A phase III test of roluperidone, a drug developed by Minerva Neurosciences Inc. with a goal of treating negative symptoms in schizophrenia, found that the experimental medicine failed to deliver statistically significant differences vs. placebo in improving both the trial's primary endpoint, a common measure of symptom severity, and its secondary endpoint, a score measuring social function. Company shares (NASDAQ:NERV) fell 72.5% to $3.71 on the May 29 news following a day of heavy trading.

Minerva CEO Remy Luthringer attributed the disappointing outcome to a "larger than expected" placebo effect in the last week of the trial and kept faith in the program. Citing results obtained with the highest dose tested, he said that "roluperidone merits continued investigation for the treatment of primary negative symptoms." Whether the program carries ahead or not, it seemed unlikely that plans to file an NDA for the drug earlier next year would be maintained. A long-term commercial supply agreement for roluperidone with Catalent Inc. may also be impacted.

The Waltham, Mass-based drug developer did not return a request for an interview Friday, ahead of a planned June 1 webcast slated to provide further insight into the trial's outcome.

Failure to separate

Enrollment in the multicenter, randomized, parallel group trial was delayed somewhat by a cyberattack on a contractor helping with the study, but proceeded on track otherwise. It was designed to evaluate the efficacy and safety of 32-mg and 64-mg doses of roluperidone primarily as measured by the Positive and Negative Syndrome Scale Marder negative symptoms factor score. The core 12-week portion of the study was followed by a 40-week, open-label extension period during which patients on the drug continue receiving their original dose and patients on placebo receive one of the two doses of roluperidone.

In total, 513 patients with moderate to severe negative symptoms of schizophrenia were enrolled in the study at sites in the U.S., Europe and Israel. Among them, 172 received placebo, while two groups of similar size received either 32 mg or 64 mg of roluperidone. Neither the 32-mg nor 64-mg dose of roluperidone showed a statistically significant separation from placebo (32 mg: p ≤0.256, effect size [ES]=0.1; 64 mg: p ≤0.064, ES=0.2).

Furthermore, neither dose showed a statistically significant separation from placebo on the key secondary endpoint, the change from baseline to week 12 in Personal and Social Performance (PSP) Scale Total Score (32 mg: p ≤0.542, ES=0.1; 64 mg: nominal p ≤0.021, ES=0.3).

"Although limited inferences can be drawn from this data, unadjusted statistically significant separations from placebo were observed" in PANSS Marder Negative Symptoms Factor Score at week 4 for both doses and at week 8 for the 64-mg dose. And the 64-mg dose was statistically significantly different from placebo as measured by change in PSP at all other assessment time points, the company said.

Roluperidone is designed to block the serotonin receptor subtype 5-HT2A. It's one of two candidates Minerva licensed from Mitsubishi Tanabe Pharma Corp., and the second of the pair to face a substantial setback. After the other asset, MIN-117, failed to meet primary and key secondary endpoints in a phase IIb study of adults with moderate to severe major depressive disorder, Minerva decided not to further the drug's development, leading it to recognize a $19 million expense for full impairment in 2019.

Minerva is also developing seltorexant, a selective orexin-2 receptor antagonist partnered with New Brunswick, N.J.-based Johnson & Johnson in MDD, and MIN-301, a recombinant form of the neuregulin-1beta1 protein that's currently in preclinical development for the treatment of Parkinson’s disease.

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