FDA Issues CRL for Roluperidone for Treatment of Negative Symptoms in Schizophrenia

Minerva Neurosciences has announced the receipt of a Complete Response Letter (CRL) from the US Food and Drug Administration (FDA) for roluperidone in the treatment of negative symptoms in schizophrenia.¹

Announced on February 27, 2024, the CRL for the agent cites insufficient evidence to establish effectiveness, lack of data on concomitant antipsychotic administration, lack of data demonstrating clinical meaningfulness of change in negative symptoms, and an inadequate number of subjects within the submitted safety database. According to Minerva Neurosciences, the FDA stated they must submit at least 1 additional positive, adequate, and well-controlled study to support the safety and efficacy.¹

“We are disappointed that the FDA has not approved roluperidone and will request a meeting to discuss the issues raised and attempt to address FDA’s feedback,” said Remy Luthringer, executive chairman and chief executive officer of Minerva. “There is a critical need for a treatment for the negative symptoms of schizophrenia. We believe that roluperidone is a safe and effective therapy for negative symptoms of schizophrenia and we will review FDA’s feedback and consider our potential paths forward, including continuing to work closely with the FDA and providing any additional information as needed, with the goal of bringing this much needed therapy to patients and physicians.”

Negative symptoms of schizophrenia may lead to withdrawal from society, disinterest in tasks, and the inability to feel pleasure. Although most schizophrenia treatments target positive symptoms such as hallucinations or delusions, atypical antipsychotics, namely aripiprazole (Abilify), cariprazine (Vraylar), brexpiprazole (Rexulti), clozapine (Clozaril), asenapine (Saphris), lurasidone (Latuda), iloperidone (Fanapt), paliperidone (Invega), quetiapine (Seroquel), risperidone (Risperdal), ziprasidone (Geodon), and olanzapine (Zyprexa), can treat positive and negative symptoms.³

Minerva Neurosciences announced the NDA filing for roluperidone, a compound with antagonist properties for 5-HT2A, sigma2, and a1A-adrenergic receptors, for the treatment of negative symptoms in schizophrenia on April 27, 2023. The filing occurred roughly a year after issues in the refuse-to-file decision were discussed at the Type C meeting in April 2022 and 6 months after the company requested formal dispute resolution after seeing the FDA’s refuse-to-file letter in October 2022.

Led by Michael Davidson, MD, from the Nicosia University Medical School, investigators studied roluperidone in a placebo-controlled multinational trial from December 2017 – February 2022 with 513 patients aged 18 – 55 years.⁴

After a 12-week study duration, Negative Symptom Factor Scores were reduced for roluperidone 64 mg compared to placebo with a nominal significance for a modified intent-to-treat data set (P ≤ .044). After 64 mg roluperidone, Personal and Social Performance scale scores statistically improved compared to placebo for the intent-to-treat analysis (P ≤ .021) and the modified intent-to-treat analysis (P ≤ .017).

According to the release from Minerva Neurosciences, the FDA is also requiring the submission of additional data to demonstrate safety and efficacy when coadministered with antipsychotics. Additionally, beyond the clinical deficiences described in the CRL, the FDA also provided comments on, among other items, clinical pharmacology, product quality, biopharmaceutics, and nonclinical issues.¹

^References

1. _{^{Minerva Neurosciences Receives Complete Response Letter from FDA for New Drug Application for roluperidone for the treatment of negative symptoms in patients with schizophrenia. Minerva Neurosciences, Inc. February 27, 2024. Accessed February 27, 2024. https://ir.minervaneurosciences.com/news-releases/news-release-details/minerva-neurosciences-receives-complete-response-letter-fda-new.}}
2. _{^{Davidson M, Saoud J, Staner C, et al. Efficacy and Safety of Roluperidone for the Treatment of Negative Symptoms of Schizophrenia. Schizophr Bull. 2022;48(3):609-619. doi:10.1093/schbul/sbac013}}
3. _{^{Moore, M. What Are the ‘Positive’ Symptoms of Schizophrenia? PsychCentral. July 20, 2021. https://psychcentral.com/schizophrenia/positive-symptoms-schizophrenia.}}
4. _{^{Minerva Neurosciences Announces the NDA Filing for Roluperidone for the Treatment of Negative Symptoms in Schizophrenia. Minerva Neurosciences, Inc. May 1, 2023. https://ir.minervaneurosciences.com/news-releases/news-release-details/minerva-neurosciences-announces-nda-filing-roluperidone. Accessed February 21, 2024.}}