From Academia to Pharma: Dr. Stephen Brannan’s Journey in Shaping Modern Mental Health Care

Key Topics Discussed

• Dr. Brannan’s career transition from academic neuroimaging to pharmaceutical drug development
• Development of Cobenfy (xanomeline-trospium), the first muscarinic agonist for schizophrenia
• Clinical trial design challenges: placebo response, patient selection, and maintaining study quality
• Balancing innovation with pragmatic decision-making in CNS drug development
• Future of psychiatric treatment: biomarkers, wearable technology, and neuroplastic agents

Episode Overview

Dr. Stephen Brannan brings decades of experience from both academic psychiatry and leadership roles at top pharmaceutical companies to the JCP Podcast today. He details his transition from university research to industry, offering a candid look at the forces that drive innovation in mental health care.

Dr. Brannan unpacks the complex process of bringing a new drug to market, using his work on treatments like Cobenfy (xanomeline-trospium) as a case study. The discussion covers the critical decisions in clinical trial design, from selecting the right patient populations to establishing meaningful endpoints that satisfy both regulatory bodies and clinical needs. He also addresses some of the most persistent hurdles in psychiatric research including the high placebo response rates that can obscure a drug’s true efficacy and the operational complexities of running large, multinational studies. For clinicians seeking to better understand the evidence behind new medications, Dr. Brannan’s insights provide a unique level of enlightenment in the pragmatism, science, and collaboration required to advance patient care.

The Guest

Dr. Stephen Brannan is a board-certified psychiatrist and neuroscience drug development expert who currently serves as a consultant at CNS Clinical Consulting. He has led development of numerous psychiatric and neurological treatments including Cymbalta, Trintellix, and most recently Cobenfy (xanomeline-trospium) for schizophrenia. His career spans both academic psychiatry—with research fellowships in neuroimaging—and senior roles at Eli Lilly, Takeda, and Karuna Therapeutics, bringing a unique perspective on translating neuroscience into therapeutic interventions.

Further Reading

Journal of Clinical Psychiatry: Psychiatrist.com/jcp/

Stephen Brannan in LinkedIn: https://www.linkedin.com/in/steve-brannan-b7376019/

The Host

Ben Everett, PhD, is the Senior Scientific Director for The Journal of Clinical Psychiatry and Psychiatrist.com, where he oversees editorial strategy, content development, and multimedia education initiatives. He is the creator and host of The JCP Podcast, a series that brings together leading voices in psychiatry to explore the latest research and its clinical implications. Dr. Everett earned his PhD in Biochemistry with an emphasis in Neuroscience from the University of Tennessee Health Science Center. Over a two-decade career spanning academia, publishing, and the pharmaceutical industry, he has helped launch more than a dozen new treatments across psychiatry, neurology, and cardiometabolic medicine. His current work focuses on translating complex scientific advances into accessible, evidence-based insights that inform clinical practice and foster meaningful dialogue among mental health professionals.

Full Episode Transcript

This transcript has been auto-generated and may contain errors. Please refer to the original recording for full accuracy.

00:00 – Introducing Dr. Stephen Brannan

Dr Ben Everett (0:07 – 1:56)

Welcome to the JCP podcast, where we explore the science and stories shaping mental health care today. I’m your host, Dr. Ben Everett, senior scientific director with Physicians Postgraduate Press, publisher of the Journal of Clinical Psychiatry. On this podcast, we speak with clinicians, researchers, and thought leaders advancing the field of psychiatry, with a focus on not just what’s new, but what’s meaningful for our listeners in their clinical practice.

My guest today is Dr. Stephen Brannan. He’s a board-certified psychiatrist and neuroscience drug development expert. He earned his undergraduate degree from Harvard, his medical degree from UT Southwestern, completed his residency at the University of Texas Health Science Center at San Antonio, and then pursued a research fellowship at the Audie L. Murphy VA Hospital in San Antonio. Dr. Brannan spent approximately the first decade of his career in academia before transitioning to industry. He’s since led the development of numerous treatments across psychiatry and neurology.

He currently serves as a consultant at CNS Clinical Consulting and previously held senior roles at Karuna Therapeutics, Takeda, Form Pharmaceuticals, Cyberonics, and Eli Lilly. Over the years, he’s played a central role in the development of a number of psychotropic medications including Cymbalta, Trintellix, the Exelon patch, and vagal nerve stimulation for treatment-resistant depression. And most recently, and I imagine we’ll talk about this a lot today, Cobenfy or the combination of xanomeline and trospium.

Dr. Brannan brings a rare perspective that spans both academic psychiatry and pharmaceutical drug development, and I can’t imagine a better guest to help us think through how innovations in drug development can translate to better outcomes for patients. All right, well, Dr. Brannan, let’s start with the beginning. We always like to start with just some icebreaker-type questions to kind of let people know a little bit about you.

And, you know, what initially drew you into the field of medicine?

01:56 – From Pre-Med Doubts to a Career in Psychiatry

Dr Stephen Brannan (1:57 – 2:38)

Sure, Ben, I’m not sure I was drawn into it. My father was a physician. I look a lot like him.

So when I was young, they’d all say, oh, are you going to grow up and be a doctor like your dad? To which I would say, no. Then as things progressed, I went to Harvard and took some time off and I was trying to figure out what I wanted to do with my life.

I thought about actually going into the ministry, going into law. So those are sort of two different types of things. But I actually ended up going into medicine, the combination of being really intriguing and I think the feeling that I was doing something that would be helpful in general to the world and to mankind.

So it’s a long time ago.

Dr Ben Everett (2:39 – 2:52)

Yeah, that altruistic streak, I think that gets a lot of people. And then, you know, so in med school, at some point in time, you had to think, all right, I’m going to do a residency in psychiatry. What was it about psychiatry or mental health that you found intriguing?

Dr Stephen Brannan (2:52 – 4:07)

That actually came pretty late. I can remember going to third year medical school toward the end and they say, hey, you need to start thinking about residencies and applying. And I raised my hand and I said, what if you’re not quite sure what you want to do?

And the guy looked at me and said, if you’re thinking of two or three things, it’s fine. I’m like, oh, shit, I’m thinking of eight. I’m really in a bad spot.

So pretty typical for me, but I sort of went through a strengths, work, weaknesses analysis with myself and also my roommate, who’s also a third year medical student, and started thinking about things. And one of the things was I could, plenty of smart people in medical school, but I could tolerate ambiguity better than most. And that’s extremely useful in psychiatry because it’s rare when you first see somebody or a case first comes up, you absolutely know what’s going on.

It usually takes time and patience and a tolerance for ambiguity. So, okay, they’re psychotic. Are they bipolar?

Are they, you know, schizophrenia or is it a delirium? So that was a big part of it. I also remember the last three things were radiology, neurology and psychiatry.

And then I ended up doing a neuroimaging fellowship. So I found a way to combine all three in a way. But psychiatry is where I went.

Dr Ben Everett (4:08 – 4:19)

Excellent. And then you decided to do a research fellowship at the VA there in San Antonio. And that was a three-year fellowship.

You know, a lot of people just do one year, but you stuck with it for three years.

Dr Stephen Brannan (4:20 – 5:19)

Well, the funding was for two or three years, so one year wasn’t the option. But one of the things that really intrigued me about psychiatry is we knew so little about the brain. In fact, when I was a senior resident, this newfangled thing called Prozac came out.

