clearly when I indicate it to some patients who have a very well established home health delivery system by a nurse, these patients say, “Well, I have this lady. I always nice chat, she’s ... She comes on the weekend and doesn’t bother me and then I don’t want to deal with this every day, think about it,” and so on. If this is a pen like an insulin pen, which takes two seconds to administer and it just you know, you just without interrupting a major [inaudible 00:22:17] versus it’s some sort of a pump device, which the volume is big. This would clearly influence whether twice a day is doable.
Call Leader: That’s very helpful.
Doctor: The level of desperation is also different. Somebody is already on a drug that was $800,000 a year and still needs transfusion and accumulates iron, and can a drug that is twice a week but it would really absolutely convert them into responders. This might be a different issue than somebody who’s doing very well currently on Soliris and you say, “Hey, I can switch you to something else.”
Call Leader: Mm-hmm (affirmative). Do you think there would be a market for combination therapy with Soliris?
Doctor: It remains to be explored. It’s clearly the original design of clinical trials is such that it’s easier to combine it and say, “Hey, I’m going to treat refractory patients, now the patients without adequate response with my agent.” Rather than say, “Hey I have here a 100% effective regimen.” So this will play a role, you know where the patients are. Now if patient has C3 mediated hemolysis and the drug in question is another C5 inhibitors, how will this person would be helped? Right? And visa versa, how the patient would help if you have two very effective drugs that work via C3. I hope that this answers the question.
Call Leader: Yeah. That’s very helpful. I just wanted to ask some questions. Given what happened with Alexion a couple of months ago with the sales practices being put into question, I was just wondering on a scale of 1 to 10 with 10 being the best, like how do your fellow like PNH treating physicians perceive Alexion as a company? Are generally people really happy with them? Are there some that really love them, some hate them?
Doctor: Them being?
Call Leader: Alexion.
Doctor: I think Alexion is a very well company that does everything that they have to do to succeed. They don’t nickel and dime stuff that is needed for marketing serving, such that is that some of their projects might be considered too aggressive. I clearly, I often see patients who have 1% of clone where I am stopping eculizumab because the patient never had the PNH to begin with.
Call Leader: Is that because of the sales practices you think or just aggressive marketing? Hello? Hello Doctor?
Slingshot Admin: Hey Max. I’m not sure if we lost him there Max. I can redial but I think he hit mute.
Doctor: No, no, no. Here, here, here.
Call Leader: Okay.
Doctor: I’m being disrupted because I’m running clinical service. Can you repeat the last question please?
Call Leader: Yeah, sure. The people who are being treated, if they have like 1% of clone, is it because of aggressive marketing practices by the company or sales practices?
Doctor: I think it depends on who is the prescriber or if you see somebody who is an oncologist and see breast cancer and from time to time lymphoma, and they have a patient with unclear anemia, they found that the clone is 1%, they are more likely to prescribe it. I would be by far less swayed. In some countries there are clearly guidelines, and the age has to be two and a half, the PNH clone has to be at least 20% and there has to be some alleviating circumstances.
I call them, when I do the speil to the patients that, “Listen, for your treatment, since you are not transfusion dependent, to start you on it, you would have to have the certain pros and cons and the pros as to advantage. The cons is of course the inconvenience, being bound to it, and stuff. The cons is also the fact that your hemoglobin is relatively good so we are improving hemoglobin of 10 to 11. But the pros would be of course the fact that you alleviate the risk of thrombotic complication, which is greater in patient who already had the thrombotic complication versus patients who didn’t and never have [inaudible 00:27:44]. It’s greater your patient has elevated D-dimer versus patients who don’t have elevated D-dimer, the benefit is better in patients who have more severe anemia or are transfusion dependent versus those who aren’t. Or who have more constitutional symptoms including fatigue and other, chest pains, pain swallowing, et cetera.”
Having said that, of course many of these symptoms would be before [inaudible 00:28:10] patient who have 1% clone. So these are these patients that if I would get, I see that recently had the patient like this and I see the patient is 1% clone, we’ll start it on eculizumab. His blood get crazy to continue eculizumab. If you have only 1% of white cells and .1% of red cells, what is their contribution to hemolysis? The white provide you a sort of ceiling, so you know if a patient has certain, let’s say 50% of white cells and 10% of red cells, then steady state hemolysis is such that it destroys 40% of cells from 50 to 10 of red cells. If the patient has only 5% of white cells and 1% of red cells, you know that the steady state distraction is sort of, say, 4% of cells. Now if I block this, the hematocrit would go by 4%. See what I mean?
Call Leader: Yeah.
Doctor: Now, how quick it would go up depends also on the reticulocyte count. If patient reticulocyte count is low then his anemia is more determined by the lack of productions and lack then increase extraction. If I have somebody who is 10% clone but 1% of retics how is going to help him that I block eculizumab he is not making? Right?
Call Leader: Yeah.
Doctor: These are these thoughts that one has. Having said that, I probably stopped one or two patients in the last 10 years who came like really with tiny clone and I’m like, “Why are you getting this drug?” I am more likely to do it because I have a certain confidence because I see so many patients versus nobody wants to have the liability when you have an FDA proof, the test comes in, PNH positive, nobody reads the fine print that this is only 1% clone and the patient ends up on eculizumab. I have seen these type of scenarios.
Call Leader: Just going to reimbursements, how hard is it to get reimbursement for Soliris and has it gotten easier or harder in the last year or two?
Doctor: I have no reason to assume that it will get worse. The reimbursement, what I do is I ask patient to call Source One Pharmacy, or whatever it’s called. There are a bunch of case workers who are sort of pushing this whole process through. At certain points they might need a progress report with my description that this needs to be given, this is being, you know, then sent to insurance company. This one sort of pharmacy is essentially a bunch of nurses who do nothing else but extort the permissions from industry. This good, this helps a lot. So it’s much easier for them for many other drug.
On the other hand, sometimes people get approved by the insurance but end up with a huge copay like $5,000 or something like this. This is in subject to various measures how can we alleviate it? I don’t recall the moment that the company said, “Yeah, I’m just going to eat this cost.” Sometimes they address some foundation, rare disease foundation has some fund to support deductible payments for rare drugs for rare diseases. At the end of the day, I think, I cannot recall anybody in the last whatever, 15 years that the drug was on the market, that I couldn’t give it. There was always some way found that the patient gets it. Now, it might be not entire true, we are very fancy private clinic, I have across the board better approval rate with insurance having this certain gravitas than maybe other places. It could be that the rejection it would be higher if somebody has a higher practice that specializes with breast and colon cancer.
Call Leader: Mm-hmm (affirmative). That’s very helpful.
Doctor: Then you [crosstalk 00:32:43] push less, you know.
Call Leader: Great. No, that’s very helpful. Just going to the pipeline, I’m sure this is tough just because there isn’t that much data, but which of the pipeline products do you find most exciting?
Doctor: Everybody says that at the end of the day, I think two oral drugs that I know of being developed would be the home run assuming that they don’t cost anybody’s liver to explode or some other horrible side effect. The C3 line has of course a burden to overcome is that while we know that the blockage of C5 over the extended period of time does not increase in some unreasonable risk of infection, it’s not clear that one could extrapolate the same things from C5 inhibition. I would contend that probably is going to be the same, but it’s not that easy to conclude it without having actually data. Inhibition of C3 is less valid so it might have harder time getting through clinical trials. Rather than in other C5 inhibitors, let’s say I have much better subq form of C5 inhibitors, long lasting acting C5 inhibitor, I think the issue of complication of long term inhibition with antibody C5 will be much easier to explain as saying you know I have the same toxicity profile as an antibody or something like this. These are the factors that would play significant role in this.
Call Leader: Okay. You mentioned the liver tox. How concerned are you by the liver tox that we saw in the ACH-4471?
Doctor: You mean the Achillion?
Call Leader: Yes.
Doctor: It’s always concerning, but I was told that this is not deadly to the drug. I was told that the drug is not going to be signed by it.
Call Leader: Mm-hmm (affirmative). Okay great.
Doctor: Dealing with liver toxicity is tricky, particularly in patients [inaudible 00:35:29] overload and so on, so it has to be really attributed. I think that always a question can come up in post marketing period. Now, if there is another C5 agent, let’s say oral or subq, it would clearly be helpful, but those who don’t respond to regular C5Q why would they respond to the other C5Q? You still need some sort of less stringent agent, and maybe money here. Yeah. I was thinking that whether or not one has to also measure one drug versus what’s coming on. In other words, if you have Soliris that is currently available, it’s difficult to say, “Hey I have this other drug that is ready to compete with this.”
This other drug might compete actually not with Soliris but the next generation Soliris. This is somehow dynamic process. I don’t know that it’s early enough to say that the toxicity of this Achillion drug was such that it’s going to be a death of the product. Anything that is not C5 inhibitor has to go through testing in terms of the, also increase propensity to infections because the extrapolation might not be correct. The C3 inhibition might be much wider range and therefore produce more complication or not. I don’t know that this is something that can be deduced without experimentation.
Call Leader: That’s extremely helpful. What do you think about Akari’s drug that’s developed from tick saliva?
Doctor: In my opinion the biggest advantage of the drug is the entry to a market via a sort of niche. Otherwise, let’s face it, you have a drug A and now you say my drug, I want to administer [inaudible 00:37:59] setting. Many people would say, investigator European countries or whatever I heard it all the time say, “I have already effective drug so how can I justify it to start the patient on drug B when this drug was not tested yet?” Versus then you have to result to a sort of I have the refractoriness to currently available standard care and therefore I can use the drug B, but then you narrow the number of patients “available.” Finally, you say, “Hey, this patient could be on Soliris if it were not this expensive, but if I had something cheaper I would put him on it but he is not necessary benefiting from life saving action of Soliris.”
I think I would divide this concept of how do I get on the market another drug or how is it needed by two things. Is this drug being able to be tested successfully? Then, let’s say assuming that it’s FDA approved, whether it would be used. If alternative drug to Soliris is twice as expensive to Soliris, then the insurance company might say, “Well, only if you for Soliris you can do the twice more expensive drug,” for instance, and so on. Getting there, it might be difficult to begin with. Again, if you look only for refractory patients, 10% let’s say for refractory patient with Soliris, the other who didn’t get Soliris are not severe enough so the outcome will be less well defined. Right? If outcome is death, who is dying from PNH? No one. You would take for 20 years to get the outcome like this.
So you have to have a surrogate outcome and keep it compliant by laboratory means, the rise in hemoglobin or whatever. This is the type of thing that you can test and then extrapolate what would be the benefit of giving it. If the patient is refractory C5 for my experimental drug is C5. Now the spit drug, the saliva or whatever, complement inhibitor drug, I think has a big advantage that if they find enough patient with this polymorphic that these patients are totally refractory to Soliris, they wouldn’t have to go through this ethical dilemma of yeah, I’m withdrawing the patient, the drug that is FDA approved. On the other hand, how often it has to be given and the subq drug, like they call, so efficacy issue has to be proven as well.
Call Leader: Are you concerned at all by the immunogenicity issue, or potential immunogenicity issue? Yeah.
Doctor: Yeah, no. I think that the consternation is more than let’s say in another 100% [humalized inaudible 00:41:09] molecule. Yeah. That is some sort of a more of a concern. Again, I don’t know that this is a killer to the drug or whether this will be something that’s going to be overcome.
Call Leader: Okay. Great. Just kind of to wrap up the call, if you had like a crystal ball, in five years let’s assume that some of these pipeline products have made it on the market and there might be a biosimilar Soliris out there, what percentage of the market do you think Alexion will have retained?
Doctor: If they have the long lasting drug, this might be a choice for many patients here and dealing with subq every day. I get it every two months, I don’t have to remember, I don’t have to, it’s much easier to schedule vacation around something that is every two months. I think you have to see the Soliris might not be the only thing you are running against. If let’s say the longer acting agent or the more convenient agent is priced out of equation, it might be mandated by insurance company to use this and the other will be for authorization when you fail the other stuff. There are all these caveats in the practical application, I think, that it’s difficult to sort of envision it once. I got my bullet points why this might be an issue at an institution like ours.
Call Leader: If you could put, I don’t know, just some sort of percentage, do you think they’ll be able to keep 70% of the market or do you think it’ll be like 30? Just a wild guess would be fine.
Doctor: If RA pharmaceutical comes up with an oral agent that looks completely complement and has no side effects they are going to retain zero market share. I think it depends a little bit. There will be always a niche for the patients who don’t have optimal response, a niche for patient who are not pleased that they have to drive for 200 miles to get the infusion. Currently medicare does not cover the home health. Most of the private insurance want home health because it’s cheaper than markup in the hospital. Medicare is more difficult to deal with because they don’t allow to increase the dose but you have to decrease the interval usually, maybe it depends on the state, and then the [inaudible 00:44:05]. This is the one of the important issues to remember. That patients who get Medicare usually are not eligible for home health care.
If they don’t home health they don’t have the convenience and private nurse, they have to be mobilized in order to receive the benefit. Here you have a dude who work with patient, we feel he has PNH and this guy is being started and there is three different drugs on the market. Versus, this is a guy that Soliris is still on the market and everything is something that needs to be authorized, and it’s more expensive. Or he did not respond to Soliris in which case if we have on the market another C5 inhibitor how exciting it would be? It would be not exciting at all. There is a little bit reciprocity issue here. It would be here to conceptualize that the doctor who is ... That the patient who is receiving it is the patient who has some convenient gain from it. Otherwise, what’s the point?
Call Leader: What percentage of your patients would you say are on Medicare?
Doctor: Probably 20%.
Call Leader: Okay. Great. Thank you. That was all very helpful.
Doctor: If you live close to the VA hospital you have more people. Again, there is again the bragging number to this escapades, you check whatever, if they have the website, but if you would check that they took it or whatever some other company that has a subsidy of a company that it’s different. I think many of the factors that have to be considered are a little bit unknown at the moment because it’s a little bit fluid with regard to the indication. I think going for the indication and refractoriness is easier at the beginning because there is a true medical need versus replacing.
Then, if you have another C5 you can benefit from the fact of the long term toxicity and the complication profile is known. Obviously, if somebody has a very good response to Soliris what would be the point to switch him to another drug that is every two weeks? That’s why there’s biosimilar, unless it is a gigantic financial bad gradient, it would be sort of big no-no to me. Why I’m going to mess around with another drug if it’s not much cheaper or more convenient to administer or less frequent also?
Call Leader: That makes a lot of sense. It was very helpful. Thank you so much for your time. I thought this was a very useful call for me.
Doctor: No, no, absolutely. This is such an explosion now of these companies that feel that there is ... Coincidentally I know at least about the actual chemistry of this drug from whatever spit from the saliva. Right? Of whatever, the one that you mentioned. This might be actually the best drug, for all I know. It’s just currently the advantage is that it would be easy without major deal to get the drug for patient use if I found the patient who has this polymorphous and is not going to respond to eculizumab. So this is their entry. Obviously, they are not going to survive selling drugs to patient refractory to eculizumab based on some genetic polymorphous.
I think the strategy is to show in couple of these patients that it’s safe and then go ahead and stuff. Similar in drugs that are given common to eculizumab. If this is a C3 drug, you have good result along with C5 and you have competitive or you have well thought [inaudible 00:48:43] studies in terms of the activity of C5, you can show that okay, I started the patient as a second agent but I am going to now after three months withdraw the eculizumab. I think it’s just the first step is to add it and see how you do, and then the second step would be withdraw.
Call Leader: Great. Yeah, no, that definitely makes sense. So thank you again for all of your insight, this has been extremely helpful. Yeah.
Doctor: I mean you guys incredible due diligence on these things, I am always very impressed because it’s like you know so much about this stuff. I think price issue will play a role. In Europe or in Australia you have all these committees that approve the drug or you have the centers that the patient has to be seen in order to treated with the drug, which it’s much easier. Versus here you get this sort of, you know it’s a freestyle. Somebody who is an oncologist in the field he has one patient with PNH with 1% clone, he puts him on the drug. This patient would be not necessarily a candidate for any other drug but for Soliris particular [inaudible 00:50:06].
I mean, the easier administration as in less stringent would be the indication. If I have to go through all this coo-coo plow for proving, planning and patient has to come every two weeks, potentially might need the port, it’s different. If I have a patient with aplastic anemia and 10% clone and I say, “Hey, I’m going to put you on ATG,” and then once ATG is given I cyclosporine because you have a small clone I’m going to add that, an inhibitor because it’s just another pill, it would be different. Then I have a fancy shmancy drug that costs $10,000 every infusion, how can you justify to give it to somebody who has 4% clone?
Call Leader: Mm-hmm (affirmative). That [crosstalk 00:50:51].
Doctor: The liability behind it is that it’s easier to put everybody, how the label is written, anybody on eculizumab [inaudible 00:50:59] that you might have because you felt had a patient with PNH but was relatively asymptomatic. Now the patient comes with a blood clot and you feel horrible.
Call Leader: Mm-hmm (affirmative). Is there also a little bit of a profit motive as well? I know a lot of these people get home health, but since you can get reimbursement through the infusion, is that pushing people to the prescribe it as well?
Doctor: You know, many private practice, to be honest with you, many private practice don’t like to give it because the reimbursement is very low and they have to foot out upfront a huge cost. They don’t get it for say, let’s say if you have Medicare patient whom you treat with eculizumab, they pay like six months later. Meanwhile, you have to purchase $50,000 worth of drug every month and you get paid in three months, maybe. For an institution like ours, they have probably huge supply of eculizumab all the time. I know it because sometimes I have a patient from outside who travels on the day that he’s due, so we say I’m going to see you in the clinic and I am going to infuse the drug for you, no problem. A private physician might not have, you cannot afford to stock it.
Call Leader: I can understand why they wouldn’t want to do that. Yeah.
Doctor: If a private practice doctors who yes, they would make a big overhead, markup let’s say 100%, then they don’t get paid for three months. They have to buy or foot out $100,000, very difficult to balance book this way. I got a lot of patients that we got and they come to infusion centers just simply because private doctors just doesn’t want to deal with infusion of this drug. It’s a profit motivation.
Call Leader: Yeah. There’s a lot of risk I guess for the private practices.
Doctor: Unless somebody has a huge volume, you know, whatever, Cancer Centers of America or whatever they have. Every five minutes they are on TV, so maybe they have enough patients. I see a lot of patients, we have like tons. Remember, it’s a big hospital so there is a vascular service, atypical aHus and so on. It’s much easier for us to circumnavigate it.
Call Leader: Yeah. No, no, that makes sense. Great.
Doctor: [inaudible 00:53:37] is also impossible because the DRG is so that if you get reimbursed for the total cost of visit and you have a drug that is $18,000 you never break even. You know?
Call Leader: Wait, so the DRG for which procedure?
Doctor: For eculizumab in house. Let’s say patient [crosstalk 00:53:59]. I mean, how many time patient was discharged, rode in to me and I gave it to an outpatient basis because otherwise the DRD it would be like it’s a big lawsuit the hospital. Right?
Call Leader: I wasn’t aware of that at all.
Doctor: You know this is not like these patients are frequently admitted but whenever they are, they prefer to sort of throw patient to the hospital, discharge him, get the infusion and admit him for whatever his patient is in hospitals and giving it in hospital. It would have to be like ICU or something.
Call Leader: Mm-hmm (affirmative). Yeah, I understand. That’s probably relatively rare, I would think.
Doctor: No, this is not common, but it does happen from time to time. I borrow a lot of drugs, so I have a patient coming in three days for, but I have a patient first time visit and patient needs to, this is today his dose. I say, “Can I borrow from this patient?” Meanwhile, Alexion ships a new drug. Alexion is excellent in terms of this mumbo jumbo approval and so on. I think I want to say that anybody who needs the drug really will always get it. The only issue is if there is big copay who is going to pay the copay? My feeling would be Alexion should be paying the copay, if patient cannot afford it. Usually what is they reach out to some disease foundation or some other stuff.
Call Leader: Mm-hmm (affirmative). I’m glad it ends up usually getting fixed in the end.
Doctor: Yeah, somehow, somehow. I think there is so much profit margin on people who get it and insurance pays it, the few patients who have problem getting insurance, they should be taken care of by Alexion, but that’s my opinion.
Call Leader: Mm-hmm (affirmative).
Doctor: Maybe some legal stuff, if you have to reimburse equally everybody per, across the board, you cannot just make exception. For this guy insurance paid $10,000 out of $18,000 drug so we are going to ease the price, versus the other we could have charged 18,000. I think there are some legal burden to this, doing it this way.
Call Leader: Yeah. It’s just a complete mess.
Doctor: Yeah. Yeah, yeah, yeah.
Call Leader: So thank you again for your time. This was very, very helpful.
Doctor: Absolutely.
Call Leader: Have a great day.
Doctor: Yeah, you’re welcome. Bye bye.
Call Leader: Great. Thank you. Yup, bye.

