ADC Reviews

FDA rejects NDA for Minerva to treat negative symptoms of schizophrenia


Minerva Neurosciences is a biopharmaceutical company focused on developing therapies for diseases of the central nervous system (CNS). Recently, the company announced that it received a refusal-to-file letter (RFL) from the U.S. Food and Drug Administration (FDA). The notification is related to the New Drug Application (NDA) for roluperidone (MIN-101). The FDA said the company could request a Type A meeting to discuss the contents of the RFL.

In August 2022, Minerva submitted a new drug application (NDA) for roluperidone (dose 64mg) to the FDA: the drug is an oral small molecule compound that is a serotonin 2A (5-HT2A) receptor, σ2 (sigma-2 ) receptor, alpha1A (alpha-1A) adrenergic receptor antagonist for the treatment of negative symptoms in patients with schizophrenia.

While positive symptoms of schizophrenia are often well controlled with antipsychotic medications, negative symptoms are often the major burden of the disease. There are currently no approved treatments for negative symptoms of schizophrenia in the United States. roluperidone may represent a new treatment option for negative symptoms of schizophrenia.

The roluperidone NDA is supported by results from 2 Phase 3 clinical studies (MIN-101C03, MIN-101C07). Two studies with the same design: both global, multicenter, randomized, double-blind, placebo-controlled trials evaluating roluperidone in patients with moderate to severe negative symptoms and stable positive symptoms of schizophrenia (2 doses: 32mg, 64mg) efficacy and safety.

Results from the MIN-101C03 study showed that roluperidone was superior to placebo in reducing negative symptoms of schizophrenia after 12 weeks of treatment. In the primary efficacy analysis, treatment with roluperidone at a dose of 64 mg resulted in a statistically significant reduction (p≤0.0036) in negative symptoms of schizophrenia, as measured by the Positive and Negative Syndrome Scale (PANSS) Pentagonal Structure Model Negative Score (PSM). A post hoc analysis of the change from baseline to week 12 in the PANSS Marder Negative Symptom Factor Score (NSFS) also showed a statistically significant difference between the 64 mg roluperidone and placebo groups (p≤0.001). After 12 weeks of the double-blind (DB) period, statistically significant improvements with roluperidone 64 mg relative to placebo were also observed in multiple secondary/exploratory efficacy analyses. There was also further improvement in NSFS during the 24-week open-label (OL) period.

The MIN-101C07 study also demonstrated that roluperidone was superior to placebo. Although the change from baseline to Week 12 in NSFS with roluperidone compared with placebo was slightly less statistically significant at the primary analysis (intention-to-treat [ITT]) (p≤0.064), the outcome was numerically superior with roluperidone 64 mg. In addition, an analysis of the modified intention-to-treat (mITT) population (the mITT dataset excluded data from a clinical trial site where the results of the 17 patients recruited were implausible) showed that 64 mg of roluperidone compared with placebo in NSFS There was a statistically significant improvement in nominal terms (p≤0.044). In addition, in the ITT and mITT populations, statistically significant (unadjusted) improvements in NSFS from baseline were observed with roluperidone 64 mg compared with placebo as early as Weeks 4 and 8. The PSP total score (a key secondary endpoint measuring occupational and social skills) achieved statistical significance in both the ITT population (p≤0.021) and the mITT population (p≤0.017). There was also further improvement in NSFS and PSP total scores during the 40-week open-label (OL) period.

Schizophrenia is a chronic, severe, debilitating mental illness characterized by distortions in thinking, perception, emotion, language, self-awareness, and behavior. According to the World Health Organization (WHO), schizophrenia affects 20 million people worldwide. It is estimated that 69% of patients diagnosed with schizophrenia have negative symptoms and at least 42% have significant negative symptoms.

Negative symptoms can cause people with schizophrenia to withdraw from society, become apathetic or unable to complete tasks or feel happy. Negative symptoms are characterized by 5 structures: emotional retardation, aphasia, depression, anhedonia, and social impairment. Negative symptoms are a major cause of poor functional outcomes in patients with schizophrenia and may be one of the major reasons why very high-risk adolescents may develop generalized schizophrenia.

While positive symptoms of schizophrenia are often well controlled with antipsychotic medications, negative symptoms are often the major burden of the disease and can affect a patient’s quality of life due to disability due to impaired occupational and social skills. Currently, there are no drugs approved in the United States to treat negative symptoms of schizophrenia.

roluperidone is a small molecule compound with a novel and unique mechanism of action that has been shown to block serotonin (5-HT) receptors, sigma(σ) receptors, alpha(α) adrenergic receptors , these receptors are involved in regulating important brain functions, including mood, cognition, sleep and anxiety. Currently, roluperidone is being developed to treat negative symptoms in patients with schizophrenia.

roluperidone is designed to avoid direct blockade of dopaminergic receptors (a key pharmacological target of first- and second-generation antipsychotics), while maintaining blocking of a specific subtype of serotonin receptors, 5-HT2A receptors (second-generation antipsychotics). an additional key target for the generation of antipsychotics) as well as other pharmacological targets (sigma-2(σ2) receptor and adrenergic α1A).

roluperidone blocks 5-HT2A receptors. When 5-HT2A receptors are blocked, certain symptoms of schizophrenia, such as hallucinations, delusions, agitation, thinking and movement disturbances, and side effects associated with antipsychotic treatment can be minimized. In addition, blocking 5-HT2A promoted slow-wave sleep, a sleep stage frequently seen in people with schizophrenia.

roluperidone is also able to block a specific subtype of the sigma (σ) receptor, σ2, which is involved in motor control, psychotic symptom control, and learning and memory. Blocking sigma2 receptors, as well as blocking the alpha (alpha) adrenergic receptor subtype alpha1A, and to a lesser extent alpha1B, also increases calcium levels in neurons in the brain, which improves memory. Preclinical findings provide evidence of the effects of roluperidone on brain-derived neurotrophic factor (“BDNF”), a factor involved in neurogenesis, neuroplasticity, neuroprotection, synaptic regulation, learning and memory.

Based on an innovative mechanism of action supported by science, Minerva believes that roluperidone has the potential to address unmet medical needs in the schizophrenia patient population, including negative symptoms and cognitive impairment, without the side effects of existing treatments.

Minerva Neurosciences Receives Refusal to File Letter from FDA for its New Drug Application for Roluperidone for the Treatment of Negative Symptoms in Schizophrenia