Minerva Neurosciences (NERV) Study update summary

Roluperidone clinical evidence

• Roluperidone has no direct dopamine-blocking effect; its reported targets include 5-HT2A, sigma-2 and alpha-1 receptors. Preclinical work showed increased BDNF and GDNF transcription and release.

• C03 showed a strong 64 mg vs placebo difference on negative symptoms after 12 weeks; C07 retained an efficacy signal, while PSP functioning improved in both studies.

• Reanalysis of C03 found a difference on the primary stability-weighted score (P=0.03), but not the secondary score (P=0.61); analyses linked early motivation improvement to later gains across negative symptom domains, replicated in C07.

• Responder analysis showed ~38% on 64 mg improved >20% on the primary endpoint vs ~22% on placebo; reported numbers needed to treat across three analyses were 7, 8 and 9.

• Bayesian analysis required <20% borrowing from C03 for a highly positive result on NSFS and PSP; global statistical tests combining negative symptoms and functioning were significant in C03 and C07.

C19 study and development

• C19 is enrolling and reported on track; Phase A tests 64 mg vs placebo for 12 weeks on NSFS, with results expected in H2 next year.

• Phase B is designed as a descriptive comparison of relapse rates on roluperidone vs antipsychotics in the selected study population; it will not support formal statistical testing.

• Study criteria target stable patients with impairing negative symptoms, limiting fluctuation and secondary causes to assess effects on primary, disease-related negative symptoms.

• C19 includes end-of-study questions on quality-of-life change; exit interviews will be considered alongside PSP, PANSS and NSFS results.

• A small C18 study found co-administration with olanzapine safe; preclinical data indicated limited drug-interaction risk.

Patient population and treatment rationale

• Primary negative symptoms were distinguished from secondary symptoms associated with depression, anxiety, psychosis or medication effects; speakers linked the primary phenotype to poorer functioning and described roluperidone as improving primary, not secondary, symptoms.

• In CATIE, 68%-69% of patients meeting entry criteria remained relapse-free at the last data point vs 58%-59% who did not meet criteria; other analyses associated low positive and high negative symptom profiles with lower relapse risk.

• Clinical panelists discussed possible use as monotherapy or with gradual antipsychotic tapering, and identified non-adherent patients, patients off antipsychotics with persistent negative symptoms, and some first-episode patients as potential groups.

• The speakers described possible future study opportunities beyond schizophrenia, including schizoaffective disorder, residual symptoms in major depression, apathy in Alzheimer’s and Parkinson’s disease, and other conditions; these were presented as hypotheses, not established uses.