Small Molecule · VHX-896
Milsaperidone (VHX-896)
Oral atypical antipsychotic and new chemical entity (brand: Bysanti) developed by Vanda Pharmaceuticals. Milsaperidone is the (S)-enantiomer of the major active metabolite of iloperidone (formed by carbonyl reduction; historical metabolite code P-88-8991); administered orally it rapidly interconverts to iloperidone and the two are bioequivalent across the therapeutic dosing range. It antagonizes dopamine D2, serotonin 5-HT2A and alpha1-adrenergic receptors, with a distinctive profile of strong alpha-adrenergic binding in excess of its dopamine and serotonin binding. FDA-approved (Feb 2026) for bipolar I disorder (acute manic/mixed episodes) and schizophrenia; for major depressive disorder it is in Phase 3 as a once-daily ADJUNCTIVE treatment (treatment-resistant MDD).
Also known as: VHX-896, P-88-8991, Bysanti, milsaperidone, (S)-hydroxy iloperidone, 501373-88-2
- Modality
- Small molecule
- Chemical class
- benzisoxazole, piperidine
- DEA schedule
- Unscheduled
- Chemistry
- Single enantiomer
- Mechanism
- 5-HT2A antagonist
- Highest phase
- Approved
- Lead indication
- Major depressive disorder
- Developer
- Vanda Pharmaceuticals Inc. (VNDA)
- Trials
- 3 tracked · 1 recruiting · 65 sites
- Next catalyst
- 2026 — Topline data (Major depressive disorder)
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ⓘ |
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 |
Development timeline
- UpcomingTopline data anticipated from the Phase 3 adjunctive MDD study of milsaperidone (Bysanti).Major depressive disorder↗
- On FDA approval of Bysanti for bipolar I and schizophrenia, Vanda restated that Bysanti remains in an ongoing Phase 3 study as a once-daily adjunctive treatment in treatment-resistant MDD, expected to complete by end of 2026. MDD remains investigational (Phase 3).Major depressive disorder↗
- Vanda (Q1 2025 results, SEC Form 8-K) confirmed the Bysanti Phase 3 once-daily adjunctive MDD study is ongoing with results expected in 2026; same filing reported the Bysanti NDA (bipolar I / schizophrenia, not MDD) accepted for filing with a 21 Feb 2026 PDUFA date.Major depressive disorder↗
- Phase 3 adjunctive MDD study NCT06830044 (milsaperidone vs placebo as add-on to ongoing antidepressant; primary MADRS at week 6; target n=500) initiated; program first announced by Vanda as initiated in Q4 2024 with results expected in 2026.Major depressive disorder
- 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.Bipolar disorder
- metFDA approves Bysanti (milsaperidone) for the acute treatment of manic or mixed episodes associated with bipolar I disorder (co-approved with schizophrenia).Bipolar disorder↗
- 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.Bipolar disorder↗
Milsaperidone (VHX-896) for Major depressive disorder
Phase 3ActiveMajor depressive disorder indication →
Ongoing Phase 3 study of milsaperidone (Bysanti) as once-daily ADJUNCTIVE therapy in major depressive disorder (treatment-resistant MDD). Phase 3 study NCT06830044 (initiated Q4 2024, first listed start 3 Mar 2025; recruiting) evaluates milsaperidone vs placebo added to ongoing antidepressant therapy, primary endpoint MADRS change at 6 weeks. Vanda has stated results are expected in 2026 (the registry lists primary completion in March 2028 - see _comment). MDD is a development indication only: milsaperidone is FDA-approved (20 Feb 2026) for bipolar I and schizophrenia, NOT for MDD.
Readouts
- 2026AnticipatedTopline dataNCT06830044
Topline data anticipated from the Phase 3 adjunctive MDD study of milsaperidone (Bysanti). ↗
Milsaperidone (VHX-896) for Bipolar disorder
ApprovedApprovedBipolar disorder indication →
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.
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
NCT06830044Phase 3Recruitingn=500
A Randomized, Double-Blind, Placebo-controlled Multicenter Study to Assess the Efficacy and Safety of Milsaperidone as Adjunctive Therapy in the Treatment of Patients With Major Depressive Disorder
NCT04969211Phase 1Completedn=25
An Open-Label, Two-Period, Randomized, Single Oral Dose, Crossover Study to Evaluate the Bioequivalence of VHX-896 Tablets Relative to Iloperidone Tablets in Healthy Volunteers
metprimarySingle-dose bioequivalence of VHX-896 vs iloperidone (Cmax, AUC)
Single-dose crossover study supporting that VHX-896 (milsaperidone) interconverts to iloperidone; plasma exposure parameters fell within standard regulatory bioequivalence limits relative to iloperidone. Supports the metabolite-bridging development strategy underlying all milsaperidone indications, including the adjunctive MDD program.
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').
Identifiers
- PubChem CID 10365268
- FDA UNII 7SV1ZOG031
Sources
- Bioequivalence study between VHX-896 and iloperidone tablets in healthy volunteers (NCT04969211) — ClinicalTrials.gov
- 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
- Phase 3 study of milsaperidone as adjunctive therapy in MDD (NCT06830044) — 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.
- Vanda Pharmaceuticals Form 8-K (filed 23 Feb 2026, dated 20 Feb 2026) - FDA approval of Bysanti (milsaperidone) for bipolar I and schizophrenia; ongoing Phase 3 adjunctive treatment-resistant MDD study expected to complete by end of 2026; D2/5-HT2A/alpha1 antagonism — U.S. SEC EDGAR / Vanda Pharmaceuticals Inc.