Off the scrapheap of discarded drugs and on its way to becoming the most highly anticipated approval of 2024, Bristol Myers Squibb’s schizophrenia treatment Cobenfy (KarXT) has had an unusual odyssey and one that may serve as instructive for future drug discovery.
When the FDA signed off on Cobenfy last week, it came more than three decades after Eli Lilly developed its forerunner, xanomeline. The oral muscarinic receptor agonist was designed to slow cognitive decline in Alzheimer’s disease patients but has morphed into the first meaningful innovation in the treatment of schizophrenia in 70-some years.
Who was the catalyst who transformed a drug that sat on the shelf for more than a decade into a game changer? Boston-based Karuna Therapeutics rolled the dice on xanomeline, licensing it from Lilly in 2012.
In December of last year, BMS swooped in and bought out Karuna for $14 billion, convinced of KarXT’s ability to make a sudden impact. Cantor Fitzgerald sees Cobenfy becoming a blockbuster by 2026, while Stifel analyst Paul Matteis has projected it to achieve peak sales of $10 billion.
Unearthing the potential of xanomeline
There was never much doubt about the effectiveness of xanomeline. In a phase 2 trial of Alzheimer’s patients in the 1990s, its cognitive benefits were evident. And as a bonus from the study, Lilly stumbled upon its antipsychotic value.
“They made an accidental, serendipitous discovery,” Andrew Miller, Ph.D., the co-founder and former CEO of Karuna, said in an interview with Fierce Pharma. “They discovered these antipsychotic effects, but along with that came dose-limiting, tolerability, predominantly (gastrointestinal), issues.”
The side effects were so pronounced—with patients struggling with nausea, vomiting, diarrhea, excessive salivation and sweating—that in a phase 2 trial the dropout rate for those who received a higher dose was greater than 50%.
Because of xanomeline’s promising efficacy, Lilly and a few other companies tried to improve the side-effect profile by increasing the selectivity of muscarinic agonists but those efforts came up short.
Another factor limiting Lilly’s interest in developing xanomeline was its focus on another schizophrenia treatment in its portfolio, Zyprexa, which was approved in 2009 and became an immediate blockbuster. Three years later, Lilly’s interest in xanomeline had faded so much that Karuna acquired it for just $100,000.
By this time, Karuna had realized that xanomeline’s efficacy came from its ability to bind to muscarinic receptors in the brain while its side effects were due to activating receptors outside the brain.
“Conceptualizing the problem that way, it felt like if we could find a way to selectively activate receptors in the brain without activating them on the periphery, that felt like a solution,” Miller said. “That leads to this ah-ha moment of this concept of KarXT, where we have two drugs that have the same target but the opposite effect—one activates the target, the other blocks the activation of the receptor.”
In the search for a solution, Karuna scanned literature to identify 65 muscarinic agonists and 114 appropriate muscarinic antagonists, leaving 7,410 possible combinations of potential treatments. Since testing that number of candidates was impossible, Karuna built a predictive algorithm. Eventually, the formula spit out xanomeline paired with its pharmacologic opposite, trospium chloride.
The value of trospium chloride—a generic drug for bladder control which was originally approved by the FDA as Sanctura in 2004—is that it works outside of the central nervous system and does not enter the brain. This allows trospium to counteract some of the gastrointestinal side effects and lets xanomeline do its stuff.
The combo proved itself in a landmark phase 2 trial in 2019, which set Karuna on course to check off regulatory boxes on its way to approval.
The birth of Karuna
Karuna was spawned by PureTech, which uses a hub-and-spoke business model, acquiring promising assets—be they programs, products or platforms—and establishing subsidiaries to advance them. As an asset matures, it can draw new investment. With that comes an evolution of ownership, allowing PureTech to gain capital and the subsidiary to become more independent.
Using this model, 19-year-old PureTech, which is listed on the London Stock Exchange, has not had to raise money for the last six years, CEO Bharatt Chowrira, Ph.D., explained in an interview. Two months ago, in its quarterly report, PureTech reported (PDF) it had $500 million in cash and cash equivalents, which was up from $327 million at the start of the year.
“It’s highly capital efficient as well as a quite successful model,” Chowrira said. “And the case study for that, of course, is Karuna.”
PureTech’s platform has identified solid bets as it and its subsidiaries have achieved an 80% success rate in clinical trials, which is six times the industry average, Chowrira said.
Eric Elenko, Ph.D., who co-founded PureTech along with Daphne Zohar, explained that it was formed to do innovation in a “systematic” and “problem-solving way,” as opposed to serendipitously.
“We go into a disease area and we get together a group of leading experts and we brainstorm what’s worked, what hasn’t worked, what’s exciting, what isn’t exciting,” Elenko said. “That defines the boundaries of the solution set. Then we can go and look for the ideal solution all over the world. It can come from industry. It can come from academia.”
Targeting schizophrenia
The unmet need in schizophrenia is significant. Since 1954, when chlorpromazine reached the market, there have been improvements on the treatment, but all have been tweaks on the same mechanism of action, which targets the dopamine receptor.
With these drugs, patients can experience weight gain, withdrawal, lethargy, cognitive decline and nervous ticks, leading many to abandon their treatment.
One of the reasons for the dearth of advancement in treating the disorder is the lack of understanding about how the brain works.
“If you look at the underlying pathology—what causes the disease—no one really knows,” Elenko said.
Further complicating the understanding of schizophrenia is that genetic developmental and environmental factors are likely at play, Miller said.
Because it is particularly expensive and risky, research on the brain has been spotty. As a result, companies have shied away from dedicating resources to pursue solutions.
Miller adds that because the modern tools of drug discovery and development such as genomics, proteomics and cell therapy have had little impact on psychiatry, it has directed investment away from brain disorders.
“It was never about the idea that there was never a need for new treatments,” Miller said. “It was really about: What is the source innovation and how do we turn that into new treatments?”
Another factor holding back innovation in the advancement of schizophrenia drugs is the societal views attached to the disorder.
“We simply don’t talk about it,” Miller said.
A new approach to drug discovery
The buzz around schizophrenia has increased as Karuna has made noise with KarXT. In the same month that BMS acquired Karuna, AbbVie bought out Cerevel Therapeutics for $8.7 billion. The key asset in the deal was Cerevel’s therapy emraclidine, also from the muscarinic drug class, which is in phase 2 testing for schizophrenia.
“(This approval) is a really seminal moment in the history of how we think about schizophrenia treatment,” Miller said. “But I actually think the bigger moment is going to come five or 10 years from now when we look back on what we’ve done, and we see the actual impact that we’ve generated—the improvements and outcomes that we think are possible.”
In the naming of Karuna, its founders turned to a Sanskrit word which means “an action to relieve the suffering of others.”
To accomplish the mission that its name inferred, Karuna took an approach that focused first on the patient and the indication, then on finding a therapy. It’s the opposite way drug discovery often is performed in biopharma.
“This was very non-traditional,” Miller said. “I would hope that KarXT can be an example that others can cite about why their idea—which might not be so traditional—could ultimately lead to something really important.”