MIN-101 · program
Roluperidone (MIN-101) for Schizophrenia
Lead program: roluperidone monotherapy for the primary negative symptoms of schizophrenia. The pivotal positive Phase 2b (MIN-101C03; Davidson et al. 2017) met its primary PANSS negative-symptom endpoint, but the confirmatory Phase 3 (MIN-101C07 / NCT03397134, reported May 2020) narrowly missed its primary endpoint in the ITT analysis (p<=0.064) while reaching nominal significance in the mITT analysis (p<=0.044). Minerva's NDA was submitted Aug 2022, received an FDA refuse-to-file in Oct 2022, was filed on appeal 27 Apr 2023, and received a Complete Response Letter on 27 Feb 2024 (FDA required at least one additional positive adequate and well-controlled study plus concomitant-antipsychotic, clinical-meaningfulness, and longer 64 mg safety data). After a financing of up to $200M (21 Oct 2025), Minerva launched a global confirmatory Phase 3 (MIN-101C19 / NCT07565428; first patient screened 31 Mar 2026; recruiting; topline expected 2H 2027). Current phase therefore remains Phase 3 / active.
Development timeline
- First patient screened in the global confirmatory Phase 3 (MIN-101C19 / NCT07565428, ~380 patients); 12-week placebo-controlled Phase A (primary: Marder NSFS) plus a longer active-controlled relapse phase vs common antipsychotics. Topline expected 2H 2027.↗
- missedFDA issued a Complete Response Letter for the roluperidone NDA; at least one additional positive adequate/well-controlled study required.↗
- missedPhase 3 (MIN-101C07) narrowly missed primary PANSS Marder NSFS endpoint in ITT (p<=0.064); nominally significant in mITT (p<=0.044).↗
- Confirmatory Phase 3 (MIN-101C07 / NCT03397134) initiated; 12-week double-blind placebo-controlled monotherapy in negative symptoms plus a 40-week open-label extension.
- Phase 2b monotherapy study (MIN-101C03; Davidson et al., Am J Psychiatry 2017; n=244) met its primary endpoint: both 32 mg (p<=0.024, d=0.45) and 64 mg (p<=0.004, d=0.57) significantly improved PANSS negative symptoms vs placebo at Week 12.↗
Readouts
- 2H 2027AnticipatedTopline dataNCT07565428
Confirmatory Phase 3 (MIN-101C19) 12-week topline (primary: Marder NSFS) expected 2H 2027. ↗
- 2024-02-27ReportedRegulatorymissed
FDA issued a Complete Response Letter for the roluperidone NDA; at least one additional positive adequate/well-controlled study required. ↗
- 2020-05-29ReportedTopline datamissedNCT03397134
Phase 3 (MIN-101C07) narrowly missed primary PANSS Marder NSFS endpoint in ITT (p<=0.064); nominally significant in mITT (p<=0.044). ↗
Clinical trials in Schizophrenia
NCT07565428MIN-101C19Phase 3Recruitingn=380
Study to Evaluate Efficacy and Safety of Roluperidone in Adult Subjects With Negative Symptoms and Stable Positive Symptoms of Schizophrenia and to Evaluate the Relapse Rate of Roluperidone and Antipsychotic Medications
NCT06107803MIN-101C18Phase 1Completedn=17
A Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Co-Administration of Roluperidone and Olanzapine in Adult Subjects With Moderate to Severe Negative Symptoms of Schizophrenia
NCT03397134MIN-101C07Phase 3Completedn=515
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Monotherapy, 12-Week Study to Evaluate the Efficacy and Safety of 2 Fixed Doses of MIN-101 in Adult Patients With Negative Symptoms of Schizophrenia, Followed by a 40-Week Open-Label Extension
missedsecondaryPersonal and Social Performance (PSP) total score, change from baseline to Week 12 (64 mg) (ITT p<=0.021; mITT p<=0.017)
Key secondary functioning endpoint: nominally favored roluperidone 64 mg, but the trial did not meet its primary endpoint hierarchy, so the result is not confirmatory.
missedprimaryPANSS Marder Negative Symptoms Factor Score (NSFS), change from baseline to Week 12 (64 mg) (ITT p<=0.064; mITT p<=0.044)
Primary endpoint narrowly missed statistical significance in the ITT population (p<=0.064) but reached nominal significance in the modified-ITT population (p<=0.044). Authors attributed the miss to a larger-than-expected placebo response, possibly amplified by expectations following the positive Phase 2b.
