non-racemic amisulpride (SEP-4199) / Sumitomo Pharma, Otsuka - LARVOL DELTA

Enrichment using speech latencies improves treatment effect size in a clinical trial of bipolar depression. (PubMed, Psychiatry Res) - "Speech data was obtained from 274 participants during 1,352 Montgomery-Åsberg Depression Rating Scale (MADRS) recordings in a randomized, placebo controlled, 6-week clinical trial of SEP-4199 (200 mg or 400 mg)...Excluding SL-Normal increased primary outcome effect size by 52 % and 100 % for the treatment arms. Turn latencies are an objective measure available from standard clinical assessments and may assess the severity of symptoms more accurately and screen out placebo responders."

Journal • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

A clinical trial inclusion criteria to enrich for patients presenting with canonical symptom structure in bipolar depression. (PubMed, Contemp Clin Trials) - P2, P3 | "This novel enrichment method has been prospectively implemented in a Phase 3 clinical study of SEP-4199 and is consistent with regulatory guidelines aimed at increasing the statistical power and lowering patient-burden in clinical trials. Clinical Trials Registry: NCT00868452, NCT00868699, NCT01284517, NCT01986101, NCT03543410, NCT05169710."

Journal • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

Discovery and Model-Informed Drug Development of a Controlled-Release Formulation of Nonracemic Amisulpride that Reduces Plasma Exposure but Achieves Pharmacodynamic Bioequivalence in the Brain. (PubMed, Clin Pharmacol Ther) - "Nonracemic amisulpride (SEP-4199) is an investigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression...By mathematically solving for a drug distribution step into an effect compartment, and for binding to target receptors, the discovery of a novel PK/PD model (termed here as Distribution Model) accounted for hysteresis between plasma and brain, a lack of receptor saturation, and an absence of accumulation of drug occupancy with daily doses. The PK/PD disconnect solved by the Distribution Model provided model-informed drug development to continue in Phase III using the non-bioequivalent CR formulation with diminished QT prolongation as dose-equivalent to the immediate release (IR) formulation utilized in Phase II."

Journal • PK/PD data • Bipolar Disorder • CNS Disorders • Depression • Psychiatry • DRD2

A Clinical Trial to Determine the Long-term Safety and Tolerability of an Investigational Drug in People With Major Depressive Episode Associated With Bipolar I Disorder (Bipolar I Depression). (clinicaltrials.gov) - P3 | N=64 | Terminated | Sponsor: Sumitomo Pharma America, Inc. | N=355 ➔ 64 | Trial completion date: May 2029 ➔ Nov 2023 | Enrolling by invitation ➔ Terminated; Company decided not to move forward with further accrual.

Enrollment change • Trial completion date • Trial termination • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

A Clinical Study of an Investigational Drug for the Treatment of Major Depressive Episode Associated With Bipolar I Disorder. (clinicaltrials.gov) - P3 | N=83 | Terminated | Sponsor: Sumitomo Pharma America, Inc. | N=522 ➔ 83 | Trial completion date: May 2025 ➔ Oct 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: May 2025 ➔ Oct 2023; Company decided not to move forward with further accrual.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

A narrative review of non-racemic amisulpride (SEP-4199) for treatment of depressive symptoms in bipolar disorder and LB-102 for treatment of schizophrenia. (PubMed, Expert Rev Clin Pharmacol) - "Recent phase 2 trials have demonstrated SEP-4199's efficacy in treating depressive symptoms in bipolar disorder I, capitalizing on D2-mediated anti-anhedonic and D3-mediated reward effects. The development of SEP-4199 presents a potential breakthrough for managing depressive symptoms in bipolar disorder I. Further exploration of D2 and D3 receptor-mediated effects could lead to improved treatment strategies."

Journal • Review • Bipolar Disorder • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • Schizophrenia

A Clinical Study of an Investigational Drug for the Treatment of Major Depressive Episode Associated With Bipolar I Disorder. (clinicaltrials.gov) - P3 | N=522 | Active, not recruiting | Sponsor: Sumitomo Pharma America, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

A Clinical Trial to Determine the Long-term Safety and Tolerability of an Investigational Drug in People With Major Depressive Episode Associated With Bipolar I Disorder (Bipolar I Depression). (clinicaltrials.gov) - P3 | N=355 | Enrolling by invitation | Sponsor: Sunovion | Not yet recruiting ➔ Enrolling by invitation | Trial completion date: May 2026 ➔ May 2029 | Trial primary completion date: May 2026 ➔ May 2029

Enrollment open • Trial completion date • Trial primary completion date • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

This is a Clinical Trial to Determine the Long-term Safety and Tolerability of an Investigational Drug in People With Major Depressive Espisode Associated With Bipolar I Disorder (Bioplar I Depression). (clinicaltrials.gov) - P3 | N=355 | Not yet recruiting | Sponsor: Sunovion

New P3 trial • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

A Clinical Study of an Investigational Drug for the Treatment of Major Depressive Episode Associated With Bipolar I Disorder. (clinicaltrials.gov) - P3; N=522; Recruiting; Sponsor: Sunovion; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

A Clinical Study of an Investigational Drug for the Treatment of Major Depressive Episode Associated With Bipolar I Disorder. (clinicaltrials.gov) - P3; N=522; Not yet recruiting; Sponsor: Sunovion

Clinical • New P3 trial • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

A Randomized, Double-blind, Placebo-controlled Proof-of-Concept Trial to Evaluate the Efficacy and Safety of Non-racemic Amisulpride (SEP-4199) for the Treatment of Bipolar I Depression. (PubMed, J Affect Disord) - "Study results provide preliminary proof of concept, needing confirmation in subsequent randomized trials, for the efficacy of non-racemic amisulpride in bipolar depression."

