Bill Meury, president and CEO of Karuna Therapeutics, speaks with WebMD Chief Medical Officer John Whyte, MD, about the differences in drug development in psychiatry and the importance of innovation.
This transcript has been edited for clarity.
John Whyte, MD, MPH: Bill, thanks for joining me today.
Bill Meury: Great to be here.
Whyte: I want to start off by asking you, how is drug development in the field of psychiatry different from in other fields and disease states such as oncology or cardiovascular disease?
Meury: If you think about the entire drug development process, the first place you start is in preclinical studies. The predictive value of preclinical studies in central nervous system (CNS) development is different from in other therapeutic areas. That's number one. Second, you have to deal with the blood-brain barrier, which is very different from when you're dealing with compounds that are being developed for non-CNS conditions.
The population and these conditions are very heterogeneous, and there's a lot of variability between patients if you're in oncology, hypertension, or diabetes. Last, the endpoints in CNS drug development are not physiologic endpoints; they're subjective endpoints that require physician and patient interaction. So it makes the process a little more unpredictable, whether you're in early stages or late stages of development. That being said, there have been a number of breakthrough treatments introduced over the past 20-30 years. These barriers have to be managed and understood.
Whyte: The innovation that we've seen in some other areas hasn't necessarily been matched in this area — in particular, in schizophrenia and psychosis associated with Alzheimer's. On your website, you note that your goal is "transformative medicines." I want to understand what that means. Let's take, for instance, schizophrenia, in which 30% of patients may not respond to the drug and 50% may have an inadequate response — 50%.
Meury: That's right.
Whyte: So you're saying you're going to change that; it's going to be transformative. So I have to push you.
Meury: Sure.
Whyte: What does that mean, in practical terms for listeners?
Meury: Let's talk about some transformative innovations in neuroscience over the past 30 years. Innovation, as you know, is cyclical. And it's true that in neuroscience we have not seen a lot in the past several decades. But when the atypical antipsychotics were introduced for people suffering from schizophrenia, they replaced the typicals. And they had a fundamentally different benefit-risk profile. That class of medication, which was introduced in 1993, had a profound impact on people suffering from schizophrenia. A few years later, selective serotonin reuptake inhibitors (SSRIs) were introduced and completely replaced the tricyclic antidepressants. Depression, as you know, affects millions and millions of people, and the SSRIs were better than the tricyclic antidepressants. Most recently in migraine, for example, after decades of use of drugs called the triptans, calcitonin gene-related peptide receptor (antagonists) — CGRPs — were introduced. And in 3 years, about 1 of 3 three people are receiving a CGRP instead of a triptan. That's transformational treatment. So here we are in schizophrenia, and there hasn't been a novel mechanism of action — something that wasn't a D2 antagonist, basically — in 30 years. We have a product (KarXT) that pharmacologically is treating schizophrenia very differently; it's acting on the M1/M4 receptors in the brain presynaptically, whereas the atypical antipsychotics act on the D2 receptor, antagonizing them postsynaptically. (KarXT is under review by the US Food and Drug Administration. It is not approved for therapeutic use by any regulatory authority.)
The potential benefits of KarXT are such that we could see a new class of medications in schizophrenia, just like the other classes I mentioned: the atypicals, the SSRIs, and the CGRPs. And that's how I would define innovation. Ultimately it will be measured by how many physicians, after they evaluate the data, use the product and how many patients are taking the product. But I think it could have a profound impact, just like the atypicals did back in 1993.
Whyte: I want to come back to your examples of migraine and depression, and for conditions like schizophrenia, there's still stigma associated with it. We're scared of those patients, or we don't really understand what it is. We've made amazing advances in the treatment of depression, and even the recognition of it — certainly of migraine. What role does stigma play in what you're doing here, and how are you meeting patients' needs?
