VHX-896 · program
Milsaperidone (VHX-896) for Bipolar disorder
Indications for VHX-896: Major depressive disorder · Phase 3 Bipolar disorder · Approved
Milsaperidone (Bysanti) is FDA-approved (20 Feb 2026; NDA 220358) for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, co-approved alongside schizophrenia. The FDA label (Initial U.S. Approval 2026, Reference ID 5749766) supports the bipolar I claim with a single bipolar I manic/mixed study ('Study 4'), bridged from iloperidone via documented in-vivo interconversion of milsaperidone and iloperidone and bioequivalence across the therapeutic dosing range; the underlying pivotal trial is Vanda's Phase 3 acute-mania study NCT04819776 (iloperidone, 4-week, primary endpoint YMRS change at Week 4, primary endpoint met). Bysanti is dosed orally twice daily with titration to limit orthostatic hypotension. Vanda has guided to commercial availability in Q3 2026.
Development timeline
- metFDA approves Bysanti (milsaperidone) for the acute treatment of manic or mixed episodes associated with bipolar I disorder (co-approved with schizophrenia).↗
- Vanda's Bysanti (milsaperidone) NDA 220358, covering both schizophrenia and acute manic/mixed episodes of bipolar I disorder, was submitted to FDA (FDA received the application 21 Feb 2025; the May 2025 8-K reported acceptance for filing with a 21 Feb 2026 PDUFA date). Bipolar I efficacy bridged from iloperidone studies.↗
- Pivotal Phase 3 acute bipolar I mania trial NCT04819776 (iloperidone, 4-week, n=417 enrolled / 414 dosed) reached primary completion; primary endpoint (YMRS change from baseline to Week 4) was met (LS-mean difference vs placebo -4.0, 95% CI -5.70 to -2.25, adjusted p=0.000008). This iloperidone trial became the registration basis for milsaperidone's bipolar I claim via the documented in-vivo interconversion/bioequivalence bridge.
Readouts
- 2026-02-20ReportedRegulatorymet
FDA approves Bysanti (milsaperidone) for the acute treatment of manic or mixed episodes associated with bipolar I disorder (co-approved with schizophrenia). ↗
Clinical trials in Bipolar disorder
NCT04819776VP-VYV-683-3201Phase 3Completedn=417
A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Iloperidone for 4 Weeks in the Treatment of Patients With Acute Manic Episodes Associated With Bipolar I Disorder
metprimaryChange from baseline to Week 4 in Young Mania Rating Scale (YMRS) total score — LS-mean difference vs placebo -4.0 (95% CI -5.70 to -2.25) (0.000008)
Iloperidone (titrated to 24 mg/day) significantly reduced YMRS total score versus placebo at Week 4 (LS-mean difference -4.0, 95% CI -5.70 to -2.25, adjusted p=0.000008) in adults with acute manic episodes of bipolar I disorder; CGI-S, CGI-C and YMRS responder endpoints were also significant. n=417 enrolled / 414 dosed (mITT 392). This is an ILOPERIDONE trial; it serves as the registration basis for milsaperidone's bipolar I claim via the milsaperidone-iloperidone in-vivo interconversion/bioequivalence bridge described in the FDA Bysanti label (bipolar I 'Study 4').
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Bysanti oral tablet Immediate-release oral tablets, 1/2/4/6/8/10/12 mg; schizophrenia target 6-12 mg twice daily, bipolar I mania 12 mg twice daily | Oral | Twice daily | t½ 26 h · Tmax 4 h |
Mechanism of action
Atypical antipsychotic that, with its interconversion partner iloperidone, antagonizes dopamine D2, serotonin 5-HT2A and alpha1-adrenergic receptors; the metabolite shows highest affinity at 5-HT2A, with strong alpha1-adrenergic binding in excess of its dopamine D2 binding. Published receptor data are for the racemic P88-8991 metabolite (Subramanian & Kalkman 2002): pKi 5-HT2A 9.56 (~0.28 nM), alpha1-adrenergic 8.08 (~8.3 nM), D2A 7.80 (~16 nM); lower affinity at other dopamine, serotonin, alpha2-adrenergic and histamine H1 receptors. In MDD it is being studied as adjunctive (add-on) therapy to ongoing antidepressants, consistent with the atypical-antipsychotic adjunctive-depression mechanism.
| Target | Action | Affinity |
|---|---|---|
| 5-HT2AprimaryHTR2A | Antagonist | Ki 0.28 nMⓘ |
| alpha-1A adrenoceptorADRA1A | Antagonist | Ki 8.3 nMⓘ |
| D2DRD2 | Antagonist | Ki 15.8 nMⓘ |
← Full VHX-896 compound page (identity, identifiers, all indications)
Sources
- BYSANTI (milsaperidone) Highlights of Prescribing Information, NDA 220358 — U.S. Food and Drug Administration (Drugs@FDA)
- Bysanti (milsaperidone): Side Effects, Uses, Dosage, Interactions, Warnings (FDA prescribing information) — RxList / FDA label
- Efficacy and Safety of Iloperidone in Bipolar Mania: A Double-Blind, Placebo-Controlled Study (Torres et al, J Clin Psychiatry) - YMRS Week 4 difference -4.0 (95% CI -5.70 to -2.25), p=0.000008 — The Journal of Clinical Psychiatry
- Phase 3 study of iloperidone for 4 weeks in acute manic episodes of bipolar I disorder (NCT04819776; Vanda; YMRS Week 4 primary endpoint) - registration basis for milsaperidone's bipolar I claim — ClinicalTrials.gov
- Receptor profile of P88-8991 and P95-12113, metabolites of the novel antipsychotic iloperidone (Subramanian & Kalkman, Prog Neuropsychopharmacol Biol Psychiatry 2002;26(3):553-60) — Progress in Neuropsychopharmacology & Biological Psychiatry (PubMed)
- Vanda Pharmaceuticals Form 8-K (7 May 2025) - Q1 2025 results: Bysanti NDA accepted for filing (PDUFA 21 Feb 2026); Phase 3 adjunctive MDD study ongoing, results expected 2026 — U.S. SEC EDGAR / Vanda Pharmaceuticals Inc.