Type C Meeting for roluperidone for the treatment of negative symptoms in schizophrenia

The primary purpose of the meeting was for Minerva to seek the FDA’s agreement on the use of roluperidone as monotherapy for the treatment of negative symptoms of schizophrenia in the subgroup of patients with moderate to severe negative symptoms and stable positive symptoms.

The Division agreed that there is an unmet need for negative symptom treatments and restated its position following the November 2020 Type C meeting in which they indicated a marketing application was highly unlikely to be filed. The Division also stated at the November 2020 meeting 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 novel indication. The Division acknowledged at the time that the studies appear to show promising signals and encouraged Minerva to continue the drug development program for this indication. Since the Type C meeting in November 2020, Minerva has completed the Open-label extension of the Phase III study and has continued to develop roluperidone as a monotherapy specifically for the treatment of negative symptoms of schizophrenia in the subgroup of patients with moderate to severe negative symptoms and stable positive symptoms.

At the recent meeting, Minerva and the Division discussed roluperidone’s use as a monotherapy for negative symptoms and the Division advised that several important and substantial concerns remain including: i. the applicability of the results of the Phase IIb study (conducted in Europe) to the US population. Minerva presented data in the briefing document sent to the Division in advance of the meeting showing comparable baseline data and efficacy across both US and ex-US patients in the Phase III study. ii. the proposed use of post hoc analyses for the primary endpoint results of the Phase III study. The Division added that even with the exclusion of one trial site that Minerva believes to be subject to potential data integrity issues, the overall study remains negative. For the Phase III study to be positive, where the truncated Hochberg procedure was used to control the overall Type I error, both roluperidone doses must be statistically significant versus placebo, which was not the case for the 32 mg dose. Minerva confirmed in post-meeting follow-up that the exclusion of one site had been prespecified in the SAP submitted to the Division in May 2020 before the unblinding of the double-blind data. Excluding the trial site with data integrity issues resulted in a nominal p-value of 0.044 on the primary endpoint for the 64 mg dose. In the Phase IIb study the 64 mg and the 32 mg doses of roluperidone achieved statistical significance versus placebo.

The Division sought reassurance that Minerva could reliably identify patients who do not need antipsychotics and how to evaluate the stability of those patients, and potential recurrence of positive symptoms of those patients, what would be considered a significant change in symptoms, how much time patients should be monitored to evaluate whether positive symptoms will recur, and what should be done if positive symptoms recur. Minerva informed the Division that it believes this patient population can be readily identified by clinicians, that this patient population presents commonly in clinical practice, that there is an unmet need for treatments for these patients and that Minerva expects that the population could be clearly characterized in product labelling.

The Division pointed out that prescribers are likely to use roluperidone in a way that differs significantly from the intended monotherapy use, noting that at this time, there are no data to show that roluperidone does not interfere with the safety or efficacy of antipsychotic medications. Minerva stated that it believes that findings from the completed Phase IIb (IN101-C03) and Phase III (MIN101-C07) studies, (in which roluperidone was administered in monotherapy without concomitant use of antipsychotic medications), demonstrate continued stability of positive symptoms in patients over time. Minerva stated that the relapse rate in these trials was less than 15% of the treated population compared to relapse rates of more than 25% in other trials in which patients were treated with antipsychotics. Following the meeting, Minerva submitted additional data to the Division from the Phase IIb and Phase III studies demonstrating that roluperidone does not interfere with the efficacy of antipsychotics in patients who suffered relapse and withdrew from the studies.

The Division confirmed that results from the pivotal bridging Bioequivalence study appear to be adequate for a future acceptable NDA submission but advised that final confirmation of this would be a matter of review and also acknowledged that Minerva’s initial pediatric study plan (iPSP) dated November 28, 2017, remains in force.

Minerva continues to believe that it has conducted two adequate and well controlled studies for the intended indication, and that the data from these studies are sufficient to support a marketing application. Minerva views the concerns raised regarding the data from the Phase IIb and Phase III studies as those that FDA would ordinarily consider during its review of an NDA. At the end of the meeting, the Division suggested that there may be a way to address its concerns, whether the completed studies provide substantial evidence that negative symptoms are responsive to roluperidone, concurrently with the questions about positive symptoms and co-administration with antipsychotic medication through the acquisition of additional data. The Division advised that collection of additional data could begin in parallel with Minerva’s preparations for a potential marketing application and need not be deferred until a determination about submission or filing of the application has been made.