Benzinga | Jun 29, 2021 06:34AM EDT

Cerevel Therapeutics Announces Topline Results For CVL-231 In Phase 1b Clinical Trial In Patients With Schizophrenia; Says Both Doses Demonstrated Clinically Meaningful And Statistically Significant In PANSS Total Score

Both doses of CVL-231 demonstrated a clinically meaningful and statistically significant improvement in PANSS Total score at 6 weeks and were overall well-tolerated compared with placebo



30 mg of CVL-231 once-daily improved PANSS total score at 6 weeks by 12.7 points compared with placebo (p=0.023)

20 mg of CVL-231 twice-daily improved PANSS total score at 6 weeks by 11.1 points compared with placebo (p=0.047)

No meaningful differences in gastrointestinal side effects, extrapyramidal symptoms or weight gain compared with placebo

Cerevel plans to advance CVL-231 to Phase 2 development in schizophrenia and to evaluate the potential for this mechanism in other populations, including dementia-related psychosis

Conference call and webcast scheduled for today at 8:30 a.m. EDT

CAMBRIDGE, Mass., June 29, 2021 (GLOBE NEWSWIRE) -- Cerevel Therapeutics (NASDAQ:CERE), a company dedicated to unraveling the mysteries of the brain to treat neuroscience diseases, today announced positive results from its Phase 1b clinical trial of CVL-231, a novel muscarinic M4-selective Positive Allosteric Modulator (PAM), in adult patients with schizophrenia. CVL-231 was generally well-tolerated, and discontinuation rates were similar between CVL-231 and placebo in the six weeks of dosing, at 22% each. Importantly, both the 30 mg once-daily and the 20 mg twice-daily doses demonstrated clinically meaningful antipsychotic activity with an overall well-tolerated profile compared with placebo. The CVL-231 30 mg once-daily dose resulted in a statistically significant and clinically meaningful mean reduction from baseline of 19.5 points in the Positive and Negative Syndrome Scale (PANSS) total score and a mean reduction of 12.7 points in PANSS versus the placebo group (p=0.023). The CVL-231 20 mg twice-daily dose resulted in a statistically significant and clinically meaningful mean reduction from baseline of 17.9 points in PANSS total score and a mean reduction of 11.1 points in PANSS total score compared with the placebo group (p=0.047). These results were further supported by clinically meaningful reductions in the PANSS Positive and PANSS Negative subscales.

In the previously completed Part A multiple ascending dose (MAD) phase of this study, doses of 5 mg to 40 mg (administered as 20 mg BID) were explored with up to 21 days of administration at target dosage. The Part A MAD safety and tolerability data were supportive of proceeding to 6 weeks of dosing in the subsequent Part B portion of the trial, which is being reported today. The Part B portion was designed, in part, to evaluate tolerability and explore the antipsychotic potential of CVL-231 in patients by measuring the effect on PANSS with selected doses of 30 mg once-daily and 20 mg twice-daily.

"We believe these results are impressive and provide important evidence for the specific activation of the M4 receptor as a potential treatment approach for schizophrenia," said John M. Kane, M.D., professor and chairman, Department of Psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell. "By selectively targeting the M4 receptor, CVL-231 appears to have yielded a robust and clinically meaningful antipsychotic effect while avoiding both the debilitating extrapyramidal side effects commonly seen with dopamine antagonists, as well as the serious gastrointestinal side effects that have limited non-selective muscarinic compounds in the past."

CVL-231 is an M4-selective PAM being developed as a potential treatment for schizophrenia. CVL-231 is designed as a once-daily medication that selectively targets activation of the M4 receptor in the brain to reduce dopaminergic activity without direct dopamine receptor antagonist activity. CVL-231 has the potential to be a first-in-class once-daily, M4-selective PAM that may provide antipsychotic activity without the need for titration while minimizing gastrointestinal, extrapyramidal, and metabolic side effects seen with other antipsychotic medications. By selectively targeting the M4 receptor, CVL-231 has the potential to avoid the serious gastrointestinal side effects that have commonly been associated with, and have hindered clinical development of, non-selective muscarinic agents.

"We are extremely encouraged with these results, which we believe support our hypothesis that a targeted muscarinic therapy that is highly selective for M4 receptors could deliver clinically meaningful benefit in the treatment of schizophrenia," said John Renger, Ph.D., chief scientific officer at Cerevel. "By developing a molecule that is several hundred times more selective for M4 receptors over M1, M2, M3, and M5 receptors, we are expanding our understanding of how to best leverage the potential of the muscarinic pathway to effectively treat individuals with schizophrenia, with fewer of the dose-limiting side effects that occur with currently available therapies."

CVL-231 was generally well-tolerated in the clinical trial. The incidence of treatment emergent adverse events for both dose cohorts were similar to placebo, including heart rate and blood pressure increases. The adverse event (AE) of headache had the highest incidence of reporting across all treatment groups, with placebo at 26%, 30 mg once-daily at 30%, and 26% for the 20 mg twice-daily cohort. Additionally, the rate of nausea was similar between CVL-231 and placebo (4% for placebo and 7% for both 30 mg once-daily and 20 mg twice-daily groups) and rates of other gastrointestinal AEs were very low and similar to placebo. CVL-231 was not associated with a greater incidence of weight gain than placebo and no adverse events related to extrapyramidal symptoms were reported. Serious adverse events reported in the study included COVID-19, accidental overdose, and exacerbation of schizophrenia (one instance of each).

"Novel approaches for treating schizophrenia have been challenging to identify for decades, and patients and caregivers are seeking new therapies without the debilitating side effects that lead to poor compliance and relapse," said Raymond Sanchez, M.D., chief medical officer at Cerevel. "We are working to develop CVL-231 to be a once-daily formulation with improved tolerability, and without the need for titration, which could potentially improve adherence and avoid the vicious cycle of relapse with the exacerbation of symptoms so often seen with this illness."