So it was just sort of the beginning of, you know, major psychopharmacology. And we still had a lot of analysts around kind of analyzing things. But I was attracted really to the science part of it.

Neuroimaging was starting out and that fellowship was really aimed at neuroimaging. And San Antonio, where I was at the UT Health Science Center, was getting an imaging center with scanners. And so that’s what I decided to do.

And it turned out to be very useful. It sort of oriented me to thinking about the brain in ways that many of my colleagues did not. I’ve even said later in my career, really more in pharma.

But, you know, if this disorder has a circuit related to it and you can tell me what it is, I have a half a chance of understanding what’s going on.

Dr Ben Everett (5:19 – 5:36)

So, yeah, it’s interesting how the neural circuits certainly really comes way in more and into play, you know, from it seems like historically there was a period where everything was sort of like a post-receptor defect. Okay, it’s a dopamine issue or it’s a serotonin issue. And of course, it’s much more complicated than that, right?

Dr Stephen Brannan (5:36 – 6:18)

It’s much more complicated. I was working with somebody named Helen Mayberg on imaging depression, and everybody knew at the time, quote unquote, that it was in the left front part of the brain. And we had this radical idea that the brain was made of circuits.

And we got a lot of criticism for it. But, of course, now that’s the standard theory of the brain and what was going on. And it was really interesting to sort of explore that area and see it sort of led to other developments, like I was involved with the vagal nerve stimulator.

So this is neurostimulation. You can stimulate the circuit or inhibit the circulate in various parts of the pathway and show effects. And so it’s funny how all this sort of gets combined and then used later on.

Dr Ben Everett (6:18 – 6:30)

Yeah, certainly. So when you finished up your fellowship, you know, what were you thinking then? Did you stay in a research track?

You do clinic, you know, or looking for one of those combination jobs that you can kind of do both.

Dr Stephen Brannan (6:30 – 6:51)

Well, I stayed at the Health Science Center because I was really interested in the research. Most of it, you know, based on their imaging. The other thing is we had people like Charles Bowden there who worked a lot with Depakote and Bipolar.

So thinking about medications and treatment and a strong psychiatric research was part of the department. So I naturally sort of fell into that.

06:51 – The “Push and Pull” from Academia to Industry

Dr Ben Everett (6:51 – 7:01)

Yeah, nice. So you spent, you know, about a decade in academia before you decided to move into industry. What was your motivation there for moving?

Dr Stephen Brannan (7:02 – 8:07)

Yeah, these things I always say there’s a push and a pull. Early in my career, I got exposed to some of the industry, both through the SSRIs. In fact, because I was doing the scanning of depression, I had these, quote, pretty pictures, quote, unquote.

They loved having me come and speak and show the pictures of the brain and whatnot. So I did a lot of talking for as one SSRI after the other sort of came out. And then I also was working on some studies through a research unit that I ran for a couple of years there that were involved with industry.

So that gave me some exposure and some idea about what was going on. The push really came, you know, maybe a time similar to today that we sort of lost a generation of researchers. Federal funding sort of decreased dramatically, and people were sort of trying to figure out whether they could hang in there or not.

And I wanted to continue to do research. And one of the things I thought was, well, maybe industry would be a way to do it. And then Eli Lilly came and, as I say, made me an offer I couldn’t refuse.

So I went to work on duloxetine.

Dr Ben Everett (8:08 – 8:24)

Yeah, I think that story is not too unsimilar from a lot of people who start in academia and then transition into industry. You know, were there any aspects of clinical care that you missed or, you know, you were like, oh, boy, it’s kind of hard to leave my patients? I hear that from people all the time.

Dr Stephen Brannan (8:24 – 8:50)

Yeah, I was worried about that. And Lilly would let you have half a day to see patients. But I mentioned I was involved with neuroimaging, and there was a project that I was involved in at Lilly.

And so I decided to use that. I didn’t miss it as much as I thought I might. My standard joke about it is I still got to talk to the upper echelon in the companies, and there’s plenty of psychopathology.

So I didn’t miss it that much.

08:50 – Advice for Young Psychiatrists Considering Industry

Dr Ben Everett (8:50 – 9:07)

I can relate. All right. So any advice to an aspiring young psychiatrist or neuroscientist who is currently in academia and is, like you say, funding concerns these days?

There might be other things that push-pull for them. Any advice that you would give to young and upcoming people?

Dr Stephen Brannan (9:08 – 10:20)

Well, and I’ve had the chance over the years to talk to a number of people, even some of my friends that I preceded, and then they ended up getting into industry as well. I think you need to do it for the right reasons. One of the things at Lilly at the time was huge, and they would bring six of us in in a year.

I bet half of who would not make it. And the ones who wouldn’t make it would sort of be the, I am the doctor, the captain of the ship. What I say goes.

In addition to running the research unit, I’d also been on the consulting, psych consulting division. So you’re going and talking to people like surgeons. It’s their patient, but they might have something psychiatric going on, and you’re sort of consulting.

So you don’t walk into the surgeon and say, listen here, bud, you do this. That doesn’t work very well. So, you know, I’d learned how to talk with people rather than just sort of barking in order, and that was very useful.

I think being on the imaging teams also helped. Industry is a little more, a little more team oriented than academic sometimes is. And so I didn’t make the same mistakes when I first got to industry that some people did.

And, and so I was working through the team and, you know, convincing the team, et cetera. And so that, that led to a lot more success.

Dr Ben Everett (10:21 – 10:27)

Yeah. It sounds like you’re, you, you kind of, uh, are more of a consensus builder than, uh, my way is the highway.

Dr Stephen Brannan (10:27 – 10:37)

Yeah. Collaboration. And I talk about the win-win, you know, you, you look for the win-win, you know, it’s not I win all. I get in the current day that maybe that’s a bit out of fashion, but.

Dr Ben Everett (10:37 – 10:44)

It’s a leadership style that served me well through the years looking for that and trying to, yeah. And build consensus and whatnot. So.

Dr Stephen Brannan (10:44 – 10:56)

Well, and especially this field is it’s a, it’s a small one, small world. So you’re going to see people again. So, you know, don’t, don’t piss on them.

Don’t piss them off. Try to do what you can.

10:56 – Pitfalls and Misconceptions of Pharmaceutical Work

Dr Ben Everett (10:56 – 11:05)

Yeah. All right. So how about, you know, pitfalls or misconceptions you had to, to learn or unlearn as you move from academia into, into industry?

Dr Stephen Brannan (11:05 – 13:50)

Well, it was interesting. You know, all my friends said, oh, you’re going to the dark side. And I remember talking to a couple of them at the society of biological psychiatry meeting.

I’m like, well, you know, there’s dark sides to academics too. And they all stopped and said, yeah, you’re right. One of the things, uh, very quickly I learned was it’s not a monolithic thing.

So people who are unfamiliar with it will think, oh, pharma, actually pharma and biotech are very different, but you know, it’s all one big thing and they’re all doing this and it’s not, it’s, uh, you have all sorts of different groups that are working together in these things. And so the commercial side is very different from the scientific side, which can be different from the statistical side, also different from HR, also different from quality and everybody’s sort of, and here again is where consensus is helpful because there is a tendency just in general for people, humanity, you know, they, they think of their own thing, but no one else. And so the ability to sort of see that and think about it and talk in such a way that they can understand it is helpful.

