MIN-101 (Roluperidone)
antipsychotic · negative symptoms (apathy, blunted affect, withdrawal) class / antipsychoticspec sheet6 rows
MIN-101 (Roluperidone) Roluperidone (MIN-101) is Minerva Neurosciences' attempt at an antipsychotic that deliberately avoids dopamine D2 blockade, the mechanism behind essentially every marketed antipsychotic and the reason they do so little for negative symptoms. Instead it works through sigma-2 receptor antagonism plus 5-HT2A and alpha1-adrenergic blockade, a combination chosen specifically to target apathy, blunted affect, and social withdrawal without the motor side effects of D2 blockade. One pivotal 12-week trial (Davidson et al, 2017) hit its primary endpoint on negative symptoms; Minerva filed a New Drug Application with the FDA on the strength of that single study. In February 2024 the FDA issued a Complete Response Letter, ruling that one positive trial alone wasn't substantial evidence of effectiveness and flagging gaps in long-term safety exposure at the proposed dose, so roluperidone remains unapproved in the US as of this writing.
- met primary endpoint for negative symptoms in a pivotal 12-week trial
- avoids D2-receptor motor side effects since it does not block dopamine directly
- good tolerability and metabolic profile reported across trials
- Roluperidone was actually studied first as a metabolite pathway of an older, unrelated antipsychotic program before Minerva repositioned it as a standalone negative-symptoms drug.
Mechanism
at sigma-2 receptors, receptors, and alpha1A- receptors, notably without direct receptor blockade.
Safetyrisks and cautions, not medical advice
Only patients carrying at least one working copy of the CYP2D6 enzyme were meant to receive roluperidone, because a metabolite called BFB-520 accumulates in poor metabolizers and prolongs the QT interval. No torsades de pointes, seizures, myocardial ischemia or deaths were reported in the patient trials, and across open-label extensions running 24 and 40 weeks there were no meaningful changes in vital signs, laboratory values, weight, metabolic measures or movement side effects. Headache, insomnia, agitation, somnolence, nausea and anxiety were the common complaints. The FDA still judged the twelve-month exposure at 64 mg insufficient.
History
Developed by Minerva Neurosciences (originally licensed from Marion Merrell Dow-derived assets); pivotal Phase IIb/III trial (MIN-101C03) met its primary endpoint in 2017, but the FDA issued a Complete Response Letter in February 2024 citing insufficient evidence from a single trial and inadequate long-term safety data.
Subjective profileweighing the evidence above
A genuinely novel non-dopaminergic mechanism for negative symptoms that got tantalizingly close to approval and then stalled on regulatory rather than purely scientific grounds.
Resources
This entry is here for reference.
Research
1 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Is roluperidone approved anywhere?
As of the FDA's February 2024 Complete Response Letter, it is not approved in the United States; Minerva Neurosciences has been pursuing additional data to address the FDA's concerns.
How is roluperidone different from typical antipsychotics?
Most antipsychotics work by blocking dopamine D2 receptors. Roluperidone instead targets sigma-2, serotonin 5-HT2A, and alpha1-adrenergic receptors, aiming at negative symptoms that D2 blockers don't help much.
Notes and cautions
- FDA found the efficacy evidence insufficient from a single pivotal trial
- inadequate long-term (12-month) safety exposure data at the proposed 64 mg dose
- still requires further trials before any approval decision