Karuna’s work is primarily focused on psychosis related to schizophrenia and late-stage Alzheimer’s disease, as well as analgesic effects for pain.
Neurological diseases are complex and drug development for them is notoriously difficult. One Boston-based company, Karuna Therapeutics, is showing promise in developing therapeutics for psychosis associated with several different diseases, including schizophrenia and Alzheimer’s disease.
These illnesses have a wide range of symptoms related to cognition and concentration, but psychosis is seen in a number of disorders, including schizophrenia, Alzheimer’s disease, depression, bipolar disorder and others.
Karuna’s work is primarily focused on psychosis related to schizophrenia and late-stage Alzheimer’s disease, as well as analgesic effects for pain. Its lead product candidate is KarXT, which selectively activates muscarinic acetylcholine receptors in the brain to improve the therapeutic potential of xanomeline.
Most antipsychotic drugs are based on the same primary mechanism of action that was developed in the 1950s—inhibiting D2 dopamine receptors. In the 1990s, muscarinic receptor agonists were viewed as a promising innovative approach for treating psychosis and cognitive impairment. These receptors bind to acetylcholine, a neurotransmitter. The drugs, such as xanomeline, showed efficacy for psychosis, but a major obstacle was the side effects. The muscarinic receptors are also present in peripheral tissues, which were responsible for the side effects.
Karuna Therapeutics believes it can preferentially target and stimulate muscarinic receptors in the central nervous system, and leave those in the peripheral tissues unaffected.
Andrew Miller, the company’s founder and chief operating officer, spoke with BioSpace about the company and recent financing and research news.
“We hoped to bring a different treatment profile than what was out there,” Miller said. “We looked back and it was clear there was a lot of interest and promise about taking advantage of muscarinic receptor agonists, and our drug really demonstrated some of the promise from the historical perspective.”
KarXT is an oral coformulation of xanomeline, which is a novel muscarinic receptor agonist, and trospium, an FDA-approved muscarinic receptor antagonist used to treat an overactive bladder. Trospium does not meaningfully cross the blood brain barrier, which limits its effects to the peripheral tissues. KarXT is designed to treat psychosis and related symptoms through preferential stimulation of muscarinic receptors in the CNS.
In short, xanomeline will cross the blood brain barrier and do its work on treating psychosis, while trospium will counteract that affect in the peripheral tissues, which should mitigate the negative side effects of xanomeline. And because trospium doesn’t cross the brain barrier, it won’t prevent xanomeline from working in the brain.
“The idea,” Miller said, “is we maintain the clinical benefit of xanomeline, but try to ameliorate the side effects of their activation in peripheral tissues by counterbalancing with trospium.”
On November 18, Karuna announced results from its Phase II clinical trial of KarXT for acute psychosis in schizophrenia patients. KarXT showed a statistically significant and clinically meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) score compared to placebo. It also showed good tolerability. There was also a statistically significant decrease in the secondary endpoints of PANSS-Positive and PANSS-Negative scores.
The discontinuation rate for KarXT was 20% and 21% for placebo. The overall adverse event (AE) rate for the patients receiving KarXT was 54% compared to 43% on placebo. The most common AEs were constipation, nausea, dry mouth, dyspepsia, and vomiting.
Miller noted that, “The Phase II study that was conducted and we reported topline data for was, first and foremost, a very well-established study design and primary endpoint of total PANSS for negative symptoms. That’s a study design that’s been used for decades, historically, to evaluate the antipsychotic medications in acute schizophrenia.”
The trial enrolled 182 adults, ages 18 to 60, who had been diagnosed with DSM-5 schizophrenia and were experiencing acute psychosis. Patients were washed-out of antipsychotic medications and randomized 1:1 to receive either KarXT or placebo for five weeks.
Miller is cautious, noting, “We want to be thoughtful about interpreting any one study, but in our view, it confirmed and extended previously generated data.”
The company’s immediate next step, Miller said, “is to continue to analyze the full dataset and exploratory endpoints beyond what we’ve released at this point. We also intend to meet with the FDA for end-of-Phase II meetings and clarify exactly what the Phase III program would look like. We hope to initiate the Phase III trial by the end of 2020.”
Because psychosis is associated with end-stage Alzheimer’s disease, Karuna is also looking at KarXT in Alzheimer’s psychosis, hoping to initiate a Phase Ib trial before the end of the year. It is also hoping to initiate Phase Ib trials in the first half of 2020 in the drug for cognitive symptoms of schizophrenia and negative symptoms of schizophrenia. The company also hopes to start a Phase Ib trial of KarXT in pain before the end of 2019.
“Originally,” Miller said, “xanomeline was put into development by Eli Lilly [in the 1990s] as a cognitive agent in Alzheimer’s disease, similar to other drugs marketed for quite some time. The idea was that if you could stimulate these receptors, it would have a better benefit.”
More than half of the participants in the high-dose arm of the trial dropped out from adverse events. However, Miller said, there was a dramatic antipsychotic benefit.
“So when we talk about developing it for Alzheimer’s,” Miller said, “we’re really talking about treating the psychosis associated with it. I think it’s an underappreciated part of the disease, that as much as 50% of Alzheimer’s patient develop psychosis, particularly toward the later stage of the illness. It can be a big driver of shifting at-home care to institutional care, because of the difficulties of treating it.”
These types of drugs also have potential as an effective analgesic for pain. The company expects to start studies in healthy volunteers with KarXT as well as other pipeline products for that indication.
In April 2019, the company closed an $80 million Series B financing. On June 27, the company announced pricing of its $103 million initial public offering and on November 20, the company announced the pricing of an additional $250 million follow-on public offering. The company’s cash position from the financing and the IPO should fund operating expenses and capital expenditure through the second half of 2021, including multiple clinical and development milestones.
“As complex as all the science is,” Miller said, “I think our story boils down to a few simple points. One, we’re really focused on an unmet medical need marked by an historical lack of innovation. We’re excited about what we’re doing because it has an opportunity to be fundamentally different, but beneficial.”
Miller goes on to say that from a corporate perspective, “we have a real opportunity to be out there leading the charge on improving patient outcomes in this space and we’re excited about that. That’s why the attention has come to us, but we realize there is a lot of work left to do. But we’re working on getting it done as expeditiously as possible and sharing it with patients as it becomes available.”