I think the other thing I sort of talked about going to Lilly’s like walking through the looking glass. So I’d been involved in some of these trials before, but I had never quite understood why they did certain things. And while I was at Lilly, I’d be like, oh my God, oh, that’s why people were doing this, that, the other.

And so it was a great learning experience. The other thing was it’s very highly regulated in ways that academics is not. And so a lot of my, yeah, when I first started interviewing, I think it might’ve been with Pfizer, but, you know, I went to the interviews and I came back and I said, how was it?

I’m like, well, they were nice people and they didn’t steal candy from babies, you know, because that was the thought I had is, you know, these are sort of mean, evil people and they steal candy from babies, not at all. So I think that’s part of it. There’s also certain practicality.

So I was working with Duloxetine and one of the things they had done is actually compare it against Prozac, which was a antidepressant that they had and also actually against Paroxetine. No one had ever done that before approval because it’s sort of taking a risk and they had done it. And, you know, so this data got presented to a bunch of doctors and we thought, oh, they’re going to like this because there’s an actual comparison.

They’re like, well, where are the other comparisons? I’m like, what do you mean? Which comparisons are you talking about?

Well, all drugs against all doses. And, you know, we’re just like, there’s not enough people in the world to run a trial like that. So I think there are pragmatic, practical things that oftentimes people miss because they just don’t understand some of the ins and outs and how regulated things are.

So you can’t just decide to do something, you have to go through a whole process. But maybe I’ll stop there.

Dr Ben Everett (13:51 – 14:37)

No, exactly. Yeah. So, you know, I’ve found that there is this disconnect and I think it’s especially true in mental health, but I’ve worked in multiple therapeutic areas and seen the same thing where, you know, there’s validated endpoints that, you know, the regulatory agencies want to see that might not be used in the clinic or might be used sparingly in the clinic.

You know, for example, in schizophrenia, you know, we use PANSS as the kind of gold standard, but it’s not necessarily used, you know, clinically that much. DSM is, they love the structured clinical interview and, you know, it’s all in your note and that sort of thing. And so it might not be used routinely in clinical practice, I guess is what I’m getting at.

But to what extent do you, you know, do you find balancing these types of issues, you know, this real world applicability versus regulatory realities when thinking through clinical development?

14:37 – Balancing Real-World Applicability and Regulatory Realities

Dr Stephen Brannan (14:37 – 15:45)

Yeah, well, once you get into the hang of it, then it becomes easier and easier. But I think that’s a transition that’s really tough. And then the other thing people don’t understand much is the placebo effect, which is also part of this.

So, you know, why do you have to run against placebo, you know, and there is so much variability in human behavior and the interventions that we have are of limited strength for the most part. And it makes sense. If he had something that really blasts the brain, it’s not good for the brain, you know.

So most of these are relatively subtle. They work through nuance that can be very powerful. But this is the other thing people think, you know, you can completely change a person’s thinking by giving him a pill.

And no, we’re more resilient and more complicated than that by a great deal. Anyway, so all the things that you have to think about to overcome variants to see the signals that we do. And to the flip side, you mentioned a little bit earlier, safety tolerability is a key, key thing in development of these drugs.

And that actually kills more drugs than probably anything else.

Dr Ben Everett (15:45 – 16:00)

Yeah. I’ve worked on several programs where, you know, phase one, phase two look great and you get to phase three and you’re a larger, you know, in and then all of a sudden you see a liver signal or something else. And it’s just not, you know, you’ve just got to get out of scrap the program at that point.

Dr Stephen Brannan (16:00 – 17:05)

Well, and one of the things that happens along those lines is those early phases are relatively small numbers. And again, and we do all this animal work. People also understand that.

Oh, why can’t you do that on a computer? Because the computers don’t, can’t figure this out. You know, you have to use a living mammalian system and anything that’s really directly harmful we want to avoid.

And then when you give it to people, you only give one person one dose, you know, and wait and see if there’s any funny thing that if their hair turns green or their teeth fall out or something like that. Of course, I’m joking there. That doesn’t happen.

But you want to be exceedingly cautious in the early stages. But there’s things that don’t happen except one out of a hundred or one out of a thousand. And most people don’t understand probability quite well enough.

And so you don’t see some of these things until later in the program, as you’re saying in phase two or phase three. A good example would be, you know, the COVID vaccines. They’re relatively safe.

They do have side effects, but, you know, some of the side effects they did not see until they had vaccinated, you know, several hundred thousand, even a million people. So,

Dr Ben Everett (17:06 – 17:15)

Yeah, absolutely. I can tell you that was like for me, it was just like a touch of, you know, injection site pain. My wife, like she spent, you know, two days on the couch, like pretty much like she had COVID.

Dr Stephen Brannan (17:15 – 17:15)

Yeah.

Dr Ben Everett (17:15 – 18:21)

And, and there is that, um, that spectrum that we see really with all medicines, you know, every, everybody’s going to react differently. So, yeah, yeah. And that can be difficult sometimes in trying to interpret clinical results from these phase three studies, because, you know, the clinician is treating the patient in front of them.

They’re not, okay, well, this was the average or the mean or the median, you know, result, but, you know, what are you actually going to see in clinical practice?

You’ve worked on a number of, you know, first in class or highly innovative treatments, you know, when you’re developing something new, like, let’s just say Cobenfy, you know, how do you balance this okay,

this is new. People are so excited. It’s going to be this great innovation and schizophrenia management versus going back to, you know, the regulatory side of it.

Okay. Well, you know, the FDA, the European union, you know, they’re still going to want to see these like PANSS scores and, you know, how do you go through thinking, okay, well, this is going to be our primary endpoint and then, you know, secondary endpoints and this pre-specified hierarchical analysis, which people don’t often understand, things like that. So again, it’s just back to this balance of, you know, regulatory realities versus, you know, clinical expectations.

Dr Stephen Brannan (18:21 – 20:40)

Well, and I think you’re capturing what true drug development is. It’s not treating patients. It was just talking to somebody this week, Andy Cutler, who’d been at a site for a while, and he used to talk to his patients and when he’d come in, he says, your job is not to get well, your job is to get well if you’re on the drug, but sometimes it doesn’t work for you.

And if you’re on placebo, you shouldn’t be getting well. So, you know, it’s a little bit different that way. And I think you’re also coming into this area that part of what people like me, what we will do is sort of look at the stuff and say, well, this looks like it’s working on psychosis.

You know, what where in psychosis is a disorder or something that would, you know, help a lot of people that we could easily access and so on and so forth. Oh, schizophrenia would be one. Bipolar, yeah, maybe, maybe not, but okay, let’s start with schizophrenia.

And you want to use things that the regulatory bodies like the FDA will be familiar with. So it’s not really good most of the time to come with a completely new, different way of looking at things. So you can add them in, but your primary would need to be something that’s established, that’s been verified, that people know what it does in general.

And in fact, when we were looking at Cobenfy, the preclinical data is more full of actually pro-cognitive benefit than it is of antipsychotic benefit. And so when the company had already started this, but when I got there, I heard it and I completely agreed, you know, do you go after cognition or do you go after psychosis? And psychosis was a path that was pretty clear in the regulatory landscape.

Cognition is still not. And then the other thing is cost and time. And I don’t know if you can see my hands here, but if I put them pretty close together, this is how much it is for psychosis.

And then if I extend it out a great deal, this is how much time and money it takes to do cognition. So for a small company in biotech, it was pretty clear that the psychosis path was the better one to go. And then you sometimes have a choice of different things, like in mood disorders, you can do the MADRS, you can do the Ham-D, you can do the .

