An approved drug to specifically treat primary negative symptoms in schizophrenia is still lacking. A confirmatory trial showed that roluperidone monotherapy can improve primary negative symptoms and stabilise or even improve other symptoms in schizophrenia .
Roluperidone (MIN-101) has high affinities for a specific subtype of serotonin receptor called 5-HT2A, a sigma receptor subtype called sigma2, and the α-adrenergic subtype α1A, which are involved in regulating mood, cognition, sleep, and anxiety. They were designed to avoid direct blockade of dopaminergic, cholinergic, and histaminergic receptors.
Following a multinational, phase 2b trial (n=244) with positive results, a confirmatory phase 3 trial was recently conducted . Included were 513 patients with moderate-to-severe negative symptoms of schizophrenia. They were randomised 1:1:1 to roluperidone 32 mg/day, 64 mg/day, or placebo for 12 weeks. They could then enter a 40-week, open-label extension (OLE), designed to evaluate the safety of long-term exposure to roluperidone. Patients who had received roluperidone continued to receive the same dose, while patients who had received placebo were re-randomised to 32 or 64 mg/day. The primary endpoint was the Positive and Negative Syndrome Scale (PANSS)-derived Negative Symptoms Factor Score (NSFS); the key secondary endpoint was Personal and Social Performance (PSP) total score.
After 12 weeks, NSFS scores were more favourable on roluperidone 64 mg compared with placebo for the modified intent-to-treat population (P≤0.044); it was modified because data contributed by one centre was unreliable and therefore excluded. PSP total score was statistically significantly superior on roluperidone 64 mg than on placebo (P≤0.021). An unexplained difference between the phase 2 and phase 3 trial was the magnitude of the placebo effect, which was notably higher in the phase 3 trial.
A total of 333 patients (65%) entered the OLE of the phase 3 trial; 166 were treated with the 32-mg dose, 167 with the 64-mg dose. Of these 333 patients, 202 (61%) completed the 40-week period. Negative symptoms, daily functioning, and total PANSS scores continued to improve, while positive symptoms remained stable. A low dropout rate due to relapse of 11.7% overall was observed during the 52 weeks of the study. Roluperidone was well tolerated without major or unexpected adverse events.
- Davidson M. A phase 3 trial of roluperidone, a drug for the treatment of negative symptoms in schizophrenia. S.09.03, ECNP 2021 Congress, 2–5 October.
- Harvey PD, et al. Schizophr Res. 2020;215:352–6.
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