FDA Approves Milsaperidone for Bipolar I and Schizophrenia in Adults
Key Clinical Summary
- The FDA has approved milsaperidone (BYSANTI), an atypical antipsychotic, for schizophrenia and acute manic or mixed episodes in bipolar I disorder in adults.
- Milsaperidone is bioequivalent to iloperidone (Fanapt) and rapidly interconverts to iloperidone, leveraging prior efficacy and safety data.
- The drug carries a boxed warning for increased mortality in elderly patients with dementia-related psychosis and requires QTc and metabolic monitoring.
The US Food and Drug Administration (FDA) has approved milsaperidone (BYSANTI) for the treatment of schizophrenia in adults and for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, announced manufacturer Vanda Pharmaceuticals. The agent is classified as a new chemical entity (NCE) atypical antipsychotic.
Iloperidone Bioequivalence Drives Approval
Milsaperidone rapidly interconverts to iloperidone (Fanapt), resulting in dual active moieties that antagonize dopamine D2, serotonin 5-HT2A, and alpha1-adrenergic receptors. In clinical studies, milsaperidone demonstrated bioequivalence to iloperidone across the therapeutic dosing spectrum. As a result, its approval leverages iloperidone’s established clinical development program and real-world data.
Prior iloperidone trials cited in the announcement include phase 3 studies in schizophrenia, a 4-week double-blind, placebo- and ziprasidone-controlled trial in acute exacerbations of schizophrenia, a relapse-prevention study (REPRIEVE), and a double-blind, placebo-controlled trial in bipolar mania.
Safety Considerations
Common adverse reactions in schizophrenia included orthostatic hypotension, somnolence, tachycardia, and weight gain. In bipolar mania, commonly observed reactions included tachycardia, elevated hepatic enzymes, nasal congestion, weight gain, hypotension, and somnolence.
Milsaperidone carries a boxed warning for increased mortality in elderly patients with dementia-related psychosis and is not approved in that population. Additional warnings include QTc prolongation, neuroleptic malignant syndrome (NMS), tardive dyskinesia (TD), metabolic changes, leukopenia/agranulocytosis, hyperprolactinemia, orthostatic hypotension, and seizure risk. Dose adjustments are required with strong CYP2D6 and/or CYP3A4 inhibitors, and CYP2D6 genetic testing should be considered.
Clinical Implications
Monitoring considerations for milsaperidone align closely with iloperidone, particularly regarding QTc interval prolongation and orthostatic hypotension. Clinicians should assess cardiovascular risk, review concomitant QT-prolonging medications, and monitor electrolytes in at-risk patients.
Metabolic monitoring for hyperglycemia, dyslipidemia, and weight gain remains essential. Attention to white blood cell counts in vulnerable patients and consideration of CYP2D6 metabolizer status prior to dosing may help mitigate adverse effects and optimize treatment selection.
Expert Commentary
“The BYSANTI approval marks a significant step forward, offering patients and providers a reliable new treatment grounded in extensive clinical heritage,” said Mihael H. Polymeropoulos, MD, President, CEO, and Chairman of the Board of Vanda Pharmaceuticals. He added that the drug “exemplifies a new era of accelerated innovation in drug development that can transform how we address unmet needs in behavioral health.”
The company expects the drug to be commercially available by the third quarter of 2026. Milsaperidone is also being evaluated as a once-daily adjunctive treatment in treatment-resistant major depressive disorder (MDD) in an ongoing clinical trial, with results expected by the end of the year.
