Minerva Neurosciences Announces Outcome of Type C Meeting with FDA and Next Steps in the Development of Roluperidone
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:
1. Readiness for submission of NDA
Minerva requested confirmation from FDA that, based on the totality of evidence, the data from the MIN-101C03 (Phase 2b) and MIN-101C07 (Phase 3) 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.
FDA advised that the Phase 2b study is problematic because it did not use the commercial formulation of roluperidone and was conducted solely outside of
FDA acknowledged that the data from the Phase 2b and Phase 3 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 2b and Phase 3 (the commercial formulation) and intends to perform a pivotal bioequivalence study to bridge the two formulations. In addition, Minerva believes the Phase 3 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 3 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.
2. FDA’s consideration of both ITT and mITT data analyses from Phase 3 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, can be found at the end of this press release.
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. 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.
In addition to the two main agenda items described above, the use of the PSP total score in the label and the adequacy of the PANSS and PSP instruments and related constructs to assess the efficacy of roluperidone were also discussed. Minerva expects to provide requested literature to support the instruments’ psychometric properties to FDA.
Future development of roluperidone
Minerva intends to continue development and NDA activities consistent with FDA’s
“We thank FDA for their constructive approach and comments related to the development of roluperidone and their recognition of the significant unmet medical need which exists for patients and their families,” said Dr.
|Roluperidone Phase 3: ITT and mITT NSFS & PSP total score change from baseline scores and p-values|
(Excluding patients from 1 site)
|64 mg Roluperidone
|64 mg Roluperidone
|Primary Endpoint: Marder Negative Symptoms Factor Score|
|Week 2||-1.6 (0.22)||-1.9 (0.22)||NS||-1.6 (0.22)||-1.9 (0.22)||0.311|
|Week 4||-2.0 (0.26)||-2.9 (0.26)||0.007||-2.0 (0.26)||-3.0 (0.27)||0.005|
|Week 8||-2.9 (0.30)||-3.8 (0.32)||0.027||-2.9 (0.31)||-3.9 (0.32)||0.021|
|Week 12||-3.5 (0.34)||-4.3 (0.38)||0.064||-3.5 (0.35)||-4.5 (0.35)||0.044|
|Key Secondary Endpoint: Personal and Social Performance Total Score|
|Week 4||1.3 (0.56)||3.2 (0.56)||0.005||1.2 (0.58)||3.3 (0.59)||0.004|
|Week 8||2.8 (0.66)||4.8 (0.66)||0.019||2.8 (0.68)||4.9 (0.68)||0.014|
|Week 12||3.9 (0.73)||6.1 (0.73)||0.021||3.8 (0.75)||6.2 (0.77)||0.017|
Minerva’s portfolio of compounds includes: roluperidone (MIN-101), in clinical development for schizophrenia; a potential royalty stream from seltorexant (MIN-202 or JNJ-42847922), in clinical development for insomnia and MDD; and MIN-301, in pre-clinical development for Parkinson’s disease. Minerva’s common stock is listed on the NASDAQ Global Market under the symbol “NERV.” For more information, please visit www.minervaneurosciences.com.
Forward-Looking Safe Harbor Statement
This press release contains forward-looking statements. Forward-looking statements are statements that are not historical facts, reflect management’s expectations as of the date of this press release, and involve certain risks and uncertainties. Forward-looking statements include, without limitation, statements herein with respect to Minerva’s ability to successfully address FDA’s concerns regarding the data package of roluperidone (MIN-101) and its suitability to support NDA filing or approval; Minerva’s interpretations of FDA regulatory guidance documents and precedents the likelihood of establishing bioequivalence between the formulations of roluperidone used in the Phase 2 and Phase 3 studies or the comparability of roluperidone’s US data and ex-US data; Minerva’s ability to justify exclusion of data from the Phase 3 study’s primary analysis set; whether the mITT analysis set addresses the lack of statistical separation at Week 12 in the ITT set; Minerva’s ability to address FDA’s comments regarding the adequacy of the PANSS and PSP instruments; the conduct of clinical pharmacology, non-clinical, CMC and other work needed to support NDA submission; the completion of the open label extension of the Phase 3 study; Minerva’s plan to request a pre-NDA meeting with FDA; the clinical and therapeutic potential of roluperidone; the likelihood of future sales and a royalty stream from seltorexant; the timing and outcomes of future interactions with
VP, Investor Relations/
Source: Minerva Neurosciences, Inc