 

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Edison KOL call

Conversation focus

The third in our KOL series, Edison sponsors an interview between Max Jacobs (call leader) and Dough Hillblom, President of Arena Healthcare, a strategic consultancy focusing on payers and policy makers. The conversation featured a discussion on the PBM model as well as drug pricing and formulary trends. 

Call Leader: Great. Thank you Carol. Thank you Doug for joining us today. I was just wondering if you could start by discussing your experience?

Expert: Sure. We’ll start at the beginning. I spent 18 years with the state of California, just short of 18 years, within the Medi-Cal program where I held multiple positions, and at one point in time was responsible for management of the drug formulary, and everything associated with the drug program, the medical supply and division and care programs. I left the state of California and went to Kaiser Foundation hospitals, Kaiser Permanente, as the Assistant Director of Pharmaceutical Contracting and Strategic purchasing.

From there I was then recruited away to Prescriptions Solution to what is now OptumRx, a division of the UnitedHealth Group, where over my last title was Vice President of Professional Practice and Pharmacy Policy.

I am a pharmacist by training, currently licensed in California and Nevada. I’m a past president of the California Pharmacist Association, sit on the board of trustees, active member in AMCP, NCPDP, APHA, CPHA, and will be teaching for the Keck Graduate Institute School of Pharmacy starting in January also.

Call Leader: Great. Thank you. Maybe we could just start, maybe you can explain how does a PBM decide on what level of reimbursement they will pay to the manufacturer?

Expert: Let’s think about this from contract relationship. PBMs do very little direct purchasing. Where they do do direct purchasing is in their mail service. Think about the contract between the pharmacy benefit manager and the manufacturer in two ways. The pharmacy benefit manager, for the bulk of its business, compensates a pharmacy for the services rendered. It’s then captured to utilization, and invoices to the manufacturer a rebate amount.

The easiest way to think about it is, I negotiated a rebate with somebody like a Best Buy on computers. Every computer I get a $100 back. I pay them $400, but I get $100 back in rebates. At the end of the quarter I bought seven computers, so I invoice them seven computers at $100 per unit, and I get $700 back in rebates.

Now, I’ve also negotiated where I’m going to buy some computers directly from the manufacturer. In that case, my price is $250. I bought those directly. I bought three of those directly, so I paid the manufacturer $750 in direct purchases. So between the PBM and the manufacturers are two mechanisms. Does that make sense, how I’ve explained that to you?

Call Leader: Yeah, no, definitely. How big is that mail order business, as a percentage of like a PBM’s total business generally?

Expert: Today it averages maybe up to about 15% of the volume. It’s going up and down. One of the trends that we’re seeing in the marketplace is that the PBM’s clients are wanting the availability of 90 days fill at retail. You’re starting to see PBMs ... Which is probably led by the CVS Caremark 90 days at CVS pharmacy, cutting into that mail service business by offering 90 days at retail. That has been the bread and butter [inaudible 00:06:49]. So you may see, and I say may because we don’t know what the impact of that will be, but with say, 15% of business, you may see a one or two percent impact of that, so it may end up being 12 percent of their volume rather than 15.

Call Leader: There’s probably a risk for the PBMs who don’t have a pharmacy associated with it.

Expert: I will tell you that as a retiree beneficiary that one of the things that CalPERS has required of their PBMs is that they offer that 90 days at retail. I think you’re going to see all of the PBMs being requested to offer that.

Some of the smaller players have never had their own mail service pharmacies. They’ve contracted with larger PBMs for those services. They will not be impacted to the same degree as the larger ones that have had really mail service as a major component of their revenue streams.

Call Leader: Mm-hmm (affirmative). One question I’ve always had is we often see drug prices, even if there’s a second competitor come in, still increase. Generally between the two competitors the price seems to increase in tandem. Do you have any explanation for that?

Expert: Yeah, with two competitors, each one of those ... I have PBM-A and PBM-B. They don’t really set the drug price, the manufacturer sets the drug price. They are going to respond to the price. The manufacturer reports to, let’s say first data bank is set as a pricing resource. That price is increased. What they pay the provider is going to change based upon that providing information.

Where they have a maximum allowable cost or MAC program, those programs [inaudible 00:09:19] by each individual pharmacy benefit manager is proprietary to them. The other thing that I will tell you is that in the industry there is not one MAC program for every pharmacy benefit manager. Their contract with their clients may drive multiple MAC programs via PB. You could have easily 200 different MAC programs at one PBM. When you talk about pricing, are you talking about pricing or reimbursement to the pharmacy? Because what you’re going to see on open page is representative, not necessarily what the reimbursement is for each and every claim.

Call Leader: Mm-hmm (affirmative). Could you actually expand on the MAC programs, just give a general explanation for our listeners, and just how is it that a PBM could have like, 200 different ones?

Expert: They could have 200 different ones because they have 200 different clients. Each client within their contract may request different things, so they customize the MAC program for each client. The only place that you really have consistency and reportability [inaudible 00:10:57] within the Medicaid fee-for-service program, in which case the states publish what their maximum allowable cost is. They do so whenever there is a change. The federal upper limit program also publishes that information. That’s consistent in the fee-for-service programs in every state.

When you deal on the commercial side, if I said I want a guaranteed discount of x percentage, then that’s what you do. Or they say, I only want that discount on these therapeutic categories, and I’m willing to accept a difference on another category.

Call Leader: Okay. My original question, though, what I was trying to get, was actually if you had any insight on the drug manufacturer side why they increase their prices in tandem. Is there some sort of incentive built into the system where some of the distributors or PBMs are compensated by having more higher-priced products flow through the system?

Expert: When you’re saying the manufacturer does it in tandem ...

Call Leader: For example, there were some, let’s just use EpiPen. They had a competitor, the LVQ come on, this was a few years ago, and I’ve seen data that showed that even though they had a new competitor, EpiPen’s price increased, and then the competitor’s price actually increased in tandem with it.

Expert: What you’re really seeing there is you have one who is the pricing leader, and somebody else who is responding. The secondary manufacturer is responding, saying, “well, we thought we had a price advantage, maybe we’re lower than they are. They’re going to raise their price by $100, I’ll raise my price by $100 and I’m still going to be $100 less than they were.” They cannot talk about the price, but the secondary one typically responds to the first. It’s more a market response.

Call Leader: Shouldn’t they be able to get more usage by, let’s say, not increasing it at all? What was a $100 difference might become a $200 difference?

Expert: You know, you and I would think that way, however one of the things that I have seen over the course of time, spending thirty-plus years doing this, is that often what we see is pressure on a company to raise prices. The reason you see that pressure is it’s increased its net revenue. If they only sold 100 units before, and they still sell 100 units based upon that price, that $100 price increase increases net revenues. That’s seen favorably by investors. While you may make the same margin if you kept it at, you know the delta is now $200, you would have to sell more units and is your net revenue per unit going to give you the same net gain.

Let’s say I make $20 a unit versus $40 a unit. It may come up to the same net gains, but I have to have increased production costs etc. It really is dependent upon what the management of the individual company feels is best in terms of stockholder’s equity, would be the way I would look at it. Does that help?

Call Leader: Okay. Yes, that was a great help. One other question I have on that subject is, a lot of times when they do increase their retail prices, that actually doesn’t translate into higher revenues, at least, let’s say not in that quarter. I was just wondering, is the retail price really just for show and what really matters is what PBMs or others are actually paying for the drug, which could be negotiated on a case by case basis?

Expert: Well, again, let’s go back to our original conversation about how PBMs buy drugs. They negotiate rebates. You can increase sales dollars by increasing prices, without impacting net revenues if your contract says if you raise the price by $50, your rebate increases by $50. You may have a $50 increase in the sales price, but your net revenue stays the same.

Call Leader: That’s very helpful, thank you. A question I have, I don’t know if you can speak to this, but I’ve read that there’s a trend towards increasing amounts of co-insurance for specialty drugs, so that the patients are paying a certain percentage of their costs. Have you seen that as a trend?

Expert: Yes, that has been a trend over the last several years. In response to that, what you’re seeing is a lot of state based legislation that is trying to limit the ability of payors to do that. That’s why some legislation might create an annualized cap, or some of the legislation may say that you cannot charge on these products any greater co-payment amount than you would on your standard tiering. This has been because what has happened, particularly in the specialty marketplace, is that we have an awful lot of niche biotech drugs. When you look at that, and you look at the insurance marketplace in general.

Let’s say you work for a company and you have the ability to annually select from a cafeteria plan that you can purchase from. Every year you can make a change. Insurers, because you may not see the value of that drug therapy into the second year, or you may not see the condition of the patient degrade until the second year, are going to want to make sure that they maximize their shareholder’s equity. Having a larger co-payment amount, there’s less of a financial impact on the insurer. Does that make sense to you?

Call Leader: Yes, it does. Would you have any idea of what percentage of the covered lives out there would have to pay coinsurance on specialty drugs?

Expert: Essentially everybody’s paying some coinsurance. In some cases it may be a percentage. Just like a tiered co-payment. On the first tier you have a five or ten dollar co-payment. On the second tier you have a $25 co-payment. On the third tier you have a $50 co-payment. On the fourth tier you have a coinsurance. Your specialty is in the coinsurance market, okay? That’s how we tiered it.

Call Leader: What’s the average percentage in the tier four?

Expert: It goes anywhere from around 20% is fairly common, up to some higher set fees, depending upon the nature of the drug. Again, the relationship between the insurer and the insurance company, and the third party payer, the PBM.

Call Leader: Mm-hmm (affirmative). Have you seen ... I’m guessing companies are really trying to get around this issue by doing their copay programs to try to minimize the impact on patients?

Expert: A number of the manufacturers have those types of programs available. Those become somewhat problematic for patients and for payors depending upon the type of program. If you are a Medicare Part D beneficiary, theoretically, if it comes from a prescription assistance program or PAP, that doesn’t count for your out-of-pocket expense. There are some issues with some of the co-payment plans that way.

Some of the insurers have rules that can be used in prescription assistance programs. I would say that by and large they’ve been somewhat successful in addressing those issues. Again, you’re seeing state legislators…insurance, which is what it generally falls under, is under state’s rights and state’s domain. What you see in one state may not be the same as what you see in another state. That’s because the insurance product falls under the state’s rights. Each state sets its own rules.

Call Leader: Okay. Do the insurance companies have a lower percent coinsurance levels for drugs that they see, let’s say, minimize hospital stays down the line, so it kind of helps the pharmacoeconomics of the whole thing? Do they look at that at all, or is it some other metric that they use to decide that this should be five percent coinsurance, this is twenty, this is thirty? Or is it arbitrary?

Expert: You know, I don’t want to say it’s arbitrary, I don’t want to say that they don’t. Typically, what you do see is self-insured programs have one thought process. When I say self-insured programs, let’s say that you are a union benefit but you are paying directly, you may then have a greater concern about downstream costs, because you expect that patient to be yours for their lifetime. If you are an employer buying insurance in the open market, you may not have the same feelings. The insurer may feel like, well they can change next year. The employer goes, well, I don’t know if they’re going to be here next year. They may not be concerned about second, third and fourth year costs.

Having said that, in some disease states, they’re going to want the best therapy because it’s going to impact their costs from in year one. Year one costs versus year two costs is always a concern based upon who the health insurance purchaser is, who the insurer is, and what their philosophy is. There is no one set way that the marketplace is going to look at this.

The other thing that you’re going to start seeing is a differentiation again here with the market. We’re starting to look at outcomes measures. If that’s going to be in that Medicare marketplace, it is more likely that they would look at second and third year costs and outcomes.

Call Leader: Okay. Basically, a lot of the commercial insurance companies probably aren’t looking at QALY studies or anything like that, they’re probably just looking at costs, trying to minimize it while it’s the-

Expert: They would look at these studies, the question is how much they weigh that in the evaluation.

Call Leader: Mm-hmm (affirmative).

Expert: I will look at it, but I may not weigh it at the same weight that I would back when I was with Medicaid.

Call Leader: I see.

Expert: When I worked with Medicaid, I expected to have patients for a fairly long time, because of that I look at second and third year costs.

Call Leader: Okay, great. Now, going back to more direct drug pricing questions, there seems to be a trend for generic drugs to have a higher retail price, because they know that at least in that first six months, they might be the only game in town and then people are automatically switched from branded to the generic. Is there anything that PBMs have at their disposal to control that?

Expert: No. In fact what you will see is that some PBMs will have a contract with the branded manufacturer for a rebate amount that will make it actually less than the generic at the introduced price. There was a multi-state litigation that basically looked at generic drug pricing. One of the things that if you’re very familiar with drug pricing, you’ll know that in the branded market-price, reported pricing is actually very close to market purchase price, whereas the multisource for generic purchase, that is not necessarily true. We saw, back when I was with Medicaid, oftentimes reported prices at six, seven, eight, nine thousand percentage points greater than the actual market price.

That was actually driving Medicaid costs up if they went to generic drugs, you saw a lot of Medicaid fee-for-services using branded drugs. CMS has addressed that by doing what they call national average drug acquisition costs, which is available on their website. That represents a survey of actual acquisition costs at the pharmacy level of most drugs. There are some drugs that are not on there, it’s just simply because their distribution mechanism is such that it really doesn’t fall under the general retail distribution definition.

Call Leader: Mm-hmm (affirmative). When PBMs are looking at their costs, you know the prices they’re paying, how do they decide what’s a focus area? Is it the drugs that they’re spending the most on, or is it the ones that have the highest price per unit?

Expert: Well, highest price per unit doesn’t necessarily mean that you’re spending the most money.

Call Leader: Yeah.

Expert: You look at your total expenditures, you look at ... Where they’re focusing the majority of their evaluations today is in the specialty marketplace. That’s a very small utilization but a very high cost factor.

Call Leader: Yeah, I saw a UnitedHealth presentation from 2014 saying that one percent of specialty drug use equates to 36% of drug spend? Is that accurate?

