Minerva Neurosciences announces the results of the phase III trial of roluperidone for the treatment of negative symptoms of schizophrenia following completion of the 40-week open-label extension.

Minerva Neurosciences, Inc. announced results from the 40-week open-label extension (OLE) of its phase III trial of roluperidone for the treatment of negative symptoms (NS) of schizophrenia. The OLE followed the 12-week double-blind, placebo-controlled portion of this trial. During the OLE, both investigators and patients were blinded to the roluperidone dose received. Over the 40-week OLE period, 333 patients participated, of whom 166 patients received the 32 mg dose and 167 patients received the 64 mg dose. The mean improvement in negative symptoms was 6.8 points in the 32 mg arm and 7.5 points in the 64 mg arm. PSP total score improved by a mean of 12.3 points in the 32 mg arm and 14.5 points in the 64 mg arm, suggesting functional improvement. The mean improvement in positive symptoms, as measured by the PANSS positive symptom subscore, was 1.9 points in the 32 mg arm and 1.8 points in the 64 mg arm.Reduced emotional experience, as measured by a sub-factor of the NSFS that assesses a patient's motivation to take part in everyday life activities, had a mean improvement of 2.8 points in the 32 mg group and 3.0 points in the 64 mg group.The relapse rate during the OLE, defined as patients being withdrawn from the trial due to worsening of symptoms of psychosis, was 15 patients out of 166 patients (9%) in the 32 mg arm and 10 patients out of 167 patients (6%) in the 64 mg arm. Over the one-year duration the relapse rate was 11.7% overall. Roluperidone at both doses was safe and well tolerated, and treatment-emergent adverse events (TEAE) were generally mild to moderate in severity, the most frequently reported TEAE in the overall group of 333 patients that participated in the OLE were headaches in 26 patients (7.8%), followed by worsening of schizophrenia in 18 patients (5.4%) and insomnia in 15 patients (4.5%). No other TEAE was reported by more than 4% of the patients. There was one death (45 year old male) in the 64 mg arm due to treatment-unrelated respiratory failure that occurred after treatment discontinuation. Twenty patients (6%) experienced serious adverse events, with the majority of them associated with the disease characteristics, and only 5 were judged by the investigator to be related to roluperidone. In total, 37 patients (11%) did not complete the OLE due to TEAE, with 25 patients (7.5%) due to relapse-related events and the remaining 12 patients due to a variety of other TEAE reported in ?1% of the patients. Few QT prolongations were observed during the OLE and were generally transient in duration, and only one in the 64 mg arm led to discontinuation from the study. About the trial: In the double-blind, placebo-controlled portion of the Phase III trial, a total of 515 patients were randomized in a 1:1:1 ratio to 32 mg/day roluperidone, 64 mg/day roluperidone, or placebo for 12 weeks, and 513 patients received study drugs. Of these, 333 patients (65%) entered the 40-week OLE, where patients receiving roluperidone continued to receive the same dose of roluperidone, while patients who received placebo during the double-blind phase were randomized at the beginning of the study to receive either 32 mg or 64 mg during the OLE. A total of 166 patients were treated with the 32 mg dose, and 167 patients with the 64 mg dose. A total of 202 of the 333 patients entering the OLE (61%) completed the 40-week period. Both investigators and patients were blinded to the roluperidone doses throughout the OLE. The OLE was designed to evaluate the safety of roluperidone after long-term exposure. Efficacy endpoints were also assessed throughout the 12-month duration of the study. Data collected during the OLE are not placebo-controlled and therefore their interpretation is limited. As announced on May 29, 2020, the 12-week double-blind, placebo-controlled portion of the trial did not meet its primary or key secondary endpoints in the intent-to-treat population. The 32 mg and 64 mg doses were not statistically significantly different from placebo at week 12 on the primary endpoint of NSFS (p ?0.259 and p ?0.064, respectively), or on the key secondary endpoint, PSP total score (p ?0.542 and nominal p ?0.021, respectively). The subsequent analysis of the change in baseline in NSFS and PSP total score based on the modified ITT population treated with the 64 mg dose were not statistically significantly different from placebo at week 12 on the primary endpoint of NSFS (p ?0.259 and p ?0.064, respectively), or on the key secondary endpoint, PSP total score (p ?0.542 and nominal p ?0.021, respectively). The subsequent analysis of the change in baseline in NSFS and PSP total score based on the modified ITT population treated with the 64 mg dose resulted in nominally statistically significant p ?0.044 and p ?0.017, respectively.