There’s all sorts of different things that you do. And depending on what the drug is and its mechanism, you might choose one over another aspect.

20:40 – The Science and Strategy Behind Cobenfy

Dr Ben Everett (20:40 – 21:31)

Yeah, really good stuff there. And I kind of dive into this, you know, the action of Cobenfy, the muscarinic agonist, and it’s a combination. It activates both M1 and M4, which is a little bit different than some of the other ones in development right now.

But just if we take a step back and we just kind of look at schizophrenia and, you know, remains a huge unmet need. So we have, you know, first and second, mostly second generation antipsychotics are what you use now. And they seem to do pretty well for positive symptoms.

But really what drives the disability and the morbidity and, frankly, mortality, it really is the negative symptoms and the cognitive impairment. They’ve been much harder to get at. And just recently, like in the past two years, you know, there’s Emraclidine that was a positive M4 allosteric modulator.

It didn’t hit. Pimavanserin, which is a serotonin 2A inverse agonist, it didn’t hit.

Dr Stephen Brannan (21:32)

The TAR1.

Dr Ben Everett (21:33 – 22:109

Yeah, TAR1, that didn’t hit. And then in Iclepertin , the GlyT1 also didn’t hit. And for at least three of the four, I still hadn’t seen data on Iclepertin, but it was all this placebo effect problem where the active comparator performed about how it had or pretty much how it had in phase one, phase two really is really where you’re looking at it.

You’re seeing somewhere around an 18, 20 point drop from baseline in PA and SS. But for whatever reason, and I think a lot of it is just it’s hope because these patients have been suffering for so long. But, you know, any ideas about placebo?

I know we don’t have a whole semester to talk about this.

22:10 – Understanding and Mitigating the Placebo Effect

Dr Stephen Brannan (22:10 – 24:48)

Oh, I could talk all week long. And let me go back. Actually, the very first study I ran that was mine, you know, I was responsible for it at Lilly was duloxetine. It actually failed. I basically took something that had worked before, and I thought I copied everything exactly and was doing the same thing.

And for what passed for blinded data analytics at the time we were looking at stuff, and there’s this huge difference between baseline and endpoint. And I looked at that and I knew the typical antidepressant kind of change between baseline and endpoint. I was like, oh, my God, this is for sure this is going to work because the only thing that could stop it would be a huge placebo response.

Famous last words. And we had that. The trial barely missed, but it doesn’t matter.

It’s like except for hand grenades and horseshoes. You miss, you miss. And I went back and looked at that, and it turned out there was one thing that I had not copied, which is the people had to have one prior episode of depression.

And about 30% of my trial had people with one, their first episode, and they were the ones with the huge placebo response. Now, we may never quite figure out why, but one of the things that happens in the field of psychiatry is our, we call them soft endpoints, but our diagnoses are soft, too. So you can’t take an x-ray or a blood test and say, does this person have depression?

And a lot of people with a first episode, it may be what we used to call adjustment disorder with depressed mood. You know, something happened, they get depressed, and it can look very much the same. But people with just tincture of time will get better.

And so that’s, I think, where you see oftentimes in the mood disorder trials. And in schizophrenia and other things, it’s harder to give face valid answers to why there’s placebo. One of the things that does happen, unfortunately, over the past 15, 20 years, there’s been an increase of what we call duplicate patients.

They basically don’t have the disease. They may be complete frauds, or they may have some disease. But, you know, you see some of these, and one week they’re in a schizophrenia trial, one week they’re in a bipolar trial, one week they’re in an Alzheimer’s trial.

They don’t have all three. So I do think that this becomes really important. And I would not run a trial anymore these days in the United States without one of these so-called duplicate patient vendors.

So it’s pretty easy to find somebody to, they don’t completely eliminate it, but they’ll decrease the numbers coming into your study. So, you know, those are just a few of the things I think that can really have an impact that you need to think about.

Dr Ben Everett (24:48 – 25:14)

Yeah, what I’ll call a professional study subject. Yeah, that’s gotten to be a much bigger issue, again, especially in mental health for whatever reason. And I think the lack of biomarkers is another thing that, you know, it’s a lot easier to do a cholesterol management drug because it’s like, all right, we’re going to look at LDL cholesterol.

Okay, it’s going to go up. It’s going to go down. It’s going to not do anything.

Or say a diabetes trial with hemoglobin A1c.

Dr Ben Everett (25:15)

Absolutely.

Dr Stephen Brannan (25:16 – 25:17)

It’s hard to fake.

Dr Ben Everett (25:16 – 25:44)

Yeah, and, you know, blood pressure in millimeters mercury, you know, there’s things that are very validated and it also, you know, it’s very helpful in aiding clinical management, clinical care. Okay, your LDL is still not to target. You’ve already had a heart attack.

We want it less than 70 or whatever it is, you know, and okay, we’re going to be more aggressive, but it’s, we don’t have that ability in mental health because it’s a lot of it’s just structured clinical interview and how’s the patient today and that type of thing.

Dr Stephen Brannan (25:44 – 26:43)

Yeah. One of the things you were talking about earlier, and I think the last time I was on a podcast like this, we talk about that the industry is full of people who want things to go faster and I have nothing against going fast, but when I’m in front of a brick wall, I don’t accelerate my car and the bane of some of the ones you mentioned, some of the other new mechanisms in schizophrenia, some of their trials fail because they started going too fast. And you start pushing people when there’s not a good diagnostic scheme, there’s no like x-ray or blood test, they’ll find patients for you, but they won’t be the right patients. And that’s a lot of what happens.

And part of the success, I think with Cobenfy as I’ve learned over time is I’ve learned not to do that. And I, you know, they can fire me if they want, but I’m not going to, not that I won’t, adjust to step, but I will not sacrifice quality for the sake of speed.

Dr Ben Everett (26:43 – 27:14)

I think that’s a huge clinical pearl and really some sage wisdom right there is a lot of times that, yeah, you want to be first to market because that has some first mover advantage and the investors like that sort of stuff, you know, but yeah, it comes with a lot of risk. And a lot of times you’re only getting one bite of the apple because this clinical development is so expensive. And I think sometimes people don’t realize just how expensive doing these large multinational trials, you know, it costs, you know, tens of millions, if not hundreds of millions of dollars to do some of these studies.

Dr Stephen Brannan (27:15 – 27:37)

You know, and something maybe your clinicians might even be able to relate to, like if they’ve got 10 minutes to see a new patient and figure out what they have or 30 minutes to see six patients, you’re just not going to do as good a job. And we all know that, but, you know, there’s times you might have to adjust, but for the most part, most of us physicians will try not to do that or try and move so fast that you’re not doing a good job.

Dr Ben Everett (27:38 – 28:11)

Yeah, I think that’s really true. And I think another thing that got a couple of those, especially the ones that were maybe different was, you know, they’re going instead of just going for, you know, schizophrenia positive symptoms first, they’re looking at, okay, we’re just going to target cognitive impairment or negative symptoms as an adjunct to your typical, and that’s never been done before. So it’s, you know, you’re hacking through the jungle and trying to find a pathway that nobody’s done before.

And that can be, you know, it’s hard to learn from mistakes when there’s no mistakes to learn from. So maybe it’s helpful for the people down the road.

Dr Stephen Brannan (28:11 – 28:20)

No, I think you’re right on target. I think I mentioned a little bit earlier, one of the reasons Karuna chose to go the path it did is because it was one that was fairly well known.

Dr Ben Everett (28:20 – 28:55

I agree with that. It seems the better bet for me because it’s still new and it’s still a new option for patients that maybe they have unresolved positive symptoms on an atypical or whatever it is that, you know, that’s working for them or not working. And maybe, okay, we’re going to add Cobenfy because it seems to have, you know, some good cognitive impact, you know, or whatever else it is.

And then you can always do, you know, phase four, other registration trials to try and get additional indications. But you’ve got a little bit of safety knowing your drug’s on the market. It has the ability to, you know, impact patients, at least with the data we have right now.

Dr Stephen Brannan (28:56)

Yep. I think you’re absolutely right. Yeah.

28:57 – The Role of Expert Steering Committees

Dr Ben Everett (28:57 – 28:55)

Well, you know, kind of talking about this collaboration between industry and academia, you know, these large trials, they always have an executive steering committee that is made up almost entirely of academic experts in an area. And you see the same papers on these papers. And there’s a reason for that, right?

Because these people are the cream of the crop for doing these types of clinical studies. Can you speak to just, you know, executive steering committee and the role that has, I think that might be something that a lot of clinicians just are aware of.

Dr Stephen Brannan (29:27 – 32:12)

Well, particularly if you’re doing something new, you’re wanting to get as many people there who know or might know about, you know, this mechanism or especially the disease or diseases that you’re involved in. So it is very common. We did not have an executive committee, but we did have a scientific advisory board.

And actually, the head of the board was Alan Breier, who had previously worked at Lilly with Steve Paul and had worked with me and had worked with xanomeline actually 20 years ago. So it was a really nice fit. And he was both an academic, but he had been at Lilly, as I mentioned.

So he was able to kind of cross over on some of these things. There are people, I think, I remember back at the ACNP, Steve Paul, we were talking to the academics, just like, oh, they have really good ideas for phase three. And I was like, maybe, but wait for dinner tonight.

I got a couple of people in. There’s people who are really more expert in drug development. And so, you know, I had a number of these people at that dinner.

And after the dinner, to his credit, he came up to me and says, oh, I think, no, this is the crew that we want. You know, and you really need both. You need to understand the science as best you can.

You need to understand what the field is thinking and where it’s going. There are aspects to Cobenfy that, as we’ve sort of been mentioning, may mean that it could be effective for negative symptoms, may mean that it’s good for cognitive symptoms. That’s not been proven from the regulatory standpoint, but, you know, there’s certainly evidence of that.

We’ve written papers on it. And that’s where you really want to, you know, talk to some of these experts like Phil Harvey and Richard Keefe and Cognition and Steve Marder and negative symptoms and other people. So, and you also want to be able to talk to people who will tell you what’s wrong with your thinking.

One of the mistakes I think happens sometimes in industry is the industry wants to tell the experts what to think, which is not a good idea, by the way. Or, and I found this too, the very first good idea that pops up, then the whole room just it’s sort of like, you know, group think or whatever. And most of these people are well-known, so people don’t want to directly, you know, argue with them.

But I’ve learned over the years to say, okay, well, that is an idea. What’s wrong with this idea? How about some of the rest of you?

You know, what are the limitations and what other ideas do we need to think of? So, but if you can get there and you can get them to be relatively honest with you and you have to say, look, it’s not going to hurt my feelings. Tell me the warts, tell me the things that I need to watch out for.

So, you know, if they can warn you about something before it happens, let’s say an adverse event that you want to know about that ahead of time.

Dr Ben Everett (32:13 – 32:31)

Yeah, I’ve seen that same thing over and over again in industry where it’s like, oh, we’re going to do an advisory board, but we’re only inviting, you know, essentially all the people who are really big on this, you know, hypothesis. Like, yeah, you really need at least one or two people who will kick the tires a little bit and challenge you.

Dr Stephen Brannan (32:31 – 32:32)

Yeah. A few skeptics.

32:38 – Designing Trials

Dr Ben Everett (32:33 – 33:20)

You don’t want yes men at an advisory board. You want advice. You need all the advice, not just the stuff you want to hear. So, um, you know, we talked through this a little bit with Cobenfy, but maybe I’m going to ask it a little bit different way.

You know, I think in, in, in designing clinical development programs, there’s often a trade off in ensuring, you know, a broad indication that can potentially help as many patients as possible. But you also want to make sure you get signal detection as best you can. So you’re trying to test a certain hypothesis.

You obviously believe in the hypothesis, otherwise you wouldn’t do the study. But, you know, you’ve, you’ve got to figure out this, this sweet spot between, you know, you want to trial that hits, but at the same time, you’re, you’re trying to, you know, to be as impactful for as many patients as possible. So there’s this sort of trade off. Any words of wisdom for how you’ve navigated that?

Dr Stephen Brannan (33:21 – 35:09)

Yeah. And one thing that’s not quite what you were saying, but, but sometimes people make their studies too complicated. Don’t do that.

Answer one question at a time or maybe two. When I first joined industry, there was some, Lilly, there’s a commercial guy that I learned this from, of all people, but we were talking about Duloxetine as an antidepressant and some of the commercial people, not him were like, Oh, we, we want everybody to be able to use this. It’s like, no, that’s crazy.

You know, not everybody’s going to use this. It’s not going to be good for everybody. Nothing is.

So what is the right patient for this drug? And you hear people talk more about this now that was like two and a half decades ago, but and he would say, you want your beachhead and your beachhead is where what’s the best segment of patients. And for Duloxetine, we were talking about patients with depression, but who had pain.

We had to say it as physical symptoms. Otherwise pain sort of drew people in a another way that we didn’t mean. But that was the right thing.

And it established a beachhead of patients that it really worked for. And then people can experiment and go outwards. The other thing is no one ever comes close to a hundred percent of the market in something like depression.

It’s just huge. And it’s very heterogeneous too, which is another reason why you have to think not everybody’s going to do this. Schizophrenia is also heterogeneous.

And so not everybody is going to benefit from Cobenfy. And I’m sorry for that. I think a lot of people apparently do benefit from it, but it doesn’t mean it’s right for everybody.

So again, for those clinicians, those really good clinicians out there, it’s a good tool, but it is a tool and it may not be the right tool for that particular time in that patient.

Dr Ben Everett (35:11 – 35:22)

Yeah, very well said. What about inclusion exclusion criteria? Because I think that does kind of get to, okay, we understand this phenotype, but a lot of times we don’t understand the phenotype.

You know, think through this.

Dr Stephen Brannan (35:22 – 36:31)

Well, and there’s some very common things you can do. And again, this is where people don’t understand. You don’t want somebody with uncontrolled diabetes or end-stage heart disease, because that adds to the variance.

So people are, you know, things are happening, but it’s not due to the drug or to the schizophrenia, it’s due to heart disease or diabetes or whatever. So you have some very typical inclusion exclusion criteria. One of the things, this isn’t quite what you asked, but I have done with the sites when we’re getting with them is I’ll tell them, I say, look, you know, no one has ever been able to capture everything in a list in the INE, that’s inclusion exclusion criteria.

So if you’re looking at somebody and something isn’t quite right, you know, and if your spidey sense says, this doesn’t feel right, this isn’t the right patient, think of me. And I don’t care what time it is. If it’s 2 a.m. in the morning, you call me, get on the phone, you call me, we’ll talk it through. And if you can get the sites to that place, you’ve got a great chance of getting the right patients in and having success if you have a successful drug, a good drug.