Expert: Yeah. Fairly accurate. You have a very small number of patients but very expensive product. Anything you can do to control expenditures is, going back to an earlier part of our conversation, that’s the reason why those copayment amounts have gone up. That is one of their cost controls in that specialty environment.

Call Leader: Okay. Why don’t they come out with plans that are, maybe, either generic only or just limited branded coverage? I saw another statistic from that presentation, generics are either 80% of the usage and 20% of the cost. Couldn’t you get a much cheaper plan if it’s generic only?

Expert: Well, there are some generic only plans in the Part-D space. The reality is that generics don’t make everything. If you’re looking at, particularly in the specialty marketplace, generics are not in that marketplace today. Most of the new drugs that they’re looking at doing, the bioidenticals or biosimilars. However, those larger complex molecules will not have the same price reduction as the small molecules. Where you saw an 85% or 90% reduction in the small molecules, you’re maybe looking at a 20% delta between the branded and the multisource product here. The delta’s not going to be the same. Often times, that delta is such that if you’re doing contracting, it’s not even a difference there, in terms of net costs.

Call Leader: Okay.

Expert: You could do it, but they don’t really address the high-cost areas today.

Call Leader: Okay. Just maybe focusing on the biotechs a little bit, you know, we start seeing a trend from CVS and Express Scripts, I think it was just this year that they said they are no longer going to cover Lantus, and they’re kind of for switching to the Lilly version, which I thought was kind of shocking, considering insulin is a really vital product for people. Do you think that’s a trend, or the PBMs going to get braver in terms of not covering certain products in order to maybe control costs a little better?

Expert: That’s a contracting issue. In other words, they were able to negotiate a contract with one manufacturer versus another manufacturer. That is not all that unusual. That has been done in the marketplace for many years.

What happened in this case is somebody came out and made a significant, should we say, change. My guess is the manufacturers came up with a much better value proposition that allowed the company to change. You know, because of the way you do diabetes, looking at hemoglobin A1Cs and you’re looking at your glucose levels, you can adjust dosages between the various insulins.

All the insulins today are basically either synthetic insulin, etcetera; they don’t have the same problems that we had in the past. The treatment of diabetes is so significantly different than it was five or ten years ago that I think you’re more readily able to make those types of changes than you were, say, 10, 15, 20 years ago.

Call Leader: Okay. Do you see companies ... Is it becoming more frequent that some of the drug manufacturers are offering steep discounts, in order to get some sort of exclusivity? One of the reasons I’m asking is there’s a drug, Soliris, for an orphan disease called PNH. It’s one of the most expensive drugs out there, between $400,000 and $600,000 a year. There’s a lot of potential competitors out there, biosimilars that are in development. I’m thinking in the future, couldn’t someone price their drug at, let’s say, $200,000 a year and then get exclusivity with one of the PBMs, or all the PBMs?

Expert: Potentially, yeah. You could, theoretically, do that. Again, the question that you have to ask yourself is how many potential patients are there, what are your fixed production costs? When you’re doing these biotech drugs, your production costs are far different than making small molecules. Where it might cost me $20,000 to make a batch of a small molecule drug, the fractionating column for some of these biotech drugs maybe cost a million dollars. I can use it one time. Those production costs are going to be different.

Call Leader: Yeah, no, I understand, but I mean in the case of like a Gilead, though, they were charging $1000 for a pill, so it doesn’t always correlate.

Expert: Well, they’re charging $1000 per pill. That is not necessarily the net cost of that drug. Every manufacturer who has a Medicaid rebate agreement on that brand of product has about a 23% rebate mandatory under federal law. States can negotiate over and above that, as can private third party payors. That $1000 quote pill, a) was not that much to begin with, but that is a sales value. Okay? Not a net revenue value. That’s why I keep going back to - think about $1000 is the sales dollars that’s reported, the net revenue factor, net of rebates, the discount, I can’t say what that delta is today, but it’s fairly significant.

Call Leader: Yeah, I think for the Gilead product, it’s at least ... I think the actual price they’re getting is probably below 50% of the retail price, from what I’ve heard.

Expert: I would say that that’s a good estimate. There’s what you pay and what it costs. One of the big differences in understanding the United States marketplace, versus another country’s marketplace. If I’m going to Europe, that drug price is part of the drug introduction, but I don’t do rebates in those types of contracting. What my price is, is what my price is. Whereas in the United States, I charge $1000 and I give you 55% back.

There’s a delta in the way we look at pricing and costing etc between what we do in this country versus maybe what you do in Canada or Europe or Japan or Australia, New Zealand, etc. It’s really hard to say, well, this is the reported price, but it’s actually not the true market value price that we say.

Call Leader: Before you were saying that the PBMs are probably willing to accept a lower ... have an exclusive biologic if the manufacturer gives them a much lower price. I was just wondering if ... Does that extend also to new versions? Let’s say, just in the case of Soliris, the company is developing a once monthly product. Once a biosimilar Soliris comes on the market, could they say, well, you know, once every week or once every two weeks is fine, you don’t need the once monthly product.

Expert: They could say that I’m going to incentivize you to use the biweekly product versus the monthly product and they can do so because it’s not a requirement, you’re providing the same therapeutic entity.

Call Leader: Would they just not cover the other product, or would it just be different levels of coinsurance? What is the levers that they can pull?

Expert: They can have a differential coinsurance and they would make it subject to prior authorization. You may have a higher level of prior authorization requirement for the monthly product versus the twice monthly product.

Call Leader: Great, no, thanks, that’s very helpful. Just moving on to another biotech drug that was a little bit controversial. This company, Sarepta that developed Exondys, which is for Duchenne Muscular Dystrophy, it received a controversial approval from the FDA, where one of the FDA staff, or actually the head reviewer, said it was a scientifically elegant placebo. In such a case, do you see the PBMs pushing back at all on covering them? Do they have to cover any drug that’s approved by the FDA for a serious disease? How much wiggle room do they have?

Expert: What they’ll do is they’ll put it on a) prior auth, and b) interesting enough I’m fairly familiar with that drug product and some of the issues associated with it. The FDA and the way they responded to the three products that were in development, two of them dropped out. The Sarepta product is the only one that made it through to an FDA drug approval process. If you think about it from a competition and marketplace, if the FDA basically didn’t approve one of the three products, would any other manufacturer be willing to do research into the area of Duchenne Muscular Dystrophy?

Call Leader: But if the drug doesn’t ... I mean, do you need to have kind of that global perspective?

Expert: The drug product does work, the question is what degree of improvement?

Call Leader: Okay.

Expert: In the opinion of a reviewer, maybe the improvement is not significant enough. I don’t know the particular reviewer, but I do know, because I happen to have friends in three companies, that the way some of those study designs were altered by the FDA, they almost ensured that the drugs would fail, by the study design. The question is, in this case, was there an improvement? If you have a drug for this disease that’s 100% fatal, and now you have a 3% survival rate, and I’m just saying 3% for the sake of saying 3%, is that 3% significant? From a policy ...If you’re one of the three percent, it’s very significant to you.

Call Leader: Yes, but is that 3% enough for insurance coverage, generally?

Expert: What else is available that’s going to ... there’s nothing else.

Call Leader: Yeah. It’s a question though of costs and benefits. These aren’t free, this costs, like, $300,000 or up to $600,000 really, depending on the weight. That could be used, maybe, to pay for other people’s drugs. Unfortunately we don’t have all the money in the world.

Expert: Well, I will tell you what I used to say when I worked with the Medicaid program. I would put a dollar on the table. This is the dollar we have. We have to figure out how to work within that. Now, $300,000, $600,000, again, let’s go back and say, you’ve got 23% of that is going to be Medicaid rebate, which is going to be a large percentage of these patients. Probably 85% to 90% of them are going to be paid under some type of Medicaid program. Automatically, you’ve got that discount. Will private, third party payors negotiate discounts? Likely, yes.

Let’s say this marketplace, everybody gets 20% discount because that doesn’t impact their Medicaid best price. Everybody’s getting 20% off that $300,000. That automatically drops it down. Then you’re going to have a 20% co-payment based upon $300,000. You’re at 60% of that cost. That’s what you’re paying out. I can’t give you absolutes, but if you think about it from there’s going to be some kind of contract negotiations, there’s going to be some kind of co-payment, you’re going to have prior authorization in place, your exposure is going to be fairly limited.

Call Leader: Okay. Just maybe to follow through on- [crosstalk 00:44:07]-

Expert: By the way, guaranteed insurability, you cannot deny access to that patient.

Call Leader: Okay.

Expert: What it transfers into is to higher rates.

Call Leader: Mm-hmm (affirmative), yeah. You mentioned Medicaid best price, and I was just thinking, because drug pricing obviously is this big issue, that’s why we’re having this call. What would happen if the Medicaid best price regulation was expanded to cover Medicare?

Expert: Oh, there is actually, under the Affordable Care Act, an exception for Medicaid best price in the language. That exemption is to lower Medicare drug costs. If you’re negotiating with a manufacturer for a rebate that is in excess of the Medicaid rebate, it does not impact the dollars that they owe to the Medicaid programs. That was done specifically in order to address the affordability of Medicare Part D. It would have a negative impact if you apply the Medicaid best price to those contracts.

Call Leader: Okay. I didn’t really think of that. I guess it affects ... Since it would affect a very large proportion of your contracts then you’d be negotiating less.

Expert: Yeah, or your amount would be lower because you wouldn’t want ... If you think about it from the manufacturer’s perspective, I have a drug that’s going to be used in Medicaid in Medicare, because it’s exempt from best price in Medicare, I can be more aggressive in negotiating with payors. If it were not, I can’t be as aggressive, because that’s going to impact my Medicaid portion of the business also.

Call Leader: Okay. That’s very helpful. If you were the secretary of HHS, what would you do to reign in drug prices?

Expert: Hm, boy. A couple of things, and they’re going to require statutory changes. One would be under the Medicaid drug rebate program there’s a BPI penalty. That BPI penalty is a lifelong increase in Medicaid rebate if you raise your price greater than the CPI. The other thing that does not exist in there is if a manufacturer has that CPI penalty in place. There’s no incentive to lower the price.

The question that I keep asking people who are decision makers is, is it time to create an opportunity that a drug that’s going off patent, and lower the price, and lower it’s rebate liability? Would that, in effect, give an incentive to lower prices?

Call Leader: What have people said?

Expert: We just don’t think they would do it. Why not? Well, there’s really no basis why they think they wouldn’t do it, it’s just that the opinion is that they would not do it.

Call Leader: Okay.

Expert: Well, I’m not sure that they would or would not, but there is no mechanism currently to even test that.

Call Leader: Other than the CPI penalty issue, what else would you do?

Expert: I’m not sure how familiar you are with how they do pricing in other countries.

Call Leader: Relatively, I mean I know reference pricing, etc.

Expert: Yeah, but that is part of the drug approval process. They may have a reference price in establishing the price of a product going into the market. If you look at Europe, they use kind of that reference in value perception. Is there a significant increase in value based on a reference price. They come up with a formula, what’s the allowable price.

As an example, you would look at that and say, okay, the price is a dollar as our reference price. We think that this has a, is 20% better, so you could charge a dollar and twenty cents for that product. If you look at Canada, their generic drug prices are very close to their branded price and they don’t have the same number of generic manufacturers producing products in Canada, for sales in Canada. It is an interesting issue. I believe in Japan, the highest price you ever have for a drug is the year you introduce it, and then they have a calculated decline in price. It would require that we change from a free market type of idea to very much a controlled environment in terms of drug pricing, and that could have a significant impact.

One of the issues that you have there as we’ve talked about is I have this $1000 tablet and when I report sales at $1000, that’s what I’m reporting, that’s what the market looks at. If all of a sudden we change that to, you’re only going to be able to charge $550, although that may be on the same net revenue, how is the marketplace going to look at that? You have to look at it from not only the drug price but what are the downstream impacts on the marketplace side of it. Does that make sense?