Phase 2Completedn=244
Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia (Davidson et al., Am J Psychiatry 2017)
metprimaryPANSS Marder Negative Symptoms Factor Score, change from baseline to Week 12 (32 mg) — Cohen's d = 0.45 (<=0.024)
Roluperidone 32 mg also significantly improved negative symptoms vs placebo at Week 12.
metprimaryPANSS pentagonal/Marder Negative Symptoms Factor Score, change from baseline to Week 12 (64 mg) — Cohen's d = 0.57 (<=0.004)
Roluperidone 64 mg significantly reduced negative symptoms vs placebo at Week 12 (pentagonal/Marder PANSS negative factor). This was the single positive pivotal study later referenced by the FDA.
MIN-101C03Phase 2Completedn=244
Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia (Davidson et al., Am J Psychiatry 2017)
metprimaryPANSS pentagonal/Marder Negative Symptoms Factor Score, change from baseline to Week 12 (64 mg) — Cohen's d = 0.57 (<=0.004)
Roluperidone 64 mg significantly reduced negative symptoms vs placebo at Week 12 (pentagonal/Marder PANSS negative factor). This was the single positive pivotal study later referenced by the FDA.
metprimaryPANSS Marder Negative Symptoms Factor Score, change from baseline to Week 12 (32 mg) — Cohen's d = 0.45 (<=0.024)
Roluperidone 32 mg also significantly improved negative symptoms vs placebo at Week 12.
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Roluperidone oral modified-release tabletgastro-resistant (enteric-coated) modified-release tablet 32 mg or 64 mg once daily, taken in the morning with or without food | Oral | Once daily | t½ 7 h · Tmax 3.5 h |
Mechanism of action
Non-dopaminergic antagonist with high affinity at the 5-HT2A serotonin receptor, the sigma-2 receptor (TMEM97), and the alpha1A-adrenoceptor (in vitro Ki ~8.19, ~7.53 and ~4.17 nM respectively), plus weaker activity at the sigma-1 and alpha1B-adrenoceptor and negligible binding to dopamine (IC50 >1000 nM), muscarinic, cholinergic or histaminergic receptors. This dopamine-sparing profile is hypothesized to improve the primary negative symptoms of schizophrenia (e.g., avolition, blunted affect) without the dopamine-blockade liabilities of conventional antipsychotics.
| Target | Action | Affinity |
|---|---|---|
| 5-HT2AprimaryHTR2A | Antagonist | Ki 8.19 nMⓘ |
| alpha-1A adrenoceptorADRA1A | Antagonist | Ki 4.17 nMⓘ |
| sigma-2 receptorTMEM97 | Antagonist | Ki 7.53 nMⓘ |
← Full MIN-101 compound page (identity, identifiers, all indications)
Sources
- Confirmatory Phase 3 study of roluperidone in negative symptoms of schizophrenia (MIN-101C19, NCT07565428) — ClinicalTrials.gov
- Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial (Phase 2b; Davidson et al. 2017) — American Journal of Psychiatry
- Efficacy and Safety of Roluperidone for the Treatment of Negative Symptoms of Schizophrenia (Phase 3 results) — Schizophrenia Bulletin (PMC)
- Minerva Neurosciences announces first patient screened in global confirmatory Phase 3 of roluperidone (31 Mar 2026) — Minerva Neurosciences (GlobeNewswire)
- Minerva Neurosciences receives FDA Complete Response Letter for roluperidone NDA (27 Feb 2024) — Minerva Neurosciences (GlobeNewswire)
- Phase 3 study of roluperidone (MIN-101) in negative symptoms of schizophrenia (MIN-101C07, NCT03397134) — ClinicalTrials.gov
- Roluperidone + olanzapine co-administration PK/PD/safety study (MIN-101C18, NCT06107803) — ClinicalTrials.gov
- Roluperidone monotherapy, a treatment for negative symptoms in schizophrenia — International Journal of Neuropsychopharmacology (Oxford)