Efficacy and Safety of Roluperidone for the Treatment of Negative Symptoms of Schizophrenia

Abstract

Background This is a placebo-controlled multi-national trial of roluperidone, a compound with antagonist properties for 5-HT2A, sigma2, and α1A-adrenergic receptors, targeting negative symptoms in patients with schizophrenia. This trial follows a previous trial that demonstrated roluperidone superiority over placebo in a similar patient population. Methods Roluperidone 32 mg/day, roluperidone 64 mg/day, or placebo was administered for 12 weeks to 513 patients with schizophrenia with moderate to severe negative symptoms. The primary endpoint was the PANSS-derived Negative Symptom Factor Score (NSFS) and the key secondary endpoint was Personal and Social Performance scale (PSP) total score. Results NSFS scores were lower (improved) for roluperidone 64 mg compared to placebo and marginally missing statistical significance for the intent-to-treat (ITT) analysis data set (P ≤ .064), but reached nominal significance (P ≤ .044) for the modified-ITT (m-ITT) data set. Changes in PSP total score were statistically significantly better on roluperidone 64 mg compared to placebo for both ITT and m-ITT (P ≤ .021 and P ≤ .017, respectively). Conclusions Results of this trial confirm the potential of roluperidone as a treatment of negative symptoms and improving everyday functioning in patients with schizophrenia. Study registration: Eudra-CT: 2017-003333-29; NCT03397134.

Progress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia

“…In the field of modifications of serotonergic neurotransmission, the most promising results were reported for the 5HT 2A receptor antagonist roluperidone (MIN-101) [214][215][216], pimavanserin (already approved by the FDA for hallucinations and delusions in patients with Parkinson´s disease) [209,211,212] and the selective 5-HT 6 receptor antagonist AVN-211 [217,218]. The efficacy of pimavanserin and AVN-211 are currently being intensively investigated in large clinical trials.…”

“…Improvement of negative symptoms (marginally missing statistical significance), and statistically significant improvements in the Personal and Social Performance Scale total score under roluperidone 64 mg/day (phase II study, n = 513) [ 215 ]…”

“…Results of a post hoc analysis suggested a possible benefit on cognitive performance that correlated significantly with the improvement of negative symptoms [ 214 ]. In a large phase III study (NCT03397134, sponsored by Minerva Neurosciences; n = 513), monotherapy with roluperidone (64 mg/day) improved negative symptoms in the modified intent-to-treat dataset marginally missing statistical significance, whereas improvements in the Personal and Social Performance Scale total score were statistically significant [ 215 ]. The only cognitive endpoint in this study (verbal fluency) did not change significantly.…”

A New Treatment Paradigm

“…This has led to interest in developing agents that specifically target 5-HT 2A receptors, which regulate glutamatergic and dopaminergic transmission 93 . One such agent, roluperidone, is an antagonist at 5-HT 2A , σ 2 , and α 1A -adrenergic receptors 94 . In a 12-week phase 3 trial conducted in patients with stable schizophrenia who had moderate-to-severe negative symptoms, roluperidone monotherapy versus placebo marginally missed statistically significant improvement for the primary end point, the PANSS-derived Negative Symptom Factor Score, in the intent-to-treat data set 94 .…”

“…93 One such agent, roluperidone, is an antagonist at 5-HT 2A , σ 2 , and α 1A -adrenergic receptors. 94 In a 12-week phase 3 trial conducted in patients with stable schizophrenia who had moderate-to-severe negative symptoms, roluperidone monotherapy versus placebo marginally missed statistically significant improvement for the primary end point, the PANSS-derived Negative Symptom Factor Score, in the intent-to-treat data set. 94 However, the improvement associated with roluperidone did reach statistical significance in a modified intent-to-treat data set that excluded participants from one site that had reported implausible behavioral and physiologic data.…”