Dr Ben Everett (36:31 – 36:47)

Yeah, and that really gets to clinical trial conduct. And yeah, yeah, I think like, yeah, you use your, you know, lean on your contract research organization, your associate that’s there, you know, those people are there to liaise and to support you.

Dr Stephen Brannan (36:47 – 37:04)

Yeah, well, and it gets back to that collaborative mode, you know, that they don’t get up in the morning and say, how can I screw somebody today, you know, but we have different goals. But if we can collaborate and get that win-win mantra down, then it works much better for everybody,

Dr Ben Everett (37:05 – 37:42)

and we see this across all clinical trials, not just in mental health, um, you know, but the trials tend to be pretty, pretty white. And, you know, depending on, on the disease state, we understand sometimes there’s a predominant, uh, preponderance for, for female versus male at PTSD is predominantly female, for example.

Is that, you know, is there, is there a, a balance with like trying to, you know, get your, your demographics as broad as possible? Or again, you’re just trying to, you want a clean study, let’s just get to the finish line and then we can go back and try and address special populations and minority populations later.

Dr Stephen Brannan (37:42 – 40:15)

It’s a great question. And I’ll tend to be more toward the latter than the former that you were talking about. Uh, and this is based on some of my past.

I know we like to think that people are different, but we’re not that different. I don’t care what your race is, what your skin color is, male or female. Yes.

There’s differences between males and females. I have a son and a daughter. I can tell you there’s differences, but they’re, we’re all a hell of a lot more alike than we’re different.

I also work for a Japanese company and, and, you know, people within the United States think the United States may be extreme. No, the Japanese truly feel like they are different from everybody else. And actually at Lilly, I first saw this, I was doing, I was asked to consult on an imaging study with Prozac.

And so we had a ligand to, to look at the, the SERT or the serotonin receptor uptake site. And, uh, so we did a study, they were doing a study in, um, Toronto, which has a big Japanese population in the first generation, second generation population. And it turns out when you did the PET scans and you looked at the, you know, everybody in Canada who is not Japanese and, you know, the Japanese in Canada, they didn’t look any different in terms of the major stuff at the break.

I mean, so I’m not trying to, yes, there are a few differences here and there, but we are so much more alike. Now, some of these things, and actually in schizophrenia, by the way, in the United States, you’re going to see a lot more African-Americans in schizophrenia. And it’s probably for sociodemographic reasons.

Many of them will not have the same opportunities for treatment as a group, not individuals, as the group of, say, Caucasians. And for that reason, they seem, the Caucasians don’t volunteer for these trials in the same numbers that you do see in the African-American black, quantity. So, you know, so you need to look at this and you do need to look at the differences in an individual study.

You may not be able to do that. Um, we actually, one of our papers in the last year or so for Cobenfy is when you look at the whole program, then you can look at some of these individual differences, uh, even difference between males and females is hard to see. And there are some for some medications, but, but they’re hard to see until you get several hundred, maybe a thousand people that then you have a lot more, um, power to be able to, you know, to see a difference.

Dr Ben Everett (40:15 – 41:16)

Yeah. I believe you did have the, uh, and, and, and that’s very common to see those, uh, you know, analyses come out after the big phase three. But yeah, I’m pretty sure there was, a Cobenfy sex poster at ASCP, which we’re the official journal for American society of clinical psychopharmacology.

So, um, yeah, it’s near and dear to my heart. So, for the emergent program with, with Cobenfy is with many of these trials, you know, patients need to wean off of, of current psychotropic medications.

And I think, again, it’s a disconnect. I think a lot of times, you know, people, a drug will want, so I’d be like, well, you know, in these studies, they, they took them off everything. That’s just not how we practice medicine.

Okay. If you’ve got a patient who’s completely off their meds, they’re in the hospital now, that’s a little bit different, but, um, you know, how do you explain the, the need for, for this taper and the weaning off of current psychotropics in drug development?

Dr Stephen Brannan (41:16 – 42:35)

Well, and, and I’ll kind of reference some, some other programs as well. So, uh, these medicines that are used, they, they do have an impact, usually a beneficial impact that can also have some side effects. So for instance, uh, EPS is, uh, very common with first generation and not as common with second, but, but with Cobenfy, you have probably none, the, the TAAR1, Ulotaront, probably none.

Um, and so when you have this overlap or whatnot, you, you’ll have some side effects and you can’t tell in the purposes of the trial, whether it’s due to the previous, uh, antipsychotic or to the Cobenfy. And, and so you, you’re trying to parse things out. It’s a little artificial, but you’re trying to make the comparison as sharp as possible.

And, uh, that’s helpful because if you don’t do that, then you need to have much larger trials, uh, which exposes more people at an early stage to a new medication that may or may not be completely benign. So, uh, the ethics of it has been thought out, but I think the current way we do things is a pretty reasonable compromise to get benefit as quickly as possible, but also avoid any major missteps that could harm a group of people.

Dr Ben Everett (42:35 – 42:35)

Thanks for that.

Dr Stephen Brannan (42:36 – 42:36)

Yeah.

42:37 – The Nuances of Safety Surveillance in Clinical Trials

Dr Ben Everett (42:37 – 43:35)

Um, you know, regarding safety, we talked a little bit about safety earlier. You know, there’s, it’s another area where I find there’s just a big understanding because, you know, people are, even if they don’t really understand statistics, they see a P value of less than 0.05 and they understand that statistically significant, they can’t really define it for you maybe. But, um, you know, but, but safety, they look at like an adverse event table and they say, well, why are there no statistics here?

And I know why, I’m just curious, like, if you can kind of talk to, to safety and safety surveillance, what, what goes into, into that, you know, making sure that you’re like, okay, we really do want to know the side effects. It’s very important that we get these, you know, and be honest, um, because it’s, you know, the, the, um, adjudication as to cause happens later, because if you’re the clinician there, you know, you’re blinded to what the patient’s on too. So you’re just kind of making, or the patient had a headache, maybe drug related, I don’t know.

But anyway, you can just kind of talk to some of that.

Dr Stephen Brannan (43:36 – 46:43)

Well, and actually headaches is a good thing to maybe start with. So if you look at the old SSRI tables, you had headaches, 15 to 20% of pretty much every SSRI. And if you look at the placebo that was done at the same time, it’s also 15 to 20%.

What it means is you have a six to 12 week trial of most people in the United States or wherever it is down in the world, they’re going to have a headache sometime during that trial. So, uh, and the other thing I think without the statistics is because we generally treat this with a, what’s called an overabundance of caution. So if you see, let’s say a couple of people with LFTs, excuse me, liver function tests that, that start to go high, uh, you’re not going to wait and keep treating patients until you have a significant number.

You’re going to be really worried and cautious and look at these patients very carefully. So, so that’s one of the reasons statistics is not done and it’s not to avoid it. It’s actually because of the overabundance of caution.

And this is both from the sponsor, as well as from the regulatory side of things. There’s also things that sometimes the, interestingly enough, the sponsor may pick up before an individual PI. There’s some exceptions.

I’ll tell you a few stories on the other side where they were over-interpreting stuff, but, but, you know, they’ll say, oh, well, this is, you know, minor or whatnot, but we’re aware of some, you know, you’re in California. Somebody in Idaho had the same thing, but it was a little bit more moderate. And then somebody else in Florida may be having the same thing.

