Minerva Neurosciences (NASDAQ:NERV) provided an update on its development program for roluperidone, which the company described as a potential first treatment option aimed at the negative symptoms of schizophrenia—an area where management has historically lagged behind treatments for positive symptoms.
Company focus: negative symptoms and unmet need
In the presentation, Minerva’s team emphasized that schizophrenia symptoms are commonly grouped into three categories: positive symptoms, negative symptoms, and cognitive deficits. While currently available antipsychotics are described as improving positive symptoms, the company said they do not improve negative symptoms, which it characterized as a major driver of long-term disability and reduced quality of life.
What Minerva highlighted about negative symptoms and trial challenges
Minerva described negative symptoms as spanning “experiential” and “expressive” dimensions, and singled out avolition—a lack of motivation and drive—as particularly important. The team suggested that improving avolition could be linked not only to overall negative symptom improvement, but also to better functioning and potentially cognitive outcomes, citing increasing consensus in the field.
The company also outlined why developing therapies for negative symptoms has been difficult. In particular, the presenter discussed how certain trial designs can create “pseudo effects” when patients are brought down from acute positive symptom episodes to a baseline level that includes disease-related negative symptoms. Minerva also argued that evaluating a drug “on top of” dopamine-blocking antipsychotics presents complications, including sedation, movement disorders (EPS/akathisia), and potential worsening of negative symptoms—factors that can contribute to what it called secondary negative symptoms and make it harder to distinguish them from primary, disease-related negative symptoms.
Roluperidone: mechanism and prior study results discussed
Minerva described roluperidone as intentionally not dopamine-blocking, citing its pharmacology as including 5-HT2A antagonism, sigma-2 antagonism, and some alpha-1A antagonism. The presenter said 5-HT2A antagonism is described in the literature as helping keep patients stable in terms of positive symptoms, particularly in the stable patient population Minerva targeted.
The company shared an integrated analysis of two registrational studies, describing the primary endpoint as the Marder negative score derived from the PANSS scale, with the primary endpoint assessed at week 12. According to the presentation:
- Minerva said improvements versus placebo could be observed as early as week 2 for the tested doses.
- The company stated that by week 12, both doses showed p-values in the integrated analysis, and that 64 mg appeared to have a stronger effect than 32 mg, including on effect size.
- It characterized the first study as “extremely positive,” citing p-values of 0.0001 and effect sizes of 0.6–0.7.
- For the second study, Minerva said placebo improved more than expected, and while treatment improvement was similar, only the highest dose achieved a p-value after the statistical approach used (Hochberg correction). The company said it could therefore only describe a “nominal” improvement for 64 mg in that study, while asserting a treatment effect for 64 mg across both studies.
Minerva also highlighted functional outcomes, noting that the PSP (Personal and Social Performance) total score was the sole key secondary endpoint in the second study. The company said patients improved in functioning and stated that, to its knowledge, roluperidone is the only drug in the space improving patients’ functioning, referencing observations from the studies that some patients were able to return to work.
On safety and tolerability, Minerva said roluperidone was “extremely well-tolerated” and reported no sedation, no EPS, no prolactin increase, and no nausea in the trial experience discussed.
Monotherapy questions and relapse considerations
During Q&A, the discussion addressed how clinicians might feel about stopping antipsychotics in stable patients with residual negative symptoms. Minerva’s presenter said that while antipsychotics can reduce relapse and hospitalization risk acutely and subacutely, there are long-term follow-up data suggesting a subset of patients may not need continuous antipsychotic treatment and may function better with intermittent treatment. The presenter also said that in more than 800 patients who participated in Minerva’s trials—and referencing a Lundbeck trial with a similar patient profile—relapse rates were “extremely low” in the targeted population.
Regulatory path and next study design
Minerva said it reached agreement with the FDA on key elements of a new trial program after extended discussions, including reference to an FDA public meeting in August 2024 focused on negative symptom study design and endpoints. The company outlined the agreed framework:
- Primary endpoint: week 12 Marder negative score (from PANSS), consistent with prior studies.
- Sole key secondary endpoint: PSP (functioning), consistent with the prior Phase 3 approach.
- Design: double-blind, placebo-controlled monotherapy study in patients stable in positive symptoms and stable in negative symptoms over the prior six months, with a minimum negative symptom severity threshold.
- Dose: only 64 mg versus placebo (rather than two doses).
Minerva also described an additional longer-term component designed to provide further reassurance on relapse. The company said patients would be re-randomized to roluperidone or antipsychotic therapy, using three commonly prescribed antipsychotics. Because blinding could be complicated by antipsychotic side effects, Minerva said it planned a double-dummy design. It described this relapse comparison as descriptive rather than a formal non-inferiority analysis, stating that too few relapses would make a statistically powered non-inferiority design impractical without enrolling 2,000 to 3,000 patients.
For relapse monitoring, Minerva said the study would use both psychometric and “hard” clinical endpoints. Psychometric measures would include PANSS-based criteria informed by published consensus (the presenter referenced an increase of 12 points or more on PANSS total score as a potential signal of relapse), alongside other collected measures such as CGI and PSP. Hard clinical endpoints would include hospitalization and other serious clinical deteriorations discussed in the session.
On clinically meaningful effect size, Minerva said establishing a benchmark is difficult given the absence of approved therapies. The presenter said the company shared responder analyses and an anchor analysis tying outcomes to CGI-S, noting that a 1-point improvement on CGI-S is recognized as clinically meaningful. Minerva also referenced published work using the BNSS scale that asked patients and caregivers what magnitude of change they considered meaningful, stating roluperidone performed as well as or better than those expectations. The presenter said that in this context, achieving a p-value would be sufficient, with responder analyses also planned.
Regarding timeline, Minerva said it selected a CRO and activated multiple sites, with first patient enrollment expected in Q2 of this year. The company said top-line week 12 results are expected in the second half of next year, with relapse assessment readout coming later. Minerva said it would re-engage with the FDA on a potential NDA submission after the week 12 top-line results.
About Minerva Neurosciences (NASDAQ:NERV)
Minerva Neurosciences, Inc is a clinical‐stage biopharmaceutical company focused on developing novel therapies for central nervous system (CNS) disorders. The company’s research and development efforts are directed toward addressing unmet needs in psychiatric and neurological conditions, leveraging its expertise in neuropharmacology and receptor modulation. Minerva’s goal is to bring forward differentiated molecules that can offer improved efficacy and safety profiles compared to existing treatments.
The company’s most advanced programs include roluperidone (formerly MIN-101), which has been investigated for the treatment of negative symptoms of schizophrenia, and MIN-117, a novel serotonergic agent being evaluated in major depressive disorder.