Call Leader: Mm-hmm (affirmative). Yeah, no, definitely. Just given that we have a Republican administration and it seems to be probably more conservative and libertarian than most people would have expected, they’re probably not going to do the drug price control. Do you see any levers that they’ll be pulling to control drug prices?

Expert: I think that you have a gentleman who probably will be driving policy, who will look at it from a business perspective. From a business perspective, it’s going to be interesting to see what happens. I think he ... and I really can’t share some of the knowledge that I have, I will just upfront tell you that.

Call Leader: Okay.

Expert: I think you’re going to see some changes. I think you’re going to see potentially an aggressiveness and increase in BPI penalties, maybe? Disincentivizing those things. How they’re going to incentivize lower costs I don’t know. I actually haven’t got a really good feel what they’re going to do here. I don’t think that it’s been the number one priority to date. Some of it will depend upon how they do the Affordable Care Act rewrite. That is where I would expect to see some of that coming in. I would expect it to be changes potentially in the Social Security Act, section 1927, which is the Medicaid drug rebate. Potentially some changes in the Veterans Health Care Act, section 340B. That’s where I think they can influence things.

Call Leader: Okay great, so it looks like I think we’re out of time. Thank you so much Doug for your time and your insights. I really appreciated it.

Expert: You’re very welcome and hopefully this was helpful.

Call Leader: Yes, it was, very much. Thanks Doug, have a great day.

Expert: All right, thank you.

 

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Edison KOL call

Pediatric Epilespy

The second in our KOL series, Edison sponsors an interview between Dr Wirrell, Director of Pediatric Epilespy at the Mayo Clinic. and Max Jacobs (call leader). The conversation featured a discussion on the clinical course of various pediatric epilepsies and the place that Epidiolex might have in the treatment paradigm. 

Call Leader: Great. Thank you, Dr. Wirrell, for joining us. Could you just maybe start by just telling us about your background and your practice?

Doctor: Yes. I’m a pediatric epileptologist. I’m the Director of Pediatric Epilepsy in the clinic where I work. My clinical practice is solely focused on pediatric epilepsy. I do approximately 85 percent of my time as clinical time. In that clinical time, virtually all patients have epilepsy. They’re predominantly children with epilepsy, sorry, and the majority of them have medically intractable epilepsy.

Call Leader: Great. Thanks a lot. I was wondering, since we’re talking about Epidiolex, you know they recently had positive data in Dravet and LGS. Maybe we can start by can you just describe Dravet and LGS, how many of those patients do you normally see, and then maybe the clinical course of the disease, so when is it diagnosed and how is it diagnosed, et cetera?

Doctor: Both of those are amongst the most challenging of epilepsy syndromes in children. Dravet typically presents in the first year of life. Typically the initial presentation is with a convulsive seizure which may be a hemiconvulsive seizure often triggered with fever, typically often prolonged. Then, over the course of the first five years of life, these children have recurrent bouts of often status epilepticus with convulsive seizures often triggered by hyperthermia or photic stimulation. They also develop myoclonic seizures. Many of them develop atypical absences, other focal seizures, tonic seizures.

The children, although they are developmentally normal initially, in most cases by their later preschool years it’s clear that they’re not acquiring their developmental milestones as you would expect. The children are left with a variable degree of intellectual disability. The seizures are very medically intractable. We have some potential options that we can try, but the likelihood of complete seizure freedom with medication is very, very low. Currently I follow about 25 to 30 children with Dravet Syndrome in our practice.

Lennox-Gastaut Syndrome, a bit more variable presentation. Some of the children can present with infantile spasms initially that then evolve into Lennox-Gastaut, or some children just start to have multiple types of generalized seizures. Again, most of the children with Lennox-Gastaut have an underlying cause, either a genetic cause or a developmental change in the brain or something that injured the brain early in life. These children have, again, recurrent seizures, many of them with abrupt falls which can lead to injury. With Lennox-Gastaut, again, multiple medicines can be tried but the likelihood of seizure freedom is virtually zero. Again, cognitive impairment is part of that syndrome. Currently I’m following probably about 50 children with Lennox-Gastaut.

Call Leader: Great. Thanks. In terms of the developmental path of these patients, does their stage of development kind of regress every time they have a seizure? Are there certain seizures that are worse than others, in terms of affecting their development?

Doctor: They don’t regress with every single seizure, but certainly the recurrent prolonged seizures in Dravet Syndrome, and then very frequent nonconvulsive seizures. Some of these patients have such frequent seizures that we call it a nonconvulsive status, that they just actually go from one seizure into another seizure into another seizure into another seizure. In some of those patients that can go on for a period of several days. That also has a negative toll on their development.

Call Leader: Wow. What do you do when that happens?

Doctor: If it’s a long seizure, most of our patients do have rescue protocols and they’re given a medication based on that protocol when they come in with single prolonged seizures. The nonconvulsive seizures, we again often will admit them to hospital and try different options to try and get rid of the seizures. That can be benzodiazepines. It can be Depakote. It can be Keppra. Sometimes we give them a blast of steroid and that works. It can be quite a challenge to get the seizures under control.

Call Leader: Can you describe what your experience is with Epidiolex just in terms of were you in the trials or your knowledge is based ...

Doctor: We did participate in the trials. I obviously can’t disclose any specific information from our patients, but just the general information that has already been published on their website. We did participate in the trials. I think that that was an important thing, because this is a therapy that families really are very interested in.

Call Leader: Do you have experience with other CBD-based products or cannabinoid-based products?

Doctor: I do.

Call Leader: Can you just describe those?

Doctor: We follow patients who are working through the state ... In Minnesota we have a state supply of cannabidiol where if the patient has one of the designated indications for cannabidiol they can obtain their cannabidiol through a state supply. We also have a number of families who obtain their various products from various mail services from Colorado or Oregon or online, various other sites that they go to. I think the actual amount in what they’re using is really, who knows? It’s completely unregulated.

Call Leader: Is the state supply in Minnesota, is that pretty standardized?

Doctor: That is pretty standardized. That is pretty standardized.

Call Leader: Do you base that dose on the Epidiolex dose?

Doctor: No. The state supply is a bit weird in that we certify patients but we don’t prescribe it and that the prescribing is by a pharmacist who works in one of the dispensaries. The dose that they’re using in Minnesota is very, very low. Probably too low, I think, to be effective.

Call Leader: What’s the cost of this?

Doctor: The cost through the state supply for most families is of the order of $500 a month.

Call Leader: That’s not covered by insurance usually?

Doctor: No. It’s not.

Call Leader: For the mail order from Colorado, I know the supply is not standardized and you don’t really know what you’re getting, but what’s generally the cost for those? Do you know?

Doctor: For I think the mail order many of the families that I’ve talked to are spending somewhere between $200 and $600 a month on their supply.

Call Leader: Great. Based on what you’ve seen from the Epidiolex data, where do you think it would go in the treatment paradigm for Dravet and LGS?

Doctor: I think for Dravet there’s been very few Class I studies that have been done. The only other one has been on stiripentol and there’s currently one that’s underway with fenfluramine. I think to me this is very exciting that this is a Class I study that is, it’s a randomized, placebo-controlled, and they documented efficacy. Now, the efficacy that they documented, again, it wasn’t stellar and it didn’t result in seizure freedom, but it did clearly document efficacy. Right now the first-line medications for Dravet that we use, including valproate, clobazam, topiramate, none of those have been shown to be efficacious in Class I studies. That’s all based on more Class III/IV evidence. I think that we can certainly look at using that early on. Probably maybe not first-line, but I think certainly early on. I think with the evidence now that it does reduce frequency of seizures, I think we can make a case to insurance that this is really one of the only proven treatments that we’ve shown in this.

For Lennox-Gastaut, we have a larger number of Class I studies. I see that, when we look at where we use it in the paradigm, probably we would start with things that we would typically use earlier on, things like topiramate, potentially valproic acid. I think certainly before we get to medications that were potentially more risky, like felbamate, in Lennox-Gastaut, I think most people would choose Epidiolex prior to felbamate. I see it maybe second- or third-line in patients with Lennox-Gastaut.

Call Leader: Is the toxicity relatively innocuous? How does it differ from the other drugs that you would use?

Doctor: As far as Epidiolex, and again we have to understand that there’s been a limited number of patients exposed, but we also know that this is not a brand new compound. This is a compound that has been used probably for centuries. It looks like it’s more nuisance kind of side effects, like a bit of a decreased appetite, some loose stools, and sleepiness. Overall, pretty well tolerated compared to if we look at something like felbamate, aplastic anemia, liver failure. If you had a child, which would you choose?

Call Leader: Good point. In terms of the efficacy of Epidiolex, do you think some of that positive data could just be part of a honeymoon effect of introducing a new drug in a patient?

Doctor: I think that’s certainly possible. A lot of the difficult epilepsy medications will work for a while and then will no longer work. I think that is going to be something that we will need to evaluate better once they release the data from the long-term open-label study and once that’s actually starting to be used in clinical practice.

Call Leader: Usually when you do see a honeymoon effect in whatever antiepilepsy drug, how long does that usually last? Is it six months?

Doctor: It’s usually a couple months, actually. Somewhere between two and six months, and then it starts to wane its effect.

Call Leader: When that effect wanes, do you switch them off drug or do you add another drug?

Doctor: Typically we would add. Then if that was effective we would wean what we felt was ineffective. Sometimes we go back and recycle these medications. One of the medicines that’s pretty notorious for causing a lot of honeymoon, and it can be pretty effective initially and then the effect wanes, is clobazam or ONFI. In that situation we often will wean the child off once the honeymoon is over. We replace it with something else. Then a year or two years later you could come back and retry that.

Call Leader: Why do you think that is?

Doctor: Why they’re having their honeymoon?

Call Leader: Yeah.

Doctor: I do not know. Presumably there’s something that’s happening genetically or structurally in the brain with the different channels that is causing that to happen, but I do not know.

Call Leader: I was just wondering, when you in your dealing with the different sales forces who come by to your office and leave samples, et cetera, which companies do you think have the strongest pediatric neurology sales teams?

Doctor: I think that ... Jeez. Which has the strongest?

Call Leader: Or at least your favorite?

Doctor: They’re not my favorites. Mallinckrodt has a ... They’re always at us for it. The make the ACTH. They have a pretty ... I don’t want to use the term in-your-face, but it’s a little bit like that. They’re frequently contacting you. I think Upsher-Smith does a nice job with potential for midazolam. They contact you, but they’re not so in-your-face. Lundbeck had been pretty involved with ONFI. I think maybe a little bit less recently. Those are probably the big ones.

Call Leader: Great. That’s very helpful. Just back to Epidiolex, for the course of Dravet and LGS, what sort of seizure-free rate do you normally see for first-line therapy in Dravet and LGS patients?

Doctor: You don’t get them seizure-free.

Call Leader: You never get seizure-free?

Doctor: You don’t get seizure-free.

Call Leader: Do you get patients at least who go down like 70 percent?

Doctor: Yeah, some of them. 70 percent would be a really good response. 50 percent. We typically will say, “Jeez, I think that’s a pretty good drug,” if it’s dropped 50 percent. It also depends on the seizure type. For Dravet, if they’re having some absence seizures that’s less or myoclonics that’s less of a big deal. If they’re having the recurrent prolonged convulsive seizures, that’s what we really want to focus on.

Call Leader: Do you just keep adding additional drugs until you get to seizure-free or closer to seizure-free or some of these prolonged seizures being absent? How does that work?

Doctor: If we add drugs, we typically like to take away drugs. I really don’t like ... My ideal is to have a patient on one. For most of my kids with Lennox-Gastaut or Dravet Syndrome I typically have them on probably three. I don’t like to go above three. I think if you add a drug you need to think about, “Jeez. What’s not working?” and take one away as well. Then I think it’s really making sure that the families have reasonable expectations. That’s something that we address pretty much at diagnosis, that if you have Lennox-Gastaut or you have Dravet Syndrome, the likelihood of us being able to get your child seizure-free is pretty low. We really have to balance what are the side effects of medication and what are the risks and harm from seizures themselves.

Typically we get to a place that we say, “You know, seizure control is not 100 percent, but it’s pretty good and the quality of life is pretty good and my child is on now a regimen of medications that they’re tolerating well. They’re not causing significant sleepiness, appetite issues, behavioral issues, and so that’s a good place to be.” That’s typically how we treat that.

Call Leader: Great. That’s very helpful. When you do add another drug, I figure the biggest effect is probably with the first drug and then you get smaller effects with the add-ons. What sort of response rate do you see with those?

Doctor: It depends which drug you use. In Dravet, we’re typically starting with clobazam or valproate. Then, if one of those isn’t working, we’re typically adding in the other. Even with after those two medications, I have very few people with Dravet Syndrome who get adequate seizure control with that combination. Most of them, we’re adding in another agent which could be, right now it’s Topamax, it’s stiripentol, or it’s ketogenic diet is typically what we’re going with.

Call Leader: How effective is ketogenic diet?

Doctor: For these kids with Dravet Syndrome or Lennox-Gastaut it can be certainly in reducing seizures. Again, seizure freedom is generally pretty unlikely. I would say less than five percent. In reduction of seizures, probably half of these children can have a greater than 50 percent reduction in seizures with ketogenic diet. Then, the other thing with ketogenic diet is you can often get the kids on lower amounts of medication, so they actually brighten up if they’re not using so many medications at such high doses.

Call Leader: There’s a theory out there that Epidiolex works mainly by increasing the effects of some other antiepileptic drugs in their system. Do you share that view?

Doctor: No. I don’t. I think Epidiolex has ... Because that was the same theory that came out with stiripentol, that stiripentol in Dravet works by increasing clobazam. I think it’s bunk. I think a lot of these kids have been on much higher doses of clobazam. Typically yes it does increase clobazam, but what we see is then the children develop side effects that are clobazam-related. We reduce that and we actually get similar levels of clobazam yet seizures are better. I think that it has an independent action.

Call Leader: Do you think that, however it works, do you think that can translate into other refractory epilepsies in general?

Doctor: I think so. I think there’s certainly a lot of enthusiasm in the media. I think you always have to take that with a little grain of salt, because the media tells you about the amazing cases and they don’t tell you about the other cases that it didn’t work for. There’s certainly a lot of enthusiasm in other types of epilepsies. There’s currently a trial that is looking at tuberous sclerosis-related epilepsy. Then I think we have a whole host of patients who have other types of intractable generalized or other types of intractable focal epilepsies who likely would also benefit from CBD. That’s just not been looked at. I think that there certainly is a large population that could potentially benefit from this.

Call Leader: Would you require specific data in a specific type of epilepsy before you used it in that group, or once it’s approved will you just use it off-label and see what happens?

Doctor: We use off-label all the time. Ideally I would like data from a randomized placebo-controlled trial. The reality is that that often doesn’t happen. We often will use other medications off-label. The challenge really is, is getting the insurance to cover. If something comes out and it’s only for Lennox-Gastaut and we try and use it for something else, that can be quite a challenge to actually get the insurance companies to pay for it. One of the big issues that we run into, for example, is for clobazam, for ONFI. The trials were in Lennox-Gastaut, so when it was released it was released for Lennox-Gastaut. It clearly has a much broader benefit, but insurance has their head in a bit of a very limited tunnel vision. They say, “No. Not Lennox-Gastaut, not going to cover it.” That’s our biggest challenge.

Call Leader: Are you able to successfully appeal that decision?

Doctor: Sometimes.

Call Leader: What do you have to do to get that successful appeal?

Doctor: Typically we have to say, “Look. They’ve tried all of these other medications. This is the diagnosis they have.” We have to provide, sometimes there have been other bits of literature showing that it can be beneficial. Again, it’s pretty challenging sometimes. Some insurance companies, no matter how far you go to try and document that you’ve tried all of the other good options, they still say no at the end.

Call Leader: Which ones are especially difficult?

Doctor: I can’t give you specific ones. I can tell you that in my experience probably about 60 percent of the time we can convince them with a reasonable amount of effort. Then, 20 percent of the time, absolutely no way no how.

Call Leader: Is it a matter of just pricing? Are there certain branded drugs that they’re less strict about because of the price or does it not matter? Is it just a branded versus generic and label sort of thing?

Doctor: I think that clobazam’s a little expensive but it certainly doesn’t break the bank. That’s one that we’ve had a real challenge at times getting coverage for. I’m not sure it’s just the super expensive ones.

Call Leader: Do you have a sense of at what price would Epidiolex be a no-go generally based on your experience with payors?

Doctor: I don’t, actually. That’s probably a good question for payors. I think that probably it would need to ... The newer medicines that are available for LGS, things like Banzel or ONFI, probably they wouldn’t want to come in too much higher than those. Otherwise, they’re going to be at the latter part of the market for that.

Call Leader: What do you think about vagul nerve therapy?

Doctor: I think that certainly it can be considered. I think in some kids you can have a reduction in seizures. I think overall in our hands, and we tend to use it later down the line, we get at best a third to half of patients having a greater than 50 percent reduction. The concern with vagus nerve therapy, first of all, it’s a surgery. It’s not a big-deal surgery, but it does require placement of a wire that goes around the vagus nerve. If that device is ineffective you cannot remove that wire because of concern of injury to the vagus nerve. That wire stays with the patient through life and potentially has concerns if you’re wanting to get another MRI or things like that. I think that vagus nerve, you’re putting something in somebody, you’re not sure it’s going to work. It’s not as simple as, “Jeez, you can just stop taking this medication if it doesn’t work.” You’ve got that in you for life.

Call Leader: That sounds not terribly attractive. In terms of just other types of surgeries, how do you decide when to offer or when to suggest surgery?

Doctor: First of all, for Dravet Syndrome I don’t think there’s any evidence that, other than maybe VNS, I don’t think there’s any evidence that other surgeries, callosotomies or temporal lobectomies or anything, are effective. For Lennox-Gastaut the majority of kids are not going to be a surgical candidate for resective surgery, where they actually try and remove a certain area of the brain. Small numbers can be, but the majority will not. Callosotomy can be potentially beneficial for kids with Lennox-Gastaut if they’re having recurrent drop seizures. Typically we consider that if they’ve been on through reasonable trials of what we would say would be the usual effective medicines, so valproate, topiramate, lamotrigine, Banzel, ONFI, potentially felbamate, and then ideally ketogenic diet. If we still have patients who are still really struggling with drop seizures with that we often will have a discussion about callosotomy.

Call Leader: How many drugs usually have they already tried by the time they get to the surgery conversation.

Doctor: Most of them have tried seven or eight, anyways. Most of them have tried ketogenic diet.

Call Leader: Is that just in your general patient population? Is seven or eight generally the amount that people have tried if they’ve had Dravet for several years?

Doctor: That’s often, depending on how quickly the Dravet was diagnosed. Many patients have been tried on what are now known to be ineffective medications before the diagnosis of Dravet was made. Typically five or so medications for Dravet. As far as surgery, though, some of the ... It depends on the center. There are a limited number of places that actually are using VNS a fair bit earlier. I don’t think that’s in the patient’s best interest. I don’t know if it’s revenue generation or what, but there is a concern there.

Call Leader: You’ve mentioned that sometimes people are given the wrong drug when they have Dravet. Are a lot of the Dravet patients or LGS patients, are they sometimes misdiagnosed early on?

Doctor: Yeah. I think less so for the LGS because I think that there’s still, the LGS is still the garbage bag of all bad epilepsy that starts early in life. If you’ve got a bad epilepsy that starts early in life, you must be Lennox-Gastaut. I still think it’s a bit of a garbage bag for that. A lot of Dravet patients are not recognized as having Dravet Syndrome. They’re kind of thrown into this Lennox-Gastaut garbage bag, or whatever. “Jeez, they have intractable focal epilepsy,” or something like that. I think it’s getting better. I think there’s more recognition from the general child neurologists about what Dravet Syndrome is, but I still think that there’s a way to go.

Call Leader: Do you have any estimate for what percentage of your Dravet patients were actually originally misdiagnosed, a roundabout number?

Doctor: A large number. Actually we published data when we looked at efficacy of stiripentol a few years ago. That was multi-center data from the US. It took on average 4.8 years for a diagnosis of Dravet Syndrome to be made after the patient started developing seizures.

Call Leader: Wow.

Doctor: That’s too late. That’s too long to wait.

Call Leader: Yes. I would think so. What happens to the death rate? How high is the death rate for some of these patients? Is the death rate generally because of status epilepticus or is it due to falls or accidents?

Doctor: It really depends. Dravet Syndrome, there’s been some reasonable papers. It looks like probably 10 to 15 percent of kids with Dravet Syndrome don’t hit their adult years. Sometimes that can be status epilepticus. Not infrequently it can be sudden unexplained death in epilepsy or it can be accidental death. For kids with Lennox-Gastaut, certainly SUDEp is a risk for those as well, as is status epilepticus, but many of those children have very, very profound brain abnormalities and very severe developmental delay just on the basis of the underlying etiology for their Lennox-Gastaut. Many of those children will succumb to recurring pneumonias or just general medical problems that affect the very neurologically-impaired child, so they may not be seizure-related.

Call Leader: What are your thoughts on fenfluramine from Zogenix? Are you familiar with that at all?

Doctor: Mm hmm (affirmative). I think that actually is a very exciting potential agent. I think the initial data look really exciting. I think that we really do need to see some Class I studies done, and that is currently ongoing. I think that the data that they have, they actually show that there are patients who achieve seizure freedom for a number of years, which is almost unheard of in Dravet Syndrome.

Call Leader: Do you think that there’s potential for fenfluramine to be used, if the data holds up of course, ahead of Epidiolex, or would it just, because of the safety issues, just always be probably after?

Doctor: Probably if it looks as good as it does in their small studies, probably ahead would be my view. The data that GW put out on Epidiolex from their randomized-control trial, the stuff they put online, yes they improved but seizure freedom typically wasn’t achieved. That’s where I think fenfluramine has the benefit.

Call Leader: You think that parents would be okay with the potential side effects?

Doctor: Yeah. Again, I think that needs to be looked at. Again, if the data hold out, the cardiac issues seem to be when it was used in very high dose in combination, when it was used as fen-phen for obesity. In the more moderate doses that they used in Belgium, they did not see ... It was a small n absolutely from their sample, but that did not seem to be an issue. Cardiac issues did not seem to be problematic.

Call Leader: Great. That was very helpful. Thank you, Dr. Wirrell. Those are all my questions. Again, thank you for your time.

Doctor: All right. Thank you.

Call Leader: Have a great day.

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Edison KOL call

CAR-T therapy

On October 19 we kicked off our KOL series, sponsoring an interview between Rafael Mejar, M.D., Ph.D and Max Jacobs (call leader). The conversation featured a discussion on the delivery challenges and potential solutions to administering CAR-T therapy more widely upon eventual FDA approvals. The discussion focused on the number of specialists needed, facility requirements and cost of delivery among other potential hurdles to use. Below is a link to a recording of the event and the transcript to the call.

Call Leader: Ok, so thanks Dr. Bejar for joining today. I want to introduce myself. My name is Max Jacobs, I’m Director of Healthcare Research for North America at Edison. I’m very happy to have you here today. Can you start off by describing your practice and your experience?

Doctor: Sure, I’m a physician/scientist at UC San Diego Moores Cancer Center. I split my time between doing research and clinical care. With patients mostly with mild malignancies like myelodysplastic syndromes. I don’t know what else you’d like to know about our institution. We’re a comprehensive cancer center, so we have a complete slew of clinical offerings including clinical trials, bone marrow transplants, and the like.

Call Leader: Ok great. I know you’re an MDS specialist I was just wondering would you be able to discuss the treatment paradigm for ALL, CLL and DLBCL patients?

Doctor: Yes, in general absolutely.

Call Leader: Yea in general. How would you describe the response rates for the various lines of those therapies?

Doctor: Well all those things depend sort of dramatically on which of the diseases you’re talking about and which patient population you’re speaking of. If you’re looking at DLBCL there’s a wide range of responses that depend on the subtype and the patient themselves. But, on average I would say about 50% of patients with Diffuse Large B Cells Lymphoma can be outright cured with chemotherapy alone. Then there are some that obviously relapse and if they are not salvageable after that fact…

The numbers are very different for ALL particularly in older individuals. You guys I’m sure know that younger patients with ALL will have survival rates that approach 90%. Whereas the older patients tend to have much more aggressive disease and relapse rate are quite high, and mortality is quite high. The long term survival rate is less than 50% in many of these patients, particularly if they have adverse cytogenetic.

In CLL it is a completely different disorder, it is a much more chronic disease. More patients can live for many many years, even go through many different lines of therapy, and often will maybe die of something else. Not necessarily directly caused by the CLL. These patients tend to be substantially older than patients with lymphomas or acute leukemias.

Call Leader: My guess based on what you’re saying: There is probably more choices for DLBCL patients for 2nd line, 3rd patients than ALL patients?

Doctor: That’s certainly true. ALL, you don’t have a lot of time to go to 15 different therapies. Patients tend to be sick relatively quickly, particularly after relapse. If you are fortunate you are able to get a second line of therapy in and in rare cases a third, if transplant isn’t an option. But usually if a patient has relapsed or even has high risk disease and is very likely to relapse, we’ll be looking for a transplant option relatively early in the course of the disease. That’s about it in terms of what we can provide.

Call Leader: That was very helpful, thank you. My next question is can you give us your general thoughts on CAR-T therapy and also some of the high-level challenges you see arising from treating patients at your facility?

Doctor: Sure. We have a few of the CAR-T cell trials open here. So we’ve had experience in the institution treating these patients, but personally have not had a patient on one of these trials since they are all aimed at lymphoid malignancies and most of my patients have myeloid lymphoid malignancies. I’m sure in the future more myeloid CAR-T cell options will become available.
They’re extremely impressive therapies. They have an incredibly high rate of response in patients that are typically extraordinarily refractory to most of our treatment options, because they have been through several lines of therapy in a very advanced disease.

I think we are still learning how best to give CAR-T cells. Up until now it has really been, well it still is really considered an entirely experimental therapy. But until now, we haven’t really understood the best way to give them. We’ve encountered a lot of problems along the way that in some ways have set us back a little bit.

You asked about the challenges of giving CAR-T cell therapy? I think some of the challenges are somewhat self imposed. In that we are restricting the use of these agents in clinical trials to the most sick patients we have. The patients that are truly refractory and really are at the end of all options.

So not only are you giving a therapy that has a lot of toxicity to a patient, you’re giving it to a patient who themselves have very little reserve. Or have a lot of comorbid conditions that are a consequence of their disease. So that in itself makes it more challenging than I think it might if we are able to use these therapies in earlier lines of treatment.

Call Leader: So it would probably be more interesting to have them- to see what CAR-T therapy would do in first or second line patients?

Doctor: I think they will end up being a little bit easier to give in first or second line. We may not want to give them by themselves in first line therapy. I think there will probably be a role to do some sort of Cyto wrapping treatment. But the real problem with these diseases isn’t that we can’t treat patients and get them to respond, it is that we can’t get them to maintain their response. Or at least if they lose their response, those are patients that are truly in trouble. I really see CAR-T cells as a really complementary therapy to some of the first line therapies we have now. That can put people into remission and then the CAR-T cells can essentially keep people there.

That’s a very different paradigm than giving CAR-T cells to people who have a tremendous burden of disease because their disease is prone to spike multiple lines of prior therapy. That causes acute complications in the first few days after treatment, that may not be as severe if the patient hadn’t been significantly cyto-reduced with some other treatment.
So I do think it will be easier in the future, when we move these products closer to first line.

Call Leader: Ok, so actually it sounds like the way you see CAR-T therapy used optimally is after they are given a first line therapy, use the CAR-T to mop up any remaining tumor, and that using it that way will probably limit a lot of the toxicities.

Doctor: Exactly right. These are essentially relapse prevention or consolidation therapies to provide long term immune vigilance.

Call Leader: Does it also make sense to use it as the sort of…a bridge to transplant therapy?

Doctor: It depends on the disease.

I think there are some scenarios where it will absolutely be a bridge to transplant. I think in the myeloid malignancies there is a lot of interest in targeting markers that are not unique to the tumor. Meaning, that if you didn’t go to transplant you would essentially eradicate someone’s myeloid which is not a good thing. You want people to be able to make neutrophils after your treatment.

But if you have a therapy that kills essentially all myeloid cells, it might be very effective in eradicating leukemia, you just need some sort of rescue that will replace myeloid cell production after that fact. So I think in the myeloid malignancies one of the first things we’re going to see is these agents as mechanisms to getting people to transplant.

Call Leader: Ok great, that’s very interesting. Can you see any sorts of patients where you really think CAR-T therapy would not be appropriate? ALL, CLL, the hematological tumors?

Doctor: I’m sure there are going to be some people that are not good candidates because of their overall health status. I think more importantly there may be people who don’t necessary need it. We think of allogeneic transplantation as being curative, but not everybody gets them. In part because people can be cured with less intensive therapy. So I think for good risk, DLBCL patients or more indolent CLL cases there is no indication to do a CAR-T cell type therapy at the moment.

Maybe in the future things become proven to be extraordinarily safe and easy to give, that might change. But at the moment we are reserving these things for people who we think have high risk and likely to relapse disease.

Call Leader: That makes sense. In terms of the overall risk reward of CAR-T therapy, what do you think that looks like? Is it really heavily weighted toward reward or are you concerned by some of the neurotoxicity, the cytokine release syndrome, etc.?

Doctor: I’m concerned about those things, but I don’t think that they are going to be as big a barrier to say conditioned chemotherapy is for allogeneic transplantation.

These are things that were striking, because they were in some ways relatively unexpected. These therapies were much more effective immediately than we thought they might be, so we saw a lot of cytokine release syndrome. But I think we’re also getting much better at dealing with that. We’re learning how to get patients through that.

I see that barrier coming down. The neurotoxicity is another great example. This was something that extraordinarily worried people when we first started seeing it, particularly when we started seeing it over and over again. But I think now that we understand it, we know people can get through it and be ok it on the other side of an experience like that.

As that happens I think it will become, we’ll get more experience and we’ll be more tolerant to it and it will become easier to deal with that.

Call Leader: What are some of the strategies to get patients through a cytokine release syndrome, a severe neurotoxicity?

Doctor: What we’ve done here, which I think is extremely useful, is to try and standardize our approach and not have people reacting immediately as everything needs to be solved within sixty seconds kind of thing. We are permissive. We let people have fevers, we set thresholds at which we will do something, but we let people go right up to those threshold to try and avoid doing things that might make their cytokine release syndrome better, but might actually impact the efficacy of the treatment.

For example, we wouldn’t want to be giving high dose steroids to a patient who has just gotten the T cell therapy because we’re going to essentially impair therapy’s ability to do its job. So having protocols in place, clearly define how high of a fever and how long we’re willing to tolerate. What kind of endo organ function we’re going to accept. How long a person needs…can tolerate being Ill from neurotoxicity before we really need to get worried about permanent damage are still being fleshed out. We’re still trying to figure them out. But having standardized rules in place makes it easier to get through things like that.

Mostly what we do is supportive care. Mostly what we try and do is not get in the way of the therapy, when we know the patient will be ok on the other side of it.

Call Leader: Those thresholds, are they generally standardized amongst patients or is it very variable? For example by their age, if they have diabetes or something?

Doctor: That’s a good question. I think now the major standardization is coming from the
fact that all these therapies are being given on clinical trials. So the clinical trials
have protocols that people follow very closely.

Call Leader: Yes sorry about that I guess we’re having technical difficulties. We were talking about how we want to let people get up to their threshold and not limit the therapy. And how people have different thresholds. I think you were saying that it was a bit of an unknown because all of these are being done in a clinical trial format?

Doctor: In part. I think they are standardized by the clinical trials, but they’ve evolved as we learn more and more about what the toxicities are. In the beginning we were more aggressive in trying to combat cytokine release syndrome. And giving drugs like tocilizumab and then even steroid when we thought it was severe enough.
Now we’ve relaxed the criteria a little bit, unless people continue to have fevers in some cases for many days without any intervention, as long as we can assure ourselves the root infection doesn’t need to be addressed.

We are changing what those guidelines are, but they are still pretty standardized because these patients are being treated on uniform clinical trials.

Call Leader: OK. From the point of view of the patients, I’m sure they understand all the risks.
Are they happy to go through this process?

Doctor: Even patients that have read all the nitty gritty details are knocking down our doors to get access to these therapies. I think the people in particular who are in the trials, are in a dire situation. The toxicity hasn’t really scared anyone off as far as we know. Patients do understand what these issues are and the families understand patients might very well be in the ICU for many days after the treatment.

All this is really in the context of anti-CD19 CAR-T cell trials. We don’t really have tremendous experience with other targets in other diseases. So that may not be the norm for all CAR-T trials going forward.

Call Leader: How many specialists do you need to monitor these patients as they are going through these different toxicities?

Doctor: I think the most important person ends up being the oncologist who knows when to intervene and when not to intervene. There are a lot of support personnel that need to help get the patient through it. I think you need to have nurses who are very attuned to what’s happening. You’re really in ICU level of care.

Even in patients who don’t necessarily go to the ICU, it’s really more care than you might. At least more attention than you might need on a regular floor patient for example. You need that kind of expertise, ICU level nursing, ICU level physician, who understand how to handle pressers and other things like that.

I think there is a level of acuity that’s required, but as we’re learning more and more about toxicities. Specialists like neurologist, for example, may become less critical. In some scenarios it could be useful to have access to a neurologist if something were atypical and you really wanted to differentiate between what you thought was treatment related neurotoxicity and something else, a stroke or something different.

But for the most part the major thing you need is expertise in the person who is ordering and directing the therapy.

Call Leader: Oh ok. It sounds like you worked in the community setting in the past. A lot of community hospitals will have oncologists, they’ll have neurologists, obviously they’ll have ICU physicians and nurses. Is CAR-T therapy something that can be handled by community hospitals?

Doctor: I think it will be. It may not be now. Again for some of the same reasons that I mentioned. We’re still really learning what the toxicities are and we’re often even being a little too conservative about addressing them. I think in the future when these products become more standardized and we understand them a little bit better, there certainly will be scenarios that will be given in the community hospital setting.

The community hospital that I worked in during residency and fellowship did have a small ICU. So we did have the capacity to put central lines into patients, to put them on pressers and ventilators if need be.