So you want your group to be watching for this stuff and to get on top of it very quickly. So if it’s real, then, then there are things. The other problem is people are trying to be helpful, but, but there’s a lot of noise in the signals.

I’m thinking back, this is when I was working on the vagal nerve stimulator. So it’s an implant, sort of like a pacemaker. And there was a site in South Florida where somebody got skin cancer.

Now, I grew up in South Texas. I’m very familiar with skin cancer. It’s really due to exposure of the sun.

And it’s hard to understand how a device of any kind could be causing skin cancer. But this person, you also have these, you know, hedge words, it’s likely, unlikely gradations of that. And this person was convinced that the device had caused skin cancer.

And I still don’t understand what they were thinking today is real doctor with an MD somewhere. So, so you, you get this kind of stuff. The other thing like Cobenfy has nausea, vomiting, and it’s very clear.

It’s a muscarinic agonist. We could have predicted it. We saw it all along and all the studies, and we even saw it in rats who rarely vomit.

But I can tell you, there’s some people in there and like the long-term safety study. And, and yeah, you see it within the first couple of weeks. And if somebody has some nausea, vomiting in month nine, almost undoubtedly, it’s not the medicine it’s, you know, flu or something happened, but, you know, people never stopped to think.

I think about that and the safety people think about them. So you’re also trying to get the wheat from the chaff, you know, where’s the signal in the midst of all this kind of crazy noise of people having headaches and having a bad hair day and all this other stuff.

Dr Ben Everett (46:44 – 47:16)

And that can be very helpful for counseling patients. Like once a patient gets, you know, once a medication gets to market, because you can say, all right, look, you know, this might cause some nausea and vomiting. Typically it’s in the first couple of weeks when we’re just getting you up to your maintenance dose from the starting dose, but it’s got this other medicine in there that’s supposed to help with that.

You know, make sure you take it on an empty stomach. There’s these things that we need to make sure that we understand so we can counsel patients to have the best outcome possible, which includes, reducing the adverse effects as much as possible. And then hopefully, you know, you get the efficacy too.

Dr Stephen Brannan (47:16 – 48:06)

A good example of this was Cobenfy and this is sort of a minor thing, but a food effect affects trospium, which is there to ameliorate the nausea, vomiting stuff. So if you, and again, after the first week or so, it probably doesn’t make too much of a difference, but in those first few days, do not take it on a, after a full breakfast, take it on an empty stomach, you know, and, and I’m not part of BMS now, but I’m hearing from some of their people that they’re seeing people, you know, sort of verifying this. It’s like, oh yeah, you know, I’ve learned to do this, especially the first couple of weeks.

And it may not be what I do with other medicines, but now I know how to do it. And that happens too, with any new medication, people in the field sort of figure out the best ways to do it. And then hopefully we’ll communicate with each other so we can all share and do it better for everyone.

Dr Ben Everett (48:06 – 49:14)

Yeah. We’re actually doing a project with BMS right now where we, we did a focus group of clinicians and there’s some of the people who have the most robust experience, you know, for a new drug. And yeah, we got them together and just ask these questions.

How are you managing this? What are you finding? What are you doing?

And we’re, we’re gonna, you know, help them get it written up and it’ll be published as an academic highlight and a journal clinical psychiatry. And I think that’s one of the things that JCP really tries to do is, is the clinical pearls.

You know, we, we’d like to publish, you know, all sorts of things, but really we’re, we’re trying to, it’s all about the clinical management of mental health and psychiatric disorders, which includes, all right, this is a new drug. I’ve never used a muscarinic modulator before. Like, how do I do it?

How does it start? You know, all those types of things. And so, yeah, we’re excited about that.

Yeah. Well, look, we’re, we’re kind of closing to an end, but, we talked a little bit about negative symptoms, cognitive impairment. I’m just wondering if you could, you know, speculate or, or talk to us a little bit about, you know, M1, M4, and why, you know, the hypothesis, what is the hypothesis behind why we think it might be good for cognitive impairment, maybe negative symptoms as well?

Dr Stephen Brannan (49:15 – 50:46)

So, and again, there’s limitations to what I’m going to say. There, there’s limitations to what we know about the brain. So M1 is purportedly more associated with cognition and M4 is purportedly associated more with antipsychotic effect.

We have speculated that the having both may be useful for both treating the psychosis, but also helping with cognitive impairment. And there’s some papers that are out. People can take a look at Phil Harvey’s part of that, I know.

So, you know, again, regulatory wise, that’s not been approved, but there’s certainly some evidence that would make one wonder if it might not be helpful. And negative symptoms, less so, but there’s also some evidence there and there’s this new stuff called ecological momentary assessment. This has been actually presented at a couple of conferences now.

As you were saying, this probably is, leads more to the impairment than the positive symptoms, but, you know, measuring things like, you know, how are you feeling now? Or who are you with? Anyone else?

What are you doing? And so these EMA things track very nicely. So you see people being with more folks over time and doing more positive activities than negative activities, just sit in front of a TV and smoking.

And even the actigraph shows that they’re moving around more. So, you know, we’re a ways off from, quote, proving anything, but I think there’s both some techniques for looking at this, as well as some evidence that there could be some benefit.

Dr Ben Everett (50:47 – 51:43)

I think that’s great. And yeah, like physical exercise, we’ve got more and more, you know, really good evidence that it really helps with everything, but especially with schizophrenia and with negative symptoms, cognitive impairment, it can be, it can be beneficial. Yeah, it’s not good for us to sit in front of the couch all day or sit in front of the TV on the couch all day.

We need to, we need to move a little bit. So, you know, in these large phase three programs are typically multinational, you know, can you talk to just how, how that’s different from doing a small phase two study at maybe three or four sites just in the United States versus now we’re dealing with multiple regulatory agencies. You also like the last drug I worked on, we had an issue with Ukraine.

We had, you know, Ukraine typically is a pretty large enroller for Eastern Europe in patients and clinical trials. That was an issue for us, you know, with dealing with that. So just to comment on, you know, multinational trials and, you know, the need, the rationale, difficulties, all those things.

Dr Stephen Brannan (51:43 – 53:26)

So it’s not a tip when you go from phase two to phase three, you’re really increasing the numbers that are needed in those studies. And the nice thing about phase two is it’s relatively few sites and relatively localized, which decreases variance. Again, you’ve heard me say that various times.

So any new country you go to, any new language you add, it’s going to increase the variance, particularly if you’re like looking at cognition, that will have a big impact. So you can’t not have an increase in variance, in my opinion, going from phase two to phase three. So you’re going to have to bite the bullet and figure out how to do that.

One of the things we tried to do is go to as few other countries as possible. The United States has a large population, it’s an English-speaking population. If you can get away with it and you’re dealing with outcome measures that are language-based, then you want to stay with English as much as you can.

So Australia, England, most of Canada, but you’re limited. And like if you’re doing Alzheimer’s trials, which are huge, you’re going to have to go multinational and you’re going to need to pay attention to where you’re going. One of the things that I find really important is and usually small companies cannot do this, but the large companies, Lilly’s, Pfizer’s, Merck’s, they have boots on the ground in every continent except Antarctica.

And you sort of want to know the sites and you want to have a collaborative dialogue with it. And so this gets much harder once you go into these large global trials. So it’s something you have to overcome.

You definitely have to think about it very carefully. And I’m a big fan of choosing, being very active in your choices and very thoughtful about them.

