A 12-Month Open-label Extension Study to Evaluate the Long-term Safety, Tolerability, and Effectiveness of SEP-4199 Controlled Release (CR) for the Treatment of Major Depressive Episode Associated With Bipolar I Disorder (Bipolar I Depression)

This is 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). Participants in the study will receive the drug being studied. This study is accepting male and female participants between 18 and 65 years old who have completed Study SEP380-301. This study will be conducted in approximately 90 study centers worldwide. The treatment duration for this study is one (1) year.

Start Date17 Mar 2022

Sponsor / Collaborator

Sumitomo Pharma America, Inc.

NCT05169710

/ TerminatedPhase 3

A Multi-region, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Evaluating SEP-4199 Controlled Release (CR) for the Treatment of Major Depressive Episode Associated With Bipolar I Disorder (Bipolar I Depression)

A clinical trial to study the efficacy and safety of an investigational drug in people with major depressive episodes associated with with Bipolar I disorder (bipolar I depression) Participants in the study will either receive the drug being studied or a placebo. The study will be conducted in approximately 90 sites in North America, Europe, Latin America and Japan. It will be have both male and female participants ages 18-65. Participation in the study will be approximately 10 weeks.

Start Date21 Dec 2021

Sponsor / Collaborator

Sumitomo Pharma America, Inc.

NCT03543410

/ CompletedPhase 2

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of SEP-4199 for the Treatment of Major Depressive Episode Associated With Bipolar I Disorder (Bipolar I 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

Start Date26 Jun 2018

Sponsor / Collaborator

Sumitomo Pharma America, Inc.

100 Clinical Results associated with Aramisulpride/Esamisulpride

100 Translational Medicine associated with Aramisulpride/Esamisulpride

100 Patents (Medical) associated with Aramisulpride/Esamisulpride

Literatures (Medical) associated with Aramisulpride/Esamisulpride

01 Oct 2024·PSYCHIATRY RESEARCH

Enrichment using speech latencies improves treatment effect size in a clinical trial of bipolar depression

Article

Author: Siegel, Joshua S ; Szabo, Steven T ; Opler, Mark ; Cohen, Alex S ; Tomioka, Sasagu ; Hopkins, Seth ; Kirkpatrick, Brian

Clinical trials in depression lack objective measures. Speech latencies are an objective measure of psychomotor slowing with face validity and empirical support. 'Turn latency' is the response time between speakers. Retrospective analysis was carried-out on the utility of turn latencies as an enrichment tool in a clinical trial of bipolar I depression. 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). Post-randomization turn latencies were compared between patients with moderate to severe depression and patients whose depression had remitted. A cutoff was determined and applied to turn latencies pre-randomization to classify individuals into two groups: Speech Latencies Slow (SL-Slow) and Speech Latencies Normal (SL-Normal). At week 6, SL-Slow (N = 172) showed significant separation in MADRS scores between placebo and treatment arms. SL-Normal (N = 102) showed larger MADRS improvements and no significant separation between placebo and treatment arms. 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.

01 Oct 2024·Contemporary Clinical Trials

A clinical trial inclusion criteria to enrich for patients presenting with canonical symptom structure in bipolar depression

Article

Author: Szabo, Steven T ; Tomioka, Sasagu ; Hopkins, Seth C ; Koblan, Kenneth S

Clinical drug development in psychiatry is challenging due to heterogeneous patient populations and the uncertainty of measuring neuropsychiatric constructs with symptom rating scales. Here we describe the development and implementation of an enrichment algorithm that identifies canonical versus anomalous symptom presentations, at the individual subject level, based on MADRS ratings obtained at screening and baseline. Data from 5 randomized, placebo-controlled, phase 3 trials in bipolar I disorder was used (N = 2026 subjects and 15,239 MADRS assessments). A variance-covariance difference (VCD) vector was developed to encode individual symptom structure using the 10 items of MADRS from the two sequential assessments. An anomaly score, calculated from each subject's VCD vector was derived by isolation forest to quantify the degree of disparity from the hypothesized canonical item structure. A retrospective application of the algorithm reliably identified a threshold anomaly score above which the psychometric properties of MADRS deteriorate. Consistent with increasing the certainty of MADRS ratings, subjects with a canonical symptom structure at baseline demonstrated greater effect sizes post-baseline in a phase 2 placebo-controlled trial of non-racemic amisulpride (SEP-4199) for bipolar depression, analyzed retrospectively. Our analyses show that the developed algorithm can reduce the symptom structure heterogeneity at baseline and thus improve the measurement certainty of psychiatric symptoms in clinical trials. 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.