Meury: What you're describing has had a profound impact just in general on mental health, but especially on schizophrenia. It is a condition that strikes people in the prime of their lives — they're in their late teens and early 20s. It can have a major impact on families, much more than, for example, depression, anxiety, or migraine. We interact with patients with schizophrenia regularly. In fact, this week, we had a patient advocacy meeting here in Boston, and I will tell you that when you're in front of people suffering from schizophrenia, it's incredibly inspiring. And it's also very humbling. They have so much courage. And there are three things they talk about: stigma, isolation, and marginalization. Patient advocacy groups like Mental Health America and National Alliance on Mental Illness, for example, are so committed to educating people all around the United States so that there's not stigma but understanding; so that there's not isolation but acceptance. It's going to take time, and it took time in depression, which people understand today. In schizophrenia, it's the same explanation, which is that there are environmental factors. But more importantly, there are potentially genetic factors. And there are biological factors; it's no different than if someone suffers from hypertension or diabetes. But because the condition can have such a profound impact on the people around them, people with schizophrenia suffer from these problems.
Whyte: Another area where there's been a lot of publicity lately is Alzheimer's disease — how do we prevent progression? How do we better diagnose it? But you're also very interested in how to address the psychosis associated with Alzheimer's disease. Why did you choose that particular space as opposed to some of these other areas that we've been hearing a lot about?
Meury: It starts with the pharmacology of KarXT, which is an M1/M4 receptor agonist. We know, from various preclinical studies of psychosis, that it has an antipsychotic effect, which means that it deals with the hallucinations and the delusions. We also know from preclinical studies that it may have a procognitive effect, which is especially relevant. In schizophrenia, today there's one class of medications approved by the FDA. In depression, there are eight. You have this condition that can have such a profound impact on people, but there's only one class of medication. So when you marry the pharmacology of the product with the unmet medical need in the market, it made sense that our first step was in schizophrenia.
Whyte: This series is about changemakers. What made you decide to say, "I'll go into the area where there's only one class of medication"? Let's be honest — other people have tried and have not had the type of transformation that you're trying to achieve.
Meury: The preclinical evidence supporting the use of an M1/M4 receptor agonist in schizophrenia was very, very compelling. The unmet medical need in schizophrenia, for the reason that you just mentioned, is very, very high; it shouldn't be the case that one of the most severe mental illnesses is served by one class of medication, especially given that the idiosyncratic response to most of these products is very, very high. It's not like an antihypertensive, where there's a 90% chance that blood pressure will drop by 10 mm Hg. Response rates in schizophrenia are 20%-30%; the rest are partial responders or nonresponders. So when we added all that up, it made sense that the first indication would be for schizophrenia. We just thought that the unmet need is so high and the scientific support for going in was too strong to pursue any other avenue.
Whyte: But others have failed and you forged ahead. Why?
Meury: First I give credit to the founder, Andrew Miller, who was the one who designed xanomeline and trospium into KarXT. We had an idea, and then we had to actually execute against this idea and run a full clinical program in schizophrenia. We ran three trials: EMERGENT-1, -2, and -3, and then two long-term safety studies. Running clinical trials is challenging. You need a very experienced team. You have to have people who have experience operating these studies. And they managed it very, very carefully. We were able to activate sites, enroll patients in the study, work with the site investigators, and make sure that we produced a high-quality dataset that would isolate the benefits and risks of KarXT. So it was about managing the program very, very effectively. Drug development is high risk. CNS drug development is even higher risk, but we did it skillfully.
Whyte: What's the future of CNS drug development? Is this a move toward precision medicine or is it modulators?
Meury: I think neuroscience is in the midst of a renaissance, and I do think we could be entering a golden age. There are probably more research trials being done right now in neuroscience than there have been for a very long time in depression and anxiety, and Alzheimer's and schizophrenia, Huntington's and ALS. What you see in the scientific literature is biomarkers being developed, imaging solutions being used, stem and cell therapy being examined. Our understanding of the brain is very different from that of the rest of the body.
Whyte: The heart's easy.