53:27 – Reflections on the Future of Psychiatric Treatment

Dr Ben Everett (53:26 – 53:57)

Yeah, excellent. We’ll kind of move into the close here. Maybe some reflections and some, you know, you look at your crystal ball, maybe it’s better than mine.

Maybe it isn’t. I don’t know. But, you know, where do you see sort of the, you know, lots of lots of unmet need in psychiatry and mental health?

Is there something that really jumps out at you is, all right, we’ve got new technology. We’ve got, you know, there’s some drugs in development. Is it Alzheimer’s?

Is it, you know, is it schizophrenia? Is it depression? You know, is there an area where you think we’re really on the cusp of doing something important for patients?

Dr Stephen Brannan (53:58 – 55:26)

Well, some of this is, it will be a change in regular regulatory. So there’s these new things like ecological momentary assessment and wearables. So this, I think, can really change.

It’s already changing Parkinson’s disease. So the LBD, a number of these things, it’s going to make a big difference. I think the continued advance in biomarkers is going to be helpful.

I was just at the AAIC, which is a big Alzheimer’s conference. And, you know, five years ago, you’d sort of hear amyloid, amyloid, amyloid, tau, amyloid, amyloid, amyloid. And, you know, it turns out, according to some people I was listening to just a week ago, only 20% of Alzheimer’s is, quote, pure.

You know, everything else has alpha-synuclein or TDP-43 or all these other biomarkers in there. So the better we understand that and we’re able to pick treatments based on biomarkers, I think that that’s going to make a huge impact. Certainly in the dementias, I think there’s still a huge part of schizophrenia.

We talked a little bit earlier about negative symptoms and cognition that, you know, even though there’s promise with Cobenfy, you know, those studies need to be done and it would be very helpful. And again, negative symptoms, I sort of alluded to, there’s some things that we can now do that aren’t ready for prime time just yet, but in another five, 10 years, I think will be. And so I hope that’s part of it.

Autism is still a huge area, by the way. Not a lot we really know about it and we can treat certain aspects of it, but not most of it. So how’s that?

Dr Ben Everett (55:26 – 56:11)

Yeah, it’s excellent. Thank you. Yeah, you know, you mentioned a lot of these things, you know, I think AI is certainly going to continue to play a role.

We’re looking at digital therapeutics, a lot of apps that I think can at least maybe help address, and this is all hypothesis because, you know, there’s some on the market, but I know it hasn’t been an easy path, but could potentially help address some of the access gaps where, you know, okay, well, if you live near an academic medical center, okay, yeah, you’re going to have access to great, you know, therapists, social workers, psychologists, but if you’re in a more rural area or even suburbia, you know, just trying to get there could be problematic. Getting it paid for can be problematic. So I think there’s a lot of things that we have to look forward to that can be exciting.

Dr Stephen Brannan (56:12 – 56:41)

You know, you just made me think of something I should have said, PTSD and a huge area, and we don’t have jack yet that can really be helpful. And that also brings up, you know, these so-called psychedelics, you know, I think of it more as neuroplastic agents of which a subset is psychedelics, but it’s a whole new area. I’m looking, hoping that it opens up some areas that before now we’ve really not been able to address very well.

Dr Ben Everett (56:42 – 57:50)

Well, I’m going to have some guests on to talk just about that in the not too distant future. And that was my last gig was at Lykos Therapeutics, formerly MAPS Public Benefit Corporation. We were doing the MDMA, midomafetamine for PTSD.

They could have consulted with somebody, I think, like you, but very difficult because we were doing psychotherapy along with the drug. It was a very ambitious and very difficult program. And the FDA said, all right, we, you know, we need a little bit more.

But I mean, they said the same thing to what to Otsuka just a couple of weeks ago with Brexpiprazole as an add-on to, I can’t remember which SSRI they used, Sertraline. And it was one of these things that had that one phase three study that went really well and the other one that, you know, didn’t have an effect. And it was just too muddy in the end for the advisors at the Adcom to vote positively.

So kind of back to the drawing board, but huge unmet need there for patients with PTSD. All right. So final question.

So what’s something about your work, you know, drug development process more generally that you think clinicians might not fully appreciate? Is there anything that we haven’t talked about?

Dr Stephen Brannan (57:50 – 59:07)

Yeah, I think I’m going back to one of the first things I said is how pragmatism or being practical dictates a lot of what you have to do. It’s nice to think of pie in the sky sorts of things, but, you know, even on your therapy, you know, how do you know the therapy is done more or less the same way each time? You know, it’s a big issue for not just for the regulators, but, you know, in a way I might look at is what’s the minimal amount of therapy you have to achieve that’s going to be helpful to make it a useful thing, not just a distraction.

Distraction is the wrong word. Something that doesn’t really contribute sufficiently to be part of the therapeutic armamentarium. So that’s probably, you know, it’s a little general, but it covers so many and it covers placebo.

Expectations are important. So one of the things I remember telling our PIs at the start of the phase three program, you know, half joking, and it was during the pandemic. So it was over the airwaves, but I said, if I hear any of you talking about to your staff or to the patients, how great this drug was in the phase two study, I’m going to fly out there and beat you myself with a stick.

You want to control those sorts of things in your trial. And people, I think, unless they’re in these sorts of things, don’t understand those aspects.

Dr Ben Everett (59:08 – 59:59)

I think that’s a really good point. Yeah. And that expectation bias hope is how I spent, I said earlier, I mean, I worked on a myasthenia gravis program at one point in time where, you know, these are patients that are, you know, on walkers and wheelchairs, you know, really fully denuded, you know, neuromuscular junctions.

And, you know, there was a huge placebo response, which is just like, wow, like you wouldn’t. It’s one thing to think, okay, in depression, we’re going to see it. But, you know, placebo response is a problem across really all of medicine and clinical development.

It’s not unique to psychiatry. And it’s going to, I think, continue to confound some, you know, some really good candidate drugs. But, you know, it is what it is.

The process is the process. And we have to, you know, you’ve got to have a separation from placebo to see an effect. So in parting, anything we didn’t talk about that you wanted to bring up or talk through today?

Dr Stephen Brannan (1:00:00 – 1:00:03)

No, I don’t think so. Thank you so much. It’s been good talking with you.

Dr Ben Everett (1:00:04 – 1:00:22)

Absolutely. In closing, I want to thank Dr. Brannan for joining us today. He is a consultant at CNS Clinical Consulting. If you need any help with clinical development, he’s your guy.

For joining us today on the podcast, sharing his experience and expertise in CNS research and drug development, it’s been a real pleasure having you on today. I really enjoyed our talk.

Dr Stephen Brannan (1:00:22 – 1:00:22)

You bet.

Dr Ben Everett (1:00:22 – 1:01:12)

I want to invite our listeners to tune in next time. My guest will be Dr. Margaret Sibley. She is Professor of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine and a clinical psychologist at Seattle Children’s Hospital.

Dr. Sibley has authored over 120 papers on ADHD in adolescents and adults. We’ll be exploring her recent paper that was published The Journal of Clinical Psychiatry, Characteristics and Predictors of Fluctuating ADHD and Multimodal Treatment of ADHD Study. This was actually the American Society of Clinical Psychopharmacology’s Wender Award for Paper of the Year last year.

So really excited to have Dr. Sibley on next time. This has been the JCP Podcast. Insightful, evidence-based, human-centered.

Thanks for joining us. Until next time, stay curious, stay informed, and take care.