01 Aug 2024·CLINICAL PHARMACOLOGY & THERAPEUTICS

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

Article

Author: Tsushima, Yuki ; Snowden, Thomas J. ; Lew, Robert ; Shi, Lei ; Watanabe, Takao ; Rabiner, Eugenii A. ; Hopkins, Seth C. ; Wilding, Ian ; Koblan, Kenneth S. ; Searle, Graham E. ; Darpo, Borje ; Corriveau, Taryn J. ; Zann, Vanessa ; Galluppi, Gerald R. ; Asada, Takumi ; van der Graaf, Piet H. ; Szabo, Steven T. ; Toongsuwan, Siriporn

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. During testing of SEP‐4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled‐release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24‐hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non‐human primates produced significantly greater D2R occupancies during a gradual 6‐hour administration compared with a single bolus; (iii) concentration–occupancy curves were left‐shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects. 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.

News (Medical) associated with Aramisulpride/Esamisulpride

26 Aug 2024

·www.prnewswire.com

Schizophrenia Market: RISVAN's Approval Has Sparked a Competitive Race Among Pharmaceutical Companies | DelveInsight

The recent approval of Rovi Pharmaceuticals Laboratories' OKEDI/RISVAN (risperidone ISM) has spiked the competition among the other pharmaceutical companies that are developing novel therapies to improve the treatment landscape. RISVAN has the potential to become a blockbuster drug. LAS VEGAS, Aug. 26, 2024 /PRNewswire/ -- Schizophrenia is a severe mental illness affecting about 1% of Americans, cognitive functions, emotional responses, decision-making, and social interaction. Onset typically occurs in late teens to early 20s for men and late 20s to early 30s for women. Currently, as per the WHO, the vast majority of schizophrenia patients around the world are not receiving mental health care. Approximately 50% of people in mental hospitals have a schizophrenia diagnosis, and only 31.3% of people with psychosis receive specialist mental health care. As per DelveInsight analysis, in 2023 the total diagnosed prevalent cases of schizophrenia in the 7MM were found to be approximately 4 million cases out of which the US accounted for nearly 1.5 million cases. It is anticipated that these numbers will rise by 2034 due to several factors, including population growth, improved diagnostic techniques, increased awareness, and reduced stigma around mental health issues prompting more individuals to seek diagnosis, and potentially, environmental stressors contributing to a higher occurrence of the disorder. Schizophrenia treatment involves a blend of medication, psychological counseling, and social support. However, nearly one-third of patients do not respond sufficiently to standard treatments. Relapses, characterized by psychotic symptoms and functional impairments, are significant. Schizophrenia treatment mainly consists of antipsychotic medications that target dopamine neurotransmitters. Second-generation medications are favored because they lower the risk of severe side effects. Long-acting injectable antipsychotics can enhance adherence and improve treatment outcomes. High-dose regimens of specific medications may be advantageous for patients with severe, treatment-resistant schizophrenia. Additionally, hospitalization and electroconvulsive therapy might be necessary for patients who do not respond to medication therapy or during severe episodes. First-generation antipsychotics like chlorpromazine, fluphenazine, haloperidol, and perphenazine are effective in treating positive symptoms such as hallucinations and delusions but do not alleviate negative symptoms or cognitive impairments. Second-generation antipsychotics, including REXULTI/RXULTI (brexpiprazole), CAPLYTA (lumateperone), LATUDA (lurasidone hydrochloride), SAPHRIS (asenapine), ABILIFY MYCITE (aripiprazole tablets with sensor), VRAYLAR/REAGILA (cariprazine), SECUADO (asenapine), INVEGA SUSTENNA/TRINZA/HAYFERA (paliperidone palmitate), ARISTADA/ARISTADA INITIO (aripiprazole lauroxil), PERSERIS (risperidone), FANAPT (iloperidone), and LYBALVI (olanzapine and samidorphan), were developed to