On 17 October, Minerva Neurosciences announced that it had received a refusal to file letter from the US Food and Drug Administration (FDA) regarding the company’s new drug application (NDA) for roluperidone for the treatment of negative symptoms in patients with schizophrenia. The FDA has indicated that Minerva can request a Type A meeting to discuss the content of the refusal to file letter.

The negative symptoms of schizophrenia refer to avolition, social withdrawal and flat emotional affect; these have a major impact on the patient’s quality of life. There is significant need for a therapy targeting negative symptoms in the schizophrenia market. Prior to this news, GlobalData had assumed that roluperidone would launch in Q3 2023 in the US and generate $70.3m in sales by 2031.

The refusal to file letter is another obstacle to roluperidone’s development, following two FDA Type C meetings regarding the product in November 2020 and March this year. Minerva’s NDA is supported by results from a clinical trial conducted outside of the US (MIN-101C03; EudraCT-2014-004878-42), as well as a US-based clinical trial (MIN-101C07; NCT03397134). However, roluperidone failed to meet the primary efficacy endpoint in the US MIN-101C07 study, which was to demonstrate a statistically significant change in the Positive and Negative Syndrome Scale-derived Marder negative symptoms factor score.

The specific reasons behind the FDA’s refusal to file letter have not been disclosed. However, in the recent Type C meeting, roluperidone’s efficacy in treating negative symptoms and whether the data collected in the positive MIN-101C03 trial is applicable to US patients were both key topics highlighted by the FDA, for which they requested further clarification from Minerva. It is possible the FDA does not think Minerva has adequately addressed these topics in its filing.

Regardless of when and whether Minerva can adequately address the concerns raised by the FDA and roluperidone is approved, more hurdles lie ahead of the product. While key opinion leaders (KOLs) previously interviewed by GlobalData agreed that the schizophrenia market lacked novel treatments to target the negative symptoms of schizophrenia, they were concerned about the limited number of patients suitable for roluperidone treatment.

Roluperidone is being investigated as a monotherapy and concurrent use of roluperidone with an antipsychotic drug has not yet been evaluated. This means that the only patients eligible for roluperidone treatment will be adults who exhibit stable positive symptoms and minimal agitation, without antipsychotic use. In addition, KOLs said that they will be hesitant to switch patients from atypical antipsychotic therapy to roluperidone due to the increased risk of psychotic relapses associated with the discontinuation of antipsychotic use. GlobalData estimates that roluperidone will reach a peak patient share of 0.3%, or around 5,400 patients, in the US.

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A further competitive threat to the future of roluperidone is Acadia Pharmaceuticals’ Nuplazid (pimavanserin tartrate), which is being developed as an adjunctive therapy to target the negative symptoms of schizophrenia and is anticipated to launch in the US in Q4 2025. Unlike roluperidone, Nuplazid can be used in conjunction with antipsychotic therapies either long-term or during relapses, when positive symptoms of schizophrenia return. As such, if approved and launched, Nuplazid will likely compete with roluperidone for patient share. GlobalData forecasts that Nuplazid will generate $216.8m in sales in the US by 2031.

Should roluperidone be able to manoeuvre past the FDA’s refusal to file letter and eventually receive regulatory approval, Minerva needs to provide strong efficacy data, both as a monotherapy and adjunctive therapy, and solid marketing to set it apart from Nuplazid.