Andrew Miller, PhD, Founder and Chief Operating Officer, Karuna Therapeutics

Far more than any other type of illness, mental disorders are subject to negative judgments and stigmatization. Many patients have to cope with the often devastating effects of their condition and suffer from social exclusion and prejudices. Stigmatization of the mentally ill has a long tradition spanning thousands of years. Even the word “stigmatization” indicates negative connotations; in ancient Greece, a “stigma” was a brand to mark slaves or criminals.

Now, Karuna Therapeutics, a clinical-stage biopharma company in Boston, Massachusetts, is on a mission to set people with schizophrenia and dementia-related psychosis free. ​​Karuna has built its pipeline on the broad therapeutic potential of its lead product candidate, KarXT, an oral modulator of muscarinic receptors that are located both in the central nervous system (CNS) and various peripheral tissues.

After going public in the summer of 2019, opening at just over $20 per share, stock prices of Karuna (NASDAQ: KRTX) surged more than 230% to $85 upon announcing positive results in a phase 2 clinical trial evaluating KarXT in treating acute psychosis in schizophrenia patients. Since then, the stock has steadily increased to more than $100, peaking at $135 on June 21 this year.

We sat down with Andrew Miller, PhD, founder and chief operating officer, to talk about how the company is making headway in the notoriously challenging clinical field of psychiatric medicine.

GEN Edge: Andrew, what were Karuna’s founding mission and vision?

Andrew Miller: Our founding mission is reflected in the company name. Karuna is the Sanskrit word for compassion or action to relieve the suffering of others. When you look at the history of drug discovery and development in psychiatry, the field hasn’t moved forward in many medical areas. The biggest challenge in psychiatry is not identifying what the needs are and what the impact could be, but rather how to fill that in with breakthroughs.

From a scientific perspective, we had the serendipitous discovery of an anti-psychotic drug 69 years ago in 1952—the dopamine antagonists. Every medicine that’s approved for schizophrenia right now is an antagonist. This is an area where there’s a tremendous need and opportunity to have a medical impact. That’s the vision for the company—to introduce something that can be helpful with people in an area that has moved at a frighteningly slow pace.

GEN Edge: In this historically difficult area of treating psychotic disease, what sets Karuna apart, the product or the company?

Miller: Both! Maybe it’s more about the product and its origins, but there’s also a lot of very intentional, pragmatic ways that we’ve gone about the development efforts that have helped us to be successful. Medicine can work, but you have to do the proper study and get the data to demonstrate that those are foregone conclusions. In psychiatry, the source of original innovation for anti-psychotic drugs—and the same story holds for antidepressants—is that the discoveries have been these serendipitous in humans. The first antipsychotic drug Promazine was originally an anesthetic drug, which was discovered by accident.

That’s not so dissimilar to the story of our lead program, KarXT. It’s based on a molecule called xanomeline, developed initially as a pro-cognitive treatment for dementia by Eli Lilly. They took it into a large-scale phase II study in Alzheimer’s disease. They did see pro-cognitive benefits, but they also—entirely accidentally—observed or discovered very robust and chronic effects in that population. That clinical serendipitous finding launched efforts and interest in this field and this kind of target.

Unfortunately, we haven’t seen in schizophrenia any success in understanding the underlying biology, translating that into a therapeutic target, which we can make into a small-molecule therapeutic. There aren’t any treatments available that have followed that paradigm, which is what’s revolutionized drug discovery and development over the last 20-30 years.

But in psychiatry, we just don’t have that. The idea that this is based on an accidental discovery may not sound like the scientific method in its best form, but we’re in a position where we’re taking advantage of a lot of work and science done by the field and others. It’s that novel insight that launched the company and put us on this trajectory towards introducing the first mechanistically unique class of antipsychotic drugs.

GEN Edge: What is Karuna’s business structure?

Miller: We did have the advantage of taking one molecule, which we licensed. But like many companies, we embrace certain parts of the virtual biotech company ecosystem in places like San Diego, San Francisco, and Boston. You can operate in this ecosystem to decide whether to bring certain functions in-house or keep them outside the company. Indeed, for things like manufacturing, we do that all with partners and contract manufacturing groups.

We’ve focused on building internal scientific expertise around preclinical and clinical development and building a team of very experienced people and have a combination of knowledge and strategic insights. But a lot of the end work happens outside the walls at Karuna. For our clinical study, we have our own clinical operations and clinical development group. We do work with contract research organizations to help us execute a lot of those things.

We’ve embraced certain aspects of that virtual model, but we have an office and a senior team of leaders. We have a team of intellectually experienced people who help guide this whole process. We’re continuing to build that. Every company progressing through development has bandwidth requirements. We’ll continue to grow tremendously as we continue to develop towards being a commercial-stage company.