address both positive and negative symptoms, as well as cognitive symptoms. Although these medications typically have fewer extrapyramidal side effects, they can cause weight gain, sexual dysfunction, and other metabolic disorders. Additionally, elderly patients using FGAs and SGAs are at an increased risk of developing pneumonia. Learn more about the FDA-approved schizophrenia drugs @ Drugs for Schizophrenia Treatment REXULTI (brexpiprazole) is an oral tablet available in strengths from 0.25 mg to 4 mg, containing various inactive ingredients. While its exact mechanism of action is not fully understood, it work as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors and as an antagonist at serotonin 5-HT2A receptors. REXULTI was first approved in the US in July 2015 for use in adults with MDD and schizophrenia. In January 2022, it received FDA approval for pediatric patients aged 13–17. The EMA approved it in July 2018, and Japan approved it in tablet form in January 2018 and as an oral-disintegrating dose in August 2021. Generic versions of REXULTI have now been approved, which may affect its market presence. Janssen Pharmaceutical's INVEGA SUSTENNA/INVEGA TRINZA/INVEGA HAFYERA (paliperidone palmitate) is an SGA agent that seems to act as a D2 partial agonist and a 5-HT-2A receptor antagonist. INVEGA SUSTENNA is administered monthly, INVEGA TRINZA every three months, and INVEGA HAFYERA twice yearly. Paliperidone is a benzisoxazole derivative. In the EU and Japan, INVEGA SUSTENNA is marketed as XEPLION. In the EU, INVEGA TRINZA is sold as TREVICTA, and in Japan as XEPLION TRI. INVEGA HAFYERA is a long-acting injectable treatment administered in the upper buttocks every six months, providing continuous treatment and symptom control over this period. Additionally, the recent approval of RISVAN (Risperidone ISM) has intensified the competition in the schizophrenia treatment space. Risperidone ISM is a long-acting injectable antipsychotic created and patented by ROVI for treating schizophrenia in adults. From the first injection, it delivers immediate and sustained plasma drug levels without the need for loading doses or additional oral risperidone. This approval is based on the positive outcomes of the pivotal PRISMA-3 study, which assessed the efficacy and safety of Risperidone ISM in patients with schizophrenia. The study's findings demonstrate that the two doses tested (75 mg and 100 mg administered once monthly) successfully met the predetermined primary and secondary efficacy endpoints for treating patients with moderate to severe schizophrenia symptoms. Furthermore, OKEDI (risperidone ISM) was launched in Germany, the UK, and Spain in 2022. The approval was based on the positive results of the pivotal PRISMA-3 study on the efficacy and safety of risperidone ISM in schizophrenia patients. As per the estimates by Delveinsight analysts, this drug has blockbuster potential in the schizophrenia market with medium-fast uptake. To know more about schizophrenia treatment options, visit @ New Treatment for Schizophrenia The schizophrenia market is crowded with so many companies working in the domain. Various potential therapies that are projected to enter during the forecast period include Boehringer Ingelheim's Iclepertin (BI-425809), Sumitomo Pharma/Otsuka's Ulotaront (SEP-363856), Reviva Pharmaceuticals' Brilaroxazine (RP5063), Minerva Neurosciences/Mitsubishi Tanabe Pharma's Roluperidone (MIN-101/MT-210), Karuna Therapeutics (Bristol Myers Squibb)/Royalty Pharma's KarXT (xanomeline-trospium), ACADIA Pharmaceuticals' NUPLAZID (pimavanserin), Teva Pharmaceutical/MedinCell/Royalty Pharma's Olanzapine LAI (mdc-TJK/TV-44749), Neurocrine Biosciences/Mitsubishi Tanabe Pharma's Valbenazine (NBI-98854), Lyndra Therapeutics' LYN-005 (long-acting oral risperidone), Newron Pharmaceuticals' Evenamide (NW-3509), Luye Pharma's LY03010 (ER paliperidone palmitate), and others. Discover which therapies are expected to grab major schizophrenia market share @ Schizophrenia Market Report Iclepertin (BI 425809) is an investigational drug and a glycine transporter 1 (GlyT1) inhibitor aimed at addressing the brain biology related to cognitive symptoms in schizophrenia (CIAS). Abnormalities in glutamatergic signaling downstream of neuronal NMDA receptors contribute to cognitive impairment in this condition. Enhancing NMDA receptor function could potentially improve synaptic plasticity and cognition. Glycine, an essential NMDA receptor co-agonist, is modulated by glycine transporters GlyT-1 and GlyT-2, which are located in presynaptic and astrocyte membranes. These transporters regulate glycine levels by taking it up into nerve terminals and adjacent glial cells, affecting synaptic cleft glycine concentration. By inhibiting these transporters, BI 425809 aims to increase glycine levels, thereby modulating NMDA receptor function. Administered orally, this potent and selective GlyT1 inhibitor is also under investigation for Alzheimer's disease. However, early 2020 Phase II trial results did not support its continued development for this indication, and the focus has now shifted to schizophrenia, with multiple Phase III trials currently underway. Since schizophrenia, patients frequently ignore certain symptoms, such as cognitive impairment. Therefore, if approved, BI-425809 will be the first approved pharmacotherapy for the treatment of CIAS. Ulotaront (SEP-363856), developed by Sumitomo Pharma and Otsuka Pharmaceuticals, is a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity. It is a small-molecule oral agent that does not bind to dopamine D2 or serotonin 5-HT2A receptors. Sunovion discovered Ulotaront in collaboration with PsychoGenics using the in vivo phenotypic SmartCube platform and associated artificial intelligence algorithms. Ulotaront is currently in late-stage development for schizophrenia and generalized anxiety disorder (GAD) in Japan and as an adjunctive treatment for major depressive disorder, schizophrenia, and GAD in the US. Top-line results from Phase III DIAMOND 1 and DIAMOND 2 trials in schizophrenia have been released, but the Phase III DIAMOND 3 trial in the US has been halted. Sumitomo Pharma has also stopped a Phase III trial for schizophrenia in Japan and another Phase II/III trial in China, Japan, Taiwan, and the Philippines, citing business strategy reasons. Despite this, two Phase III trials are still ongoing. Recently, Otsuka and Sumitomo revised their licensing agreement, excluding SEP-4199 and SEP-378614. Under this revision, Otsuka gained exclusive rights from SMPA to develop, manufacture, and commercialize ulotaront worldwide. If Otsuka successfully develops and commercializes ulotaront, they will pay up to 30 million USD (approximately 4.5 billion yen) in milestones, along with royalties based on sales, without any upfront payment. Starting January 2024, Otsuka will cover the full cost of studies conducted by both Sumitomo Pharma Group and Otsuka, except for certain studies. KarXT (xanomeline–trospium) is an oral modulator targeting muscarinic receptors found in both the central nervous system (CNS) and various peripheral tissues. This proprietary product combines xanomeline, a novel muscarinic agonist, with trospium, an approved muscarinic antagonist, to preferentially stimulate muscarinic receptors in the CNS. As a dual M1/M4 muscarinic acetylcholine receptor agonist, KarXT aims to improve the positive, negative, and cognitive symptoms of schizophrenia. The US FDA has accepted Karuna Therapeutics' NDA for KarXT for adult schizophrenia treatment, with a PDUFA date of September 26, 2024. Additionally, KarXT is undergoing multiple Phase III trials as an adjunctive treatment with standard-of-care agents for schizophrenia and is being evaluated for psychosis treatment in Alzheimer's disease patients. Following Bristol Myers Squibb's acquisition of Karuna Therapeutics, Karuna is now a wholly-owned subsidiary of BMS. At the Annual Congress of the Schizophrenia International Research Society (SIRS) in April 2024 in Italy, BMS presented promising results from the latest interim analysis of the Phase III EMERGENT-4 open-label extension trial, showing KarXT's efficacy in reducing symptoms in adults with schizophrenia. BMS plans to continue discussions with the US FDA and will release more data from the EMERGENT program later this year. Discover more about drugs for schizophrenia in development @ Schizophrenia Clinical Trials The anticipated launch of these emerging therapies for schizophrenia are poised to transform the market landscape in the coming years. As these cutting-edge therapies continue to mature and gain regulatory approval, they are expected to reshape the schizophrenia market landscape, offering new standards of care and unlocking opportunities for medical innovation and economic growth. DelveInsight estimates that the market size for schizophrenia is expected to grow from USD 2.6 billion in 2023 with a significant CAGR by 2034. This growth can be attributed to the introduction of upcoming therapies and the rising prevalence of the disease. The anticipated launch of these therapies is also expected to attract new entrants to the Schizophrenia market, resulting in increased competition and innovation. DelveInsight's latest published market report titled as Schizophrenia Market Insight, Epidemiology, and Market Forecast – 2034 will help you to discover which market leader is going to capture the largest market share. The report provides comprehensive insights into the schizophrenia country-specific treatment guidelines, patient pool analysis, and epidemiology forecast to help understand the key opportunities and assess the market's underlying potential. The schizophrenia market report proffers epidemiological analysis for the study period 2020–2034 in the 7MM segmented into: Total Prevalent Cases of Schizophrenia Total Diagnosed Prevalent Cases of Schizophrenia Gender-specific Diagnosed Prevalent Cases of Schizophrenia Severity-specific Diagnosed Prevalent Cases of Schizophrenia The report provides an edge while developing business strategies by understanding trends shaping and driving the 7MM schizophrenia market. Highlights include: 11-year Forecast 7MM Analysis Epidemiology-based Market Forecasting Historical and Forecasted Market Analysis upto 2034 Emerging Drug Market Uptake Peak Sales Analysis Key Cross Competition Analysis Industry Expert's Opinion Access and Reimbursement Download this schizophrenia market report to assess the epidemiology forecasts, understand the patient journeys, know KOLs' opinions about the upcoming treatment paradigms, and determine the factors contributing to the shift in the schizophrenia market. Also, stay abreast of the mitigating factors to improve your market position in the schizophrenia therapeutic space. Related Reports Schizophrenia Pipeline Schizophrenia Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key schizophrenia companies, including Otsuka Pharmaceutical Development & Commercialization, Inc., Gedeon Richter Ltd., Lyndra Therapeutics, Neurocrine Bioscience, Takeda Pharmaceutical Company, Memory Pharmaceuticals, Hoffmann-La Roche, Neurocrine Biosciences, Boehringer Ingelheim, Meiji Seika Pharma Co., Ltd., SK Life Science, Inc., Alkermes, Inc. , Solvay Pharmaceuticals, Mitsubishi Tanabe Pharma Corporation, SyneuRx International (Taiwan) Corp, BioXcel Therapeutics Inc, Cognitive Research Corporation, Amarex Clinical Research, Forum Pharmaceuticals Inc, Amneal Pharmaceuticals, LLC, Recognify Life Sciences, Accutest Research Laboratories (I) Pvt. Ltd., Eli Lilly and Company, Johnson & Johnson Pharmaceutical Research & Development, L.L.C, Janssen, LP, Delpor, Inc., Jiangsu Hansoh Pharmaceutical, Cerevel Therapeutics, LLC, Zogenix, Inc., Luye Pharma, Reviva Pharmaceuticals, Alkermes, Inc., Karuna Therapeutics, Autifony Therapeutics, Neumora Therapeutics, Adex Therapeutics, among others. Schizophrenia Epidemiology Forecast Schizophrenia Epidemiology Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, and schizophrenia epidemiology trends. Dementia Market Dementia Market Insights, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key dementia companies, including Hoffmann-La Roche, Forest Laboratories, Inc., Janssen Pharmaceuticals, Inc., Merck and Co., Inc., Novartis, among others. Bipolar Depression Market Bipolar Depression Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key bipolar depression companies, including Intra-Cellular Therapies, Sunovion Pharmaceuticals, COMPASS Pathways, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP

Phase 3Phase 2Clinical ResultDrug ApprovalLicense out/in

27 Mar 2024

·synapse.patsnap.com

Sumitomo Pharma Renews Collaborative Development Agreement with Otsuka Pharmaceutical for Multiple Psychiatric Disorder Treatments

On March 15th, Sumitomo Dainippon Pharma Co., Ltd., and its U.S. subsidiary, Sumitomo Pharma America, Inc. (SMPA), announced that they have amended the global collaboration and commercialization agreement originally signed with Sumitomo Dainippon Pharma, SMPA, and Otsuka Pharmaceutical Co., Ltd., on September 30, 2021, concerning the joint development of four investigational compounds in the fields of psychiatry and neurology, including ulotaront, SEP-380135, SEP-4199, and SEP-378614 (hereinafter referred to as "the Amendment Agreement"). It is reported that SEP-4199 and SEP-378614 from the original collaboration agreement will no longer be included in the scope of this Amendment Agreement. SMPA has granted Otsuka Pharmaceutical exclusive global rights to develop, produce, and market ulotaront and SEP-380135 for all indications. SMPA is entitled to receive milestone payments of up to 30 million U.S. dollars (approximately 45 billion Japanese yen) related to the development progress of ulotaront and SEP-380135 from Otsuka Pharmaceutical, as well as royalties based on Otsuka Pharmaceutical's sales revenue. Sumitomo Pharma and SMPA have been collaborating with Otsuka Pharmaceutical in the development of novel candidate compounds including ulotaront in the priority areas of psychiatry and neurology. However, given the current situation, the likelihood of these compounds generating revenue during the Mid-Term Business Plan period for fiscal 2027 (FY2023-FY2027) poses significant challenges. In light of this, the Sumitomo Pharma Group has reassessed its priority development products and has decided to focus its efforts on the development of projects in the fields of oncology and regenerative medicine/cell therapy, which are expected to come to market during the Mid-Term Business Plan period for fiscal 2027. Consequently, Sumitomo Pharma Group has transferred the development responsibilities for the aforementioned ulotaront and SEP-380135 to Otsuka Pharmaceutical. At the same time, Sumitomo Pharma Group is evaluating further development strategies for SEP-4199 and SEP-378614. Ulotaront is an agonist associated with Trace Amine-Associated Receptor 1 (TAAR1) and exhibits agonist activity at the 5-HT1A receptor. Currently, ulotaront is in the development phase for the treatment of schizophrenia, as an adjunctive treatment for major depressive disorder (MDD), and for generalized anxiety disorder (GAD). In May 2019, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to Ulotaront for the treatment of schizophrenia, making it the first and only TAAR1 agonist to enter Phase III clinical trials for schizophrenia. Additionally, Ulotaront is the first TAAR1 agonist to progress to Phase II/III clinical trials as an adjunctive treatment for Generalized Anxiety Disorder (GAD) and Major Depressive Disorder (MDD). However, on July 31, 2023, Sumitomo Pharma announced on its official website that its antipsychotic clinical candidate Ulotaront (SEP-363856) failed to meet the primary endpoints in two recent Phase III clinical studies (DIAMOND 1 and DIAMOND 2). In April 2020, the team at Sunovion, the U.S. subsidiary of Sumitomo Pharmaceuticals, published the results of a Phase 2 clinical study on the oral small molecule SEP-363856 for the treatment of schizophrenia in The New England Journal of Medicine online. The study conducted a randomized controlled trial to evaluate the efficacy and safety of SEP-363856 in adult patients with an acute exacerbation of schizophrenia. Patients were randomly assigned in a 1:1 ratio to receive SEP-363856 treatment (either 50 mg or 75 mg) or placebo once daily for a duration of 4 weeks. The primary endpoint was the change in the total score on the Positive and Negative Syndrome Scale (PANSS; range 30 to 210, with higher scores indicating more severe psychotic symptoms) from baseline to week 4. A total of 120 patients were assigned to the SEP-363856 group, and 125 patients were allocated to the placebo group. At baseline, the mean total score on the Positive and Negative Syndrome Scale (PANSS) was 101.4 for the SEP-363856 group and 99.7 for the placebo group. The mean change at week 4 was -17.2 for the SEP-363856 group and -9.7 for the placebo group. The reductions in the Clinical Global Impressions - Severity (CGI-S) and the Brief Negative Symptom Scale (BNSS) scores at week 4 were consistent with the primary outcome in terms of direction of improvement. The adverse reactions of SEP-363856 include somnolence and gastrointestinal symptoms; a case of sudden cardiac death occurred in the SEP-363856 group. The incidence of extrapyramidal symptoms in the trial group, as well as changes in blood lipid levels, glycated hemoglobin, and prolactin levels, was similar. In 2021, the Sunovion team published an article in the journal Schizophrenia, reporting on the safety and efficacy of SEP-363856 in the treatment of schizophrenia (results from a 6-month open-label extension study). According to the study report, this 26-week open-label extension study was designed to evaluate the safety and efficacy of Ulotaront (25/50/75 mg/day) in patients who completed the initial 4-week study. The results showed that after 26 weeks of extended treatment, the mean change in the observed PANSS total score compared to the open-label baseline was -22.6. The long-term treatment with the TAAR1 agonist Ulotaront had a relatively high completion rate, characterized by the absence of extrapyramidal related adverse reactions, a lower incidence of weight and metabolic adverse reactions, and no effect on prolactin levels. It is reported that the Phase III clinical trial results jointly announced by Sumitomo Pharmaceuticals and Otsuka are multicenter, randomized, double-blind, parallel-group, fixed-dose studies. The DIAMOND 1 study evaluated the efficacy, safety, and tolerability of ulotaront (50 mg/day and 75 mg/day) compared to placebo; while DIAMOND 2 assessed the efficacy, safety, and tolerability of ulotaront (75 mg/day and 100 mg/day) compared to placebo. In the DIAMOND 1 study, over time, the Positive and Negative Syndrome Scale (PANSS) total scores for all three treatment groups decreased. However, at the primary endpoint of change from baseline in PANSS total score at week 6, the ulotaront treatment groups did not show superiority to the placebo group (patients treated with ulotaront at doses of 50 mg/day and 75 mg/day had changes of -16.9 and -19.6, respectively, compared to -19.3 in the placebo group). In the DIAMOND 2 study, the 75 mg/day and 100 mg/day ulotaront treatment groups did not show statistically significant improvement over placebo at the primary endpoint. At week 6, the least squares (LS) mean changes for patients treated with 75 mg/day and 100 mg/day ulotaront were -16.4 and -18.1, respectively, compared to -14.3 for the placebo group. In both DIAMOND 1 and DIAMOND 2 studies, a substantial placebo effect was observed which may have masked the therapeutic effect of the molecule. SEP-380135 is an orally-administered small molecule drug targeting the central nervous system, jointly developed by SMPA and PsychoGenics, and is currently in Phase I clinical trials in the United States. The discovery of this drug was made possible by the in vivo phenotypic SmartCube® platform and its associated artificial intelligence algorithms. SmartCube® is a proprietary state-of-the-art automated testing platform by PsychoGenics that uses custom hardware to guide mice through a series of challenges, extracting profound behavioral and physiological insights through integrated computer vision and artificial intelligence (AI) technology. Compared to traditional behavioral testing methods, the SmartCube® system boasts the following advantages: ·High Automation: Using precise hardware devices, SmartCube® can automatically guide mice to participate in a variety of experimental challenges, reducing the errors associated with human interference and enhancing experiment efficiency and accuracy. ·Real-time Behavior Monitoring: Employing advanced computer vision technology, it captures and precisely identifies the mice's behavior in real-time, providing researchers with a wealth of behavioral data. ·AI Data Analysis: The built-in artificial intelligence algorithms are capable of deep learning and intelligent analysis on the vast amount of behavioral data collected, revealing behavioral patterns and physiological correlations that traditional methods may fail to detect. ·Multidimensional Assessment: Beyond basic behavioral parameters, SmartCube® also synchronously acquires physiological indicators, enabling comprehensive and multi-level evaluations. ·High Throughput Capacity: Compared to manual operation, SmartCube® can process large quantities of experimental samples more rapidly and efficiently, accelerating the process of drug screening and disease model research. PsychoGenics has identified thousands of active behavioral compounds through the screening of various compound libraries, which can serve as starting points for new drug discovery projects. Typically, the discovery process begins with the search for "hits" that possess desired characteristics and other specific features. For instance, a project might focus on finding compounds with antidepressant features similar to certain psychedelic compounds but without activity on the 5HT2a receptor. In preclinical studies, SEP-380135 has demonstrated a broad range of in vivo activity, preliminarily indicating its effectiveness against a variety of behavioral and psychological symptoms of dementia, including, but not limited to, agitation/aggression, psychomotor hyperactivity, and depressive symptoms. This suggests that SEP-380135 has the potential to be one of the effective medications for treating multiple complex symptoms associated with dementia, offering new possibilities for further improving the quality of life of patients with dementia. SEP-4199 is a small molecule compound that functions as a dual antagonist targeting 5-HT receptors and D2 receptors. It is currently undergoing phase 3 clinical trials for the treatment of bipolar I disorder, major depressive disorder, and severe depression. SEP-378614 is a small molecule compound jointly developed by Sumitomo and PsychoGenics, which is currently undergoing phase 1 clinical trials for the treatment of major depressive disorder.

31 Jul 2023

·www.biospace.com

Sumitomo, Otsuka’s Schizophrenia Candidate Fails Phase III Trials

Pictured: Woman in mental anguish/iStock, Marina D Ulotaront failed to meet primary endpoints in two studies. The companies said high COVID-19 placebo effect “may have masked molecule’s therapeutic effect” and plan to discuss next steps with the FDA. Pictured: Woman in mental anguish/iStock, Marina Demeshko Sumitomo Pharma and Otsuka Pharmaceutical announced Monday that two Phase III studies of ulotaront failed to meet primary endpoints for acutely psychotic adults living with schizophrenia. The studies, DIAMOND 1 and DIAMOND 2, pitted the trace amine-associated receptor 1 (TAAR1) agonist against a placebo. After six weeks, the studies showed improvement on the Positive and Negative Syndrome Scale (PANSS), but results were not superior to placebo. A “large placebo effect” was present in both studies “which may have masked the molecule’s therapeutic effect,” according to the press release. While placebo responses are frequently higher in psychiatric studies, Sumitomo CEO Hiroshi Nomura pointed to COVID-19 as a potential culprit for the high placebo effect as the studies were conducted throughout the pandemic. The molecule was part of a four-compound deal forged between Otsuka and Sunovion, a subsidiary of Sumitomo, nearly two years ago. The former made an upfront payment of $270 million to the latter with another $620 million on the line in milestone payments. Ulotaront is also in Phase II/III clinical studies as an adjunctive treatment for major depressive disorder as well as generalized anxiety disorder. Another asset from the deal, SEP-4199, is in a Phase III study for bipolar I depression. The TAAR1 agonist was safe and well-tolerated in both schizophrenia studies. The companies plan to further analyze the data and discuss next steps with the FDA, who had already granted Breakthrough Therapy Designation to ulotaront for a schizophrenia indication. Hopes had been high for ulotaront for its potential to treat both the positive psychosis symptoms in addition to the elusive negative symptoms of schizophrenia. Negative symptoms essentially zap patients of their motivation and zeal for life, affecting their ability to function normally. Recently, Roche had to axe a second Phase II trial of its investigational schizophrenia drug ralmitaront, leaving the future of its program uncertain. “In a preliminary analysis, the primary endpoint was negative, and ongoing portions of the study have therefore been discontinued,” said an update on the second Phase II trial posted to the ClinicalTrials.gov website. Karuna Therapeutics’ combination drug, KarXT, appears to treat both positive and negative symptoms of schizophrenia. It has not been specifically tested for negative symptoms. Since the drug is a non-dopamine D2 receptor antagonist, it does not cause many of the typical side effects of schizophrenia medicines like sedation and weight gain. An NDA is anticipated for the investigational M1/M4-preferring muscarinic agonist by the middle of this year. If approved, KarXT will be the first new class of drug for schizophrenia in over 50 years. Sumitomo Pharma’s stock dropped about 10% in Monday trading on the news. Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at kate.goodwin@biospace.com and on LinkedIn .

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Indication	Highest Phase	Country/Location	Organization	Date
Bipolar I disorder	Phase 3	United States	Sumitomo Pharma America, Inc.	21 Dec 2021
Bipolar I disorder	Phase 3	Japan	Sumitomo Pharma America, Inc.	21 Dec 2021
Bipolar I disorder	Phase 3	Bulgaria	Sumitomo Pharma America, Inc.	21 Dec 2021
Bipolar I disorder	Phase 3	Canada	Sumitomo Pharma America, Inc.	21 Dec 2021
Bipolar I disorder	Phase 3	Romania	Sumitomo Pharma America, Inc.	21 Dec 2021
Bipolar I disorder	Phase 3	Slovakia	Sumitomo Pharma America, Inc.	21 Dec 2021
Depressive Disorder, Major	Phase 3	United States	Sumitomo Pharma America, Inc.	21 Dec 2021
Depressive Disorder, Major	Phase 3	Japan	Sumitomo Pharma America, Inc.	21 Dec 2021
Depressive Disorder, Major	Phase 3	Bulgaria	Sumitomo Pharma America, Inc.	21 Dec 2021
Depressive Disorder, Major	Phase 3	Canada	Sumitomo Pharma America, Inc.	21 Dec 2021

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05227209 (CTgov)	Phase 3	Bipolar I disorder \| Depressive Disorder, Major	64	SEP-4199 CR	djimoooebg = hvfhhylwwi jaozhuydhq (rctfspcfuk, gbhfpfzxnx - wtzibnnzqs) View more	-	21 Feb 2025
NCT05169710 (CTgov)	Phase 3	Bipolar I disorder \| Depressive Disorder, Major	83	Placebo (Placebo)	nsvmynbwvf(hajjspfrez) = yqqtqsxtsj jylablssfw (xljhycvrga, 2.004) View more	-	19 Sep 2024
				SEP-4199 CR 200 mg (SEP-4199 CR 200 mg)	nsvmynbwvf(hajjspfrez) = hfuqdrsits jylablssfw (xljhycvrga, 2.055) View more
NCT03543410 (CTgov)	Phase 2	Bipolar I disorder \| Depressive Disorder, Major	344	SEP-4199 200 mg (SEP-4199 200 mg)	iprtvyqche(nypkgqcakb) = lhzzvhcboi hgjkqbkstg (ecitlftobd, 1.226) View more	-	18 May 2023
				SEP-4199 400 mg (SEP-4199 400 mg)	iprtvyqche(nypkgqcakb) = tjznomcwfq hgjkqbkstg (ecitlftobd, 1.182) View more

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