Minerva Neurosciences (NASDAQ:NERV) hosted a virtual key opinion leader (KOL) event focused on its development candidate roluperidone for negative symptoms in schizophrenia, outlining the clinical rationale for targeting negative symptoms, the challenges of measuring them in trials, and an update on the company’s planned confirmatory Phase 3 study.
Company frames negative symptoms as a central unmet need
Executive Chairman and Chief Executive Officer Rémy Luthringer said the company’s goal is to bring roluperidone to patients with schizophrenia who suffer from negative symptoms, which he described as the symptoms that keep patients from “any decent life,” including holding a job. Luthringer argued that after decades of research and failed trials, the field is at a point where an unmet medical need could be addressed, positioning roluperidone as a potential first treatment for negative symptoms in schizophrenia.
KOL presentation: what negative symptoms are and why they matter
Gregory Strauss, a professor of psychology and neuroscience at the University of Georgia, discussed the impact of negative symptoms on patients and caregivers and provided a framework for how negative symptoms are defined.
Strauss said schizophrenia affects about 83 million people worldwide, including about 3.4 million in the U.S., and described it as a leading medical cause of functional disability with substantial economic burden. He emphasized that negative symptoms are the strongest predictor of poor functioning and disability and often emerge years before attenuated positive symptoms, typically persisting over time with little spontaneous improvement and minimal responsiveness to antipsychotics.
He described two higher-order dimensions of negative symptoms in DSM-5—experiential and expressive—comprised of five domains:
- Avolition (reduced motivation and goal-directed behavior)
- Asociality (reduced interest in relationships and social engagement)
- Anhedonia (reduced pleasure experience and reduced anticipation of future pleasure)
- Blunted affect (reduced emotional expression in face, voice, gestures)
- Alogia (reduced quantity of speech)
Strauss said his work suggests avolition is “more central” than the other domains and may drive broader negative symptom expression and functional outcomes. He also noted that similar negative symptom-like syndromes are observed across disorders such as Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury, pointing to corticostriatal circuitry as a relevant neurobiological substrate.
On roluperidone, Strauss said network analyses applied to Minerva’s Phase 2b and Phase 3 studies indicated that improvements in avolition carried the global improvement in negative symptoms, with the avolition-related internal experience separating drug from placebo in both trials. He also described survey work from his laboratory suggesting patients and caregivers identified relatively modest improvements on the Brief Negative Symptom Scale (0–6 item scale) as meaningful, and he said the magnitude of improvement anchored to clinician-rated clinical global change in roluperidone trial data was in a similar range.
KOL presentation: measurement challenges and trial design considerations
Brian Kirkpatrick of the University of Arkansas focused on why negative symptom trials have historically struggled and how trial design can reduce confounding. He cited several challenges, including high placebo response due to attention effects in trials and difficulty detecting a signal when participants are on dopaminergic antipsychotics, which he said can inhibit reward circuitry and potentially worsen negative symptoms through sedation or anhedonia.
Kirkpatrick also emphasized “pseudo-specificity,” where negative symptom ratings may improve when positive symptoms, depression, anxiety, medication side effects, substance use, or social isolation improve—changes he described as secondary negative symptoms rather than improvements in primary negative symptoms intrinsic to the illness.
He referenced the FDA’s view on negative symptom claims in the context of pivotal schizophrenia trials for the recently approved muscarinic antipsychotic Cobenfy, stating the FDA said those trials were not designed to distinguish negative symptom changes from changes tied to psychosis improvement and therefore were not designed to evaluate efficacy on negative symptoms.
Kirkpatrick argued that a monotherapy design in a population with minimal and stable positive symptoms and minimal anxiety and depression can better isolate effects on primary negative symptoms. He added that regulators, payers, and patients focus on functional outcomes; however, function can be a “lagging indicator,” improving slowly even when symptoms improve. He highlighted the Personal and Social Performance (PSP) scale as a widely accepted clinician-rated functional measure in schizophrenia.
Discussing Minerva’s prior roluperidone studies, Kirkpatrick described separation from placebo on negative symptom measures and reported that Phase 3 data showed improvement on the PSP over 12 weeks. He also said discontinuation and relapse patterns observed in roluperidone studies were favorable when compared with antipsychotic-treated cohorts from CATIE and EUFEST datasets matched to similar eligibility criteria, which he said helped reassure the FDA about monotherapy relapse risk.
Confirmatory Phase 3 trial: structure, endpoints, and timeline
Luthringer presented the planned confirmatory Phase 3 study structure, describing three parts:
- Screening of about one month to select appropriate patients.
- Part A: a 12-week, double-blind, placebo-controlled monotherapy comparison of roluperidone 64 mg vs placebo, designed to reconfirm efficacy on negative symptoms, with PSP as the sole key secondary endpoint.
- Part B: a longer follow-on phase focused on relapse monitoring, comparing roluperidone 64 mg with standard-of-care antipsychotics using a double-dummy approach; patients receive both a tablet and a capsule so treatment assignment remains blinded.
He said Part A will enroll 380 patients, use the same primary endpoint used in the prior Phase 3 study, and employ MMRM statistical analysis. For Part B, he said relapse comparisons will be descriptive given limited relapse events, making formal inferiority-style statistics impractical.
To improve execution and reduce placebo effects, Luthringer outlined steps including limiting the number of sites to 40, emphasizing site selection based on quality metrics and recruitment capability, reducing patient interactions outside required assessments (which he referred to as minimizing a “nursing effect”), intensifying rater training for negative symptom scoring, using a 1:1 randomization (instead of two active doses vs placebo), creating a committee to support inclusion decisions, and implementing online monitoring down to the individual rater level, including tablet-based prompts to flag discrepant ratings.
Minerva selected Syneos as its contract research organization (CRO), citing its recent schizophrenia trial experience. Luthringer said multiple sites have already been activated, with a first patient expected in Q2 2026. He projected top-line results for the 12-week primary endpoint in the second half of 2027 and results from the relapse-focused portion in the second half of 2028.
Q&A highlights: powering assumptions and NDA resubmission
During Q&A, Luthringer said the 12-week portion is powered at 90%, with an assumed placebo-treatment difference of roughly 1.5 to 1.8, and that the study is “overpowered” relative to assumptions used at around 300 patients. He reiterated that relapse analyses in the longer portion are expected to be descriptive due to low event rates.
Asked whether Minerva could file after the 12-week data, Luthringer said the company plans to share the 12-week primary endpoint data with the FDA immediately and discuss next steps for NDA resubmission. He noted that as a resubmission, review time would be six months, and said the company expects to have some blinded relapse information by the time the 12-week results are available, though not the full dataset.
In another exchange, Kirkpatrick said he did not see a reason roluperidone’s potential would be restricted to older patients, noting a portion of trial participants were under 35 (he estimated roughly 15%–20%). Strauss added that efficacy in chronic patients could be reassuring given entrenched environmental factors, and he suggested earlier-stage patients might have more “plasticity” for functional change.
Closing the event, Luthringer emphasized ongoing FDA dialogue and said Minerva is preparing to begin recruitment, reiterating the company’s focus on addressing negative symptoms as a key burden for patients and families.
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.