Meury: The brain understands the rest of the body but it doesn't understand itself. But our understanding of it is much greater than it was in the past; the understanding of the pathophysiology of all of these serious mental illnesses or the CNS conditions is greater. And there's more research being done. Over time, I think you'll see more and more new therapies introduced. It's just part of a normal cycle. Clearly, there's been a little bit of a dearth in innovation over the past several years, but I think we're coming out of that.
Whyte: That brings me to your corporate name, Karuna, which was intentional. I'd like you to share with the audience what that word means and how it drives the ethos of the company.
Meury: Karuna is Sanskrit. It stands for acts that diminish the suffering of others. Every company has a purpose and we all come to work for a reason. Fortunately, when you work in the biopharmaceutical industry, you're doing things that can dramatically impact society. I think the biopharma industry does that, and our number-one job — and every decision we make and every action that we take — is to benefit patients. That's why we do this and we try never to forget that. We try to stay externally focused on the people who could be using our products, whether it be a provider, a patient, or a payer, and it's in our name, which is perfect.
Whyte: How would you describe your leadership style?
Meury: Direct, open, probably energetic.
Whyte: Why are you so energetic about this area where many people have tried and failed or have been marginally beneficial to patients? You're very excited about being transformative. What is it about Bill that says, "I'm changing things. I'm changing the future of care In neuropsychiatric disease."
Meury: I've been part of eight neuroscience development programs, FDA approvals, and launches over the past 25 or 30 years, in Alzheimer's, depression, substance abuse, fibromyalgia, and anxiety, and I find it incredibly rewarding. I think the area of neuropsychiatry is underserved by medications like we've talked about. I love doing this job. I love the people in the company.
Whyte: What do you love about it?
Meury: The challenge, the teamwork. Like many people in the United States, I have people in my life that suffer from schizophrenia. So there is a personal component to this. That's part of it, but it's also just something I enjoy.
Whyte: What is it about your style that creates this enthusiasm, this energy, that's really palpable as one walks around this office and meets your colleagues, as I've had the opportunity to prior to us talking today?
Meury: When you're in a leadership position, the first thing you have to do is just care about people — truly care about people. Not fake it, but have a genuine interest in them, their career, and put them first. So when people are negative, as a leader you've got to be positive. When people are tired, you have to be energizing. When they're pessimistic, you have to be optimistic. A For some people, it's innate, it's natural, which makes it a lot easier. And for me, it's natural. I truly enjoy what I'm doing. I enjoy all the people around me. I think the biopharma industry is the best-run, most innovative industry in the world and has done more good for society than any other. I'm proud to be part of it. I love neuroscience for all the reasons that we've talked about. And I do believe that we are at sort of an inflection point. I've had a lot of experience and success working in the neuroscience field. I love the psychiatry community. And I think the prospects for Karuna are strong.
Whyte: Let's be realistic: Karuna is a small company, and you have a lot of big competitors, even here, just in the Boston area. How do you compete?
Meury: I will tell you this: We have the capabilities. And the balance sheet needed to be successful with KarXT. There's nothing that we can't do with KarXT and any future development work on KarXT, given the infrastructure that we have in place. There's this myth out there that small companies are good at drug development and large companies are good at commercialization. I don't think it matters whether you're small or whether you're big; it's a function of the skills and experience of the management team and the people that they hire, putting in a good plan and then executing it. Size of the company doesn't matter.
Whyte: If you weren't in drug development, what would you be doing?
Meury: I probably would coach or teach. I coached a Little League baseball team, my son's, in 2012, to the Little League World Series, which for those who don't know is the top of the Little League mountain.
Whyte: What was the team called?
Meury: We were from New England; it was Fairfield, Connecticut. There were 26,000 people at the first game. It was simulcast on ABC and ESPN. I loved the relationship I had with the players. They were terrific. It was probably the best 3 months because the entire Little League season lasts about 3 months; we were on the road for 30 days — 30 straight days.
Whyte: Bill, thanks for joining me today.
Meury: Thank you very much. It was a pleasure.
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Cite this: John Whyte, Bill Meury. Change Makers: Bill Meury on Transformative Medicines - Medscape - Dec 06, 2023.
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