Clinical • Journal • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

Sunovion, Sumitomo Dainippon Pharma and Otsuka Enter Worldwide Development and Commercialization Collaboration (Businesswire) - "Sunovion Pharmaceuticals Inc...its parent company Sumitomo Dainippon Pharma Co., Ltd. (Sumitomo Dainippon Pharma) and Otsuka Pharmaceutical Co., Ltd. (Otsuka) announced today that the companies have entered into a worldwide license agreement for the joint development and commercialization of four compounds: ulotaront (SEP-363856), non-racemic ratio of amisulpride enantiomers (SEP-4199), SEP-378614 and SEP-380135....Upon the completion of the agreement, in addition to an upfront payment of USD 270 million, Sunovion is eligible for development milestone payments of up to USD 620 million for the four compounds and relevant sales milestone payments."

Licensing / partnership • Alzheimer's Disease • CNS Disorders • Depression • Major Depressive Disorder • Parkinson's Disease • Schizophrenia

Discovery of Non-racemic Amisulpride to Maximize Benefit/Risk of 5-HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders. (PubMed, Clin Pharmacol Ther) - P2 | "In contrast to the dose-occupancy relationship in the treatment of schizophrenia, the minimal effective level of dopamine receptor 2 (D2R) blockade for antipsychotics in the treatment of bipolar depression is unknown. These results led to the discovery of an 85:15 ratio of aramisulpride to esamisulpride (SEP-4199) that maximizes the potential for antidepressant benefit of aramisulpride via 5-HT7R and reduces esamisulpride to minimize D2R-related extrapyramidal side effects while still retaining D2R-mediated effects predicted to provide benefit in bipolar depression. SEP-4199 was recently evaluated in a proof of concept trial for the treatment of bipolar depression (NCT03543410)."

Benefit-risk assessment • Journal • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry • Schizophrenia

Sunovion Highlights Data from Its Late-Stage Psychiatric Medicine Pipeline at the American College of Neuropsychopharmacology (ACNP) Annual Meeting 2020 (Businesswire) - P2, N=344; NCT03543410; Sponsor: Sunovion; "Sunovion Pharmaceuticals Inc. (Sunovion) today announced that new data and analyses...at the 59th Annual Meeting of the American College of Neuropsychopharmacology virtual meeting...The primary analysis...showed numerical improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score after six weeks of treatment...Additional posters presented at the ACNP 2020 virtual meeting...discussed study results that allowed the discovery of the ratio of aramisulpride and esamisulpride to optimize the antidepressant efficacy of SEP-4199."

Clinical data • P2 data • CNS Disorders • Depression

[VIRTUAL] A Randomized, Double-Blind, Placebo-Controlled Study of SEP-4199 for the Treatment of Patients With Bipolar Depression (ACNP 2020) - "In this 6-week, double-blind trial of bipolar I patients with an acute major depressive episode, treatment with SEP-4199, in fixed doses of 200 and 400 mg/d, showed a strong trend to improvement for both doses on the MADRS compared with placebo in the primary analysis subgroup (P=0.054 and 0.054, respectively). In the full ITT analysis population, significant improvement was observed on the MADRS and the QIDS-SR-16 for both doses of SEP-4199 versus placebo. SEP-4199 doses of 200-400 mg/d were safe and well-tolerated during short-term treatment."

Clinical • Alzheimer's Disease • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

[VIRTUAL] Discovery and Development of SEP-4199 and Characterization of its Enantiomer-Specific Pharmacology (ACNP 2020) - "Background: We report here the discovery that the pharmacology of amisulpride is enantiomer-specific with antagonist activity at the 5-HT7 receptor residing in the R-enantiomer. The results of these three studies suggest that doses of 200 and 400 mg/d of SEP-4199 (in a ratio of 85% aramisulpride to 15% esamisulpride) will provide clinically significant 5-HT7 receptor antagonist activity, based on REM suppression as a proxy measure. In addition, this dose range provides a significant reduction in D2 receptor occupancy (peak range, 25% to 38%) which is expected to minimize dopamine blockade-related adverse effects. SEP-4199 is expected to have antidepressant and antimanic effects and is currently being developed for the treatment of bipolar depression."

Alzheimer's Disease • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

Sunovion Announces Topline Results from Global Phase 2 Study of SEP-4199 in Patients with Bipolar I Depression (Businesswire) - P2, N=344; NCT03543410; Sponsor: Sunovion; "Sunovion Pharmaceuticals Inc. (Sunovion) today announced topline results from study SEP380-201...for the treatment of major depressive episodes associated with bipolar I disorder (bipolar I depression)....SEP-4199 showed numerical improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score compared to placebo after six weeks of treatment....While the study did not meet its primary endpoint, a relatively large improvement in MADRS total score was observed....'The results of this study will guide us as we consider our plans to start Phase 3 studies.'"

P2 data • Bipolar Disorder • CNS Disorders • Depression

A Clinical Study to Test the Effectiveness of an Investigational Drug to Treat People That Have Major Depressive Episodes When They Have Bipolar 1 Depression (clinicaltrials.gov) - P2; N=344; Completed; Sponsor: Sunovion; Active, not recruiting ➔ Completed

Clinical • Trial completion • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

A Clinical Study to Test the Effectiveness of an Investigational Drug to Treat People That Have Major Depressive Episodes When They Have Bipolar 1 Depression (clinicaltrials.gov) - P2; N=339; Active, not recruiting; Sponsor: Sunovion; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry