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Maxim Jacobs
15 May 2017 · 3 min read

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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