GEN Edge: Why did Karuna go public, and how did that affect the company?

Miller: It’s an n-of-1 experiment. There’s undoubtedly a financial aspect of that in terms of access to capital. One thing that’s a little different for us compared to many companies that have gone public over the past 2–5 years is because we were in phase II development when we accessed the public markets. It was essential for us to access different pools of capital. Quickly after going public, we’re making the transition to phase III, and we’re starting to prepare to launch a product. There is a specific scale associated with that. That’s important.

Also, as a public company, there’s an opportunity to establish ourselves as a leader in the field. There’s a certain amount of attention and conversations that you have as a public company that are difficult to have as a private company. We look at some of the lack of activity in psychiatry as a significant opportunity for us. If we’re not doing this work then who else is going to do it? We look at that as a potential leadership position to say, ‘we think we have the expertise, capabilities, and potential to build ourselves into really a leading neuroscience-focused company’ because, frankly, there aren’t many.

We feel accountable to that mission of how can we be helpful to patients. That’s why we started the company. Now, we have the opportunity to do that in two ways. First, we can directly develop KarXT and bring along a pipeline of other products to help people. We have a more significant opportunity than that by being at the forefront of hopefully a resurgence in research for fundamentally psychiatric and neuroscience conditions. There’s a reason why a lot of people aren’t doing this anymore. People tend to follow where success is, like in immuno-oncology.

Then you go back there, and you do it again. There just aren’t that many examples of success, particularly on the psychiatric drug development side. To the extent that we can be an example of what it looks like from a success perspective, we can hopefully inspire others to do the same. It feels a little bit grandiose to say that, because we’ve come like many companies from humble beginnings, but I think that’s the opportunity. If CarXT can inspire someone to start the next Karuna or venture capital investors to fund that company, this space will eventually be helping patients. We’re very excited about what we’re doing directly, but if we can be a part of a resurgence in psychiatric condition research and drug development, that that’s also a way of accomplishing some of the goals we set out in starting the company initially.

GEN Edge: What’s the relationship been like with patients?

Miller: One of the most interesting yet sad facts that drove my fascination with psychiatry is there’s 2.7 million (give or take) Americans living with schizophrenia. That’s a considerable number. When I was becoming interested in this field, I asked myself, ‘where are these people?’ If there are so many of them, where are they?

Unfortunately, it’s a very disabling illness. Many patients cannot return to full-time employment or live and engage in a life that works. They’re almost hiding in plain sight, and that was fascinating to me. There’s a history in psychiatry with a lot of stigmas. There are many negative perceptions of mental illness that are very pervasive and harmful to patients. There’s a lack of advocacy because there’s no openness about mental illness like a cancer diagnosis, for instance.

You don’t see that publicized or talked about as much in an advocacy way that you do with other indications, which are more accessible for people to get behind because they don’t have these stigmas. We must listen to what the advocacy groups in mental health are talking about and their challenges. That’s part of what we look at as some of the indirect effects that we can have. If we can be an example of innovation and success, delivering something for patients that they’ve been waiting for quite some time will bring more attention to this.

We’ve come a long way. But there’s still a long way to go to embrace and view mental health the way that we do physical health and the way that we look at treatment and what’s acceptable and what’s not.

GEN Edge: What does Karuna’s trajectory look like, and what obstacles stand in the way?

Miller: We have our eyes set on completing our active phase III program and getting the data that we need to get this product onto the market. But how do we support that? How do we put this medicine in the hands of patients? That’s what it’s been about the whole time, and we just continue to move closer and closer to that goal. It’s the transition for any company from early- to late-stage development to commercialization. I wouldn’t say there’s ever been a quiet time of no change at the company.

Hopefully, we’re sitting five years down the road as a company that’s marketing and introducing an entirely new class of antipsychotic drugs in schizophrenia and dementia-related psychosis. That will be considered a breakthrough that the field has been waiting for for a long time. We need to stay focused on our efforts with KarXT, but we think a lot can be done from a pipeline and a product perspective with KarXT. We’re committed to this field and this space. We want to continue to build a pipeline of products that hopefully look like KarXT. That doesn’t mean copycat products of KarXT—it means products with the potential impact that we think KarXT can have in improving outcomes and prognosis.

There’s so much scientific opportunity here. Hopefully, we can address a tiny part of that in schizophrenia with KarXT. But this is a field of medicine that’s going to be around forever. We hope to look back on what we’ve done as a stepping-stone and an important one. But the biggest goal here is to shed light on what these conditions are and how society can improve mental health treatment.

We play a role in developing medicines, but it’s a broader mission than that, too. That’s really at the core of who we are and who we want to be. We’ve had some successes and hopefully that will continue, but we have to keep striving towards it. We’re pretty tireless in that pursuit. We’re looking forward to future successes and overcoming the challenges that come with them.