Minerva Neurosciences announces outcome of Type C meeting with FDA and next steps in the development of roluperidone for treatment of negative symptoms in schizophrenia.

Minerva Neurosciences, Inc. announced that it has received official meeting minutes from the November 10, 2020 Type C meeting with the FDA regarding development of roluperidone for treatment of negative symptoms in schizophrenia. The objective of this meeting was to obtain FDA input regarding the roluperidone data package and its readiness to support a New Drug Application (NDA) submission. The two main topics addressed during the meeting were:. Readiness for submission of NDA. Minerva requested confirmation from FDA that, based on the totality of evidence, the data from the MIN-101C03 (Phase IIb) and MIN-101C07 (Phase III) studies constitute substantial evidence of the effectiveness of the 64 milligrams (mg) dose of roluperidone for the treatment of negative symptoms in schizophrenia and would warrant review of an NDA submission. The FDA advised that the Phase IIb study is problematic because it did not use the commercial formulation of roluperidone and was conducted solely outside of the United States. In addition, FDA commented that the Phase III study does not appear to be capable of supporting substantial evidence of effectiveness, because neither dose of roluperidone showed a statistically significant separation from placebo at Week 12 in the intent-to-treat (ITT) analysis set. FDA cautioned that an NDA submission based on the current data from the Phase IIb and Phase III studies would be highly unlikely to be filed and that, at a minimum, there would be substantial review issues due to the lack of two adequate and well-controlled trials to support efficacy claims for this indication. The FDA acknowledged that the data from the Phase IIb and Phase III studies appear to show promising signals and encouraged Minerva to continue the development of roluperidone for treatment of negative symptoms in schizophrenia, which FDA confirmed is an unmet need. Minerva recognizes FDA’s comments but believes they can be addressed based on published regulatory guidance and precedents. The company has comparable pharmacokinetic data for the formulations used in Phase IIb and Phase III (the commercial formulation) and intends to perform a pivotal bioequivalence study to bridge the two formulations. In addition, Minerva believes the Phase III study has shown that US data and ex-US data are comparable, and that many precedents exist where drugs were approved by FDA based solely on ex-US data. Minerva believes that, in the Phase III study, results from the modified ITT (mITT) analysis set that excludes patients with implausible behavioral and physiological data from one site (17 of a total of 513 patients) address the lack of separation at Week 12. . FDA’s consideration of both ITT and mITT data analyses from Phase III study : In the briefing book for the Type C meeting, Minerva highlighted that the exclusion of implausible behavioral and physiological data from 17 patients at one site forms the basis of the mITT analysis set as outlined in the Statistical Analysis Plan submitted to FDA before unblinding the study.For the mITT analysis set, the 64 mg dose of roluperidone achieved a nominal statistically significant result (p-value ? 0.044) on the primary endpoint, the Marder Negative Symptoms Factor Score (NSFS) of the Positive and Negative Syndrome Scale (PANSS). The details of both the ITT and mITT results for the primary (NSFS) and key secondary endpoint, the Personal and Social Performance (PSP) total score were cited. The FDA advised that their consideration of both the mITT and ITT results would be a matter of review and that in principle all sites should be included in the primary analysis set, and FDA cannot determine at this time whether data from the referenced site should be removed without a thorough evaluation. The FDA indicated that Minerva should include justification for exclusion of these data in the future NDA package and provide primary results both with and without these data. Future development of roluperidone : Minerva intends to continue development and NDA activities consistent with FDA’s December 2019 draft guidance titled “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products.” Where the target indication is an unmet need such as negative symptoms in schizophrenia, the guidance allows the FDA to consider one adequate and well-controlled study and confirmatory evidence as an alternative to two adequate and well-controlled studies to establish effectiveness.