So I think you need to have that level of capacity available to you in case things don’t go well. But other than that, you just need to have a level of care that would be required for treating very sick chemotherapy patients. Someone who might run into an infectious complication, someone who might run into issues with cardiac or renal problems. Have that level of expertise available to you in the hospital. That typically is available to you in a community hospital setting.

Call Leader: I’ve seen estimates that 30% of CAR-T patients require ICU admission. Do you think that number is approximately right, or too high or too low?

Doctor: I think it might be 30% that really need need an ICU admission because they’re going to receive a therapy in the ICU that can only be given there. That could be something requiring pressors or sedation or something of that nature. There probably are more patients that need very close and careful monitoring. Right now that is happening in the clinical trial unit, which is not like a typical community hospital floor.

I think if you were in a community hospital you would see more patients in an ICU level of care. That is almost entirely going to be driven by the need for closer nursing and monitoring. Not necessarily because you’re going to need ICU only intervention.

Call Leader: Ok. In terms of drilling in on one specific toxicity, the severe neurotoxicity that JUNO saw in their trials. The alleged culprit is fludarabine. Have you had any experience with fludarabine and do you think that’s likely the culprit?

Doctor: I would separate a couple of the things you said there. I think the neurotoxicity is totally independent of fludarabine. There were 2 patients in the JUNO trial who received fludarabine and died as a consequence of their treatment and disease.

Fludarabine was blamed because it was the only thing they had in common and it isn’t something that’s necessarily in all regimens that people use with CAR-T cells.

But neurotoxicity can occur in the absence of that. I think that might be more of an antigen specific side effect. I don’t necessarily think that patients getting anti-mesothelioma CAR-T cell therapy or something like that are going to necessarily have CNS disease.

I think the short answer is I don’t necessarily know what the root cause of the neurotoxicity is. I don’t think it is the fludarabine, I think at least from the small number of patients that we’ve had to look at it’s possible the fludarabine complicated things, but those are separate issues.

Call Leader: Ok. Just going on to the more practical aspects of all this. Pricing. KITE had an analyst day yesterday and they seemed to imply, to justify a pricing between 300-450 thousand dollars per treatment. How would that work in your setting or a community setting? I know that a lot of times an oncology practice will have to pay for a drug first and then wait to be reimbursed. I was wondering if you could walk us through that.

Doctor: Yea, that could be a big challenge. It’s not just CAR-T cells that have that kind of challenge. I think in part they’re linking the valuation to comparing what else you might possibly do in a patient. Patients with lymphoma, think about autologous transplant. Autologous transplants is not an inexpensive procedure. It has a lot of the same upfront costs, having to collect stem cells from patients. Large cell B cells, you need a conditioning regimen, you have a prolonged hospitalization.

That’s really what they are basing their comparator plus the fact that CAR-T cells are at least in our early experience with them for B-Cell malignancies much more effective than autologous transplants might be.

So, I think that will be a limitation for some groups in terms of how to pay for them. I have a feeling that if these companies want to make these therapies accessible they’ll work with practices, hospitals, to figure out how to do that. It’s not necessarily hospitals that need to fund them. I think it will be part of the way these things roll out once they have been approved with some understanding that hospitals and insurance companies can get these things to people.

Call Leader: Just generally when you have to get reimbursement for one of these uber expensive drugs, what are the steps you generally have to go through beyond the initial request?

Doctor: For an allogeneic stem cell transplant case for example we go through a complete pre authorization process. We describe what we intend to do for the patient, what the indications are, what the alternatives are. It’s kind of a whole package that goes out to the insurance companies. In some cases they are so experienced in dealing with us that it is a pretty simple turn around. But others it takes quite some time to get full approval.

What we don’t want to do is assume that insurance companies are going to pay for it and then be on the hook as an institution or even worry about the patient being billed for what is an incredibly expensive procedure that continues to be expensive even after the procedure is done. People need follow-up and immunosuppression drugs and so on and so forth.

So really a lot of this is time to get pre-auth to do these procedures and explain what the costs are going to be. That works very well for allogeneic transplantation. I would think that would be the model for how we do things for expensive cell based therapies as well.

Call Leader: In other words the hospitals are pretty…Because they already deal with this expensive transplantation process, they understand how to reimburse and have it go through.

Doctor: For drugs too.

Call Leader: How long does it take to get that preauthorization usually?

Doctor: Like I said for some insurance companies where this has become relatively routine, it can be a day or two it can be very quick. You just explain the indications and you’re approved thousands of these for us in the past, they just go through the indications. It depends on the insurance.

Call Leader: Can you say which insurance or payors are easier and harder?

Doctor: A lot of the state payors like Medicare are pretty straight forward. They deal with this on such a large scale they really get how this works. Now they might not reimburse as well as some of the private payors. Essentially the larger insurance companies have very little difficulty where I can’t even recall a scenario where we had a patient we thought met the needs for transplantation where we were denied or had to go through an appeal process.

The larger insurance companies and the state funded insurance companies will have a pretty uniform policy on accepting or not accepting patients.

Call Leader: In terms of the basic economics of all this. If you have a CAR-T patient at your hospital would you expect it to be a profitable patient? An unprofitable patient?

Doctor: That’s going to depend on how these therapies are reimbursed. If we get into the age of capitated medicine where we’re capitating groups of people or doing diagnosis based payments. Where we are saying for a Hodgkin’s Lymphoma you get x amount of money per patient. Then I think these will be considered liabilities by hospitals.

I think that these types of therapies are the things that break the bank not the kind of things that generate income the way they might in a fee for service type proposal.

That’s not my area of expertise, I’m not sure how you deal with that, but it certainly an issue that we have as well. Right now bone marrow transplantation is quite a good money maker for a hospital that has expertise and can do that. But in a capitated system that may no longer be the case. I’m not sure where you would fall. Would it fall as a separate fee for service type payment or into the diagnosis for treating patients payment.

Call Leader: Ok. You mentioned earlier that besides the cost of therapy there is the cost of follow-up. Immunosuppressants. If you assume the cost is between 300 and 450k just for the therapy. What do you think the total cost of a patient will be?

Doctor: That’s a good question. I drew the analogy to allogeneic transplantation. I think these therapies would be actually less expensive in the long run. For an allogeneic transplantation you not only have all the work that needs to be done to get donor cells to a patients, you have that prolonged hospitalization afterwards which at least for ‘allo’ transplant can be much longer than it would be for a CAR-T cell type treatment. And then the follow-up for an allogeneic transplant is substantially more complicated. You’re dealing with issues of graft versus host disease, and infection, and secondary complications from that.

So I think that in the longrun that the two options are CAR-T or allogeneic transplant, and at the price point that you mentioned, it would actually be less expensive to go the CAR-T cell route.

Call Leader: Great. That’s extremely helpful. Going back to the CAR-T therapies themselves, the trials that we’ve seen so far have been relatively small, and there’s always a chance of when they get bigger and we get more long term data that the numbers would change. Is there a minimum complete response rate or a minimum durability length that you’re looking for in order for you to use it in a large number of your patients?

Doctor: That’s a great question. I think putting aside the fact that these are expected therapies, they’re also not easy to give and to tolerate these, assuming we’d want to get a lot of bang for buck so to speak. I think that in the patient population they’re being tried in right now, any level of response is probably good enough because these patients are pretty ill and are very unlikely to respond to anything else. Even if we had only 30% response rates, or prolongation of survival was in the order of months - that these therapies would compare as well as anything else that would be considered in clinical trials, and they would be considered favorable.

If we’re starting to move these therapies into earlier lines of treatments, we’re going to really demand that they be able to do more for patients, and then we’re looking for potentially curative outcomes. I think that we’re looking for things that other therapies specifically don’t do for us. So in CLL in particular, with allogeneic transplantation, we really don’t have curative outcomes. If someone has very advanced CLL and can get a therapy like this and can potentially be cured or have a relapse that lasts in the order of years, that would be considered great.

So I think in all-comers, we’d really love to see these therapies have a better than 50% complete response rate, and have those complete responses be durable, meaning that they last for more than 12 months. If they start to be less than that, then they’re starting to compete with therapies that are much less expensive and much easier to give, but also obviously not terribly effective.

Call Leader: Great, that’s extremely helpful. What are your thoughts on autologous vs. allogeneic CAR-T therapies, do you think allogeneic CAR-T would have an effect on the use of autologous CAR-T?

Doctor: I think that’s really going to really vary by indication and what it is that you’re intending to do. I think the advantage of being able to do something allogeneic is that you might come close to having something that is a more off the shelf product, where you can treat someone from the time that you decide that you’re going to do it, to the time that you get the cells can be extremely short. You may already have 1,000 A cells premade. Whereas with the autologous approach you have to go through the whole aphaeresis, hope you have quality cells, hope you’re able to transmute them and grow them and then get them back to the patient. And even though the turnaround time is remarkably short, it still is not short enough for some patients, at least within the current clinical trials. There certainly are patients that you would like to treat, but you don’t think they could actually wait as long as they need to to actually get the cells.

Call Leader: Well how long have you had to wait for some of these patients?

Doctor: It varies. I think that the ideal turnaround time would be as little as two weeks, but there’s all sorts of things that can get in the way with that, and sometimes the ability, especially with lymphoma patients who have had a lot of lympho depleting therapies in the first place, your ability to get enough cells can be challenging. So even though you make a decision to treat, and you ‘aphaeres’ and you may need to do it again.

Then there are all sorts of QC issues that would have to be in place. For whatever reason a QC test didn’t work or gave an indeterminate answer, then the delay might be longer, so I’m not sure what the averages are in clinical trials, but it certainly isn’t something where if I decided to today, by next week I’m giving someone cells. It’s most often in the order of 4-6 weeks at the earliest.

Call Leader: Ok, and the question that’s on a lot of people’s minds is do you see any hope for CAR-T being a therapy for solid tumors? I know that’s not your speciality, but I was just wondering what you thought about that.

Doctor: Yeah I think that what we’re going to find with the CAR-Ts is that they’re not going to be as effective as they are in B-cell malignancies in every solid tumor. That there’s going to be some solid tumors where either the bulk of the disease or the ability of the cells to penetrate the disease and affect their functions is not going to be anywhere near as effective.

But there are some diseases now for which immunotherapies are highly effective, and CAR-T cells are an extreme form of immunotherapies, and I think that maybe for those disorders, CAR-T cells are going to be extremely effective. So I have high hopes that they will be effective for things like renal cancer for which we don’t have much else, or melanoma for which we now have many options, but it’s still a very lethal disease.

And maybe even for disease like lung cancer which we typically think of much more occasionally complex and challenging to treat, it may be possible that combination of CAR-T cells and immunotherapy might be substantially more effective than either one alone. I could see a role for CAR-T cells in that type of solid tumor setting as well.

Call Leader: Ok thank you. Back to some of the liquid tumors, I was just wondering - Do you think the FDA should require overall survival data prior to approval, or do you think you’ll be happy giving the therapy just with 6, 9, or 12 month CR and durability data?

Doctor: I think that for the patients that are being treated right now, overall survival could be looked at; their overall survival isn’t that long. I think that we understand pretty well that in these patients complete response is going to be very important, so I think approval on that basis alone is probably reasonable.

I think in patients who you may bring the therapy into earlier lines - having a therapy that works transiently isn’t going to be very effective. You’re really going to need to show that these therapies have prolonged responses, so either ongoing you need surveillance, or such a profound effect upfront that a patient is truly cured, that their disease is eradicated. So I think in those studies when we move these therapies closer to front-line, we will need to see longer follow-up and either a longer progression free interval, based on the order of years, or overall survival data.

Call Leader: Great. Well thank you. I think that’s all of my questions Dr. Bejar. This has been extremely useful. Thank you for all of your insights. I hope you have a wonderful day and thank you everyone for listening.

Doctor: Alright. Thank you.

 

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