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. 2025 Jul 29.
doi: 10.1007/s40263-025-01197-1. Online ahead of print.

Safety Outcomes with the Long-Acting Subcutaneous Antipsychotic TV-46000 in Schizophrenia: A Post Hoc Analysis of Behavioral, Neuromotor, Endocrine, and Cardiometabolic Outcomes from Two Phase 3 Studies

Christoph U Correll  1   2   3   4 , Helena Knebel  5 , Eran Harary  6 , Roy Eshet  6 , Orna Tohami  6 , Mark Suett  7 , Nir Sharon  6 , Kelli R Franzenburg  8 , John M Kane  9   10   11
Affiliations

Safety Outcomes with the Long-Acting Subcutaneous Antipsychotic TV-46000 in Schizophrenia: A Post Hoc Analysis of Behavioral, Neuromotor, Endocrine, and Cardiometabolic Outcomes from Two Phase 3 Studies

Christoph U Correll et al. CNS Drugs. .

Abstract

Background: TV-46000 is a long-acting subcutaneous injectable formulation of risperidone approved for treatment of schizophrenia in adults. The aim of this post hoc safety analysis of the phase 3 TV-46000 RISE (NCT03503318) and SHINE (NCT03893825) studies was to examine specific adverse events (AEs) of interest related to second-generation antipsychotic use in participants receiving TV-46000.

Methods: In RISE, participants with schizophrenia who underwent stabilization on oral risperidone were randomized to TV-46000 once monthly (q1m; dose range 50-125 mg) or once every 2 months (q2m; 100-250 mg) or placebo. In SHINE, newly recruited participants and those who completed the RISE study without relapse (rollover) received TV-46000 q1m or q2m. AEs, laboratory tests, vital signs, electrocardiogram, physical examination, and safety/tolerability assessments were recorded. This post hoc analysis evaluated specific antipsychotic-related AEs of interest and assessments related to affective, behavioral, neuromotor, endocrine, sexual/reproductive, and cardiometabolic safety and tolerability.

Results: In the two phase 3 studies, a total of 653 participants with schizophrenia were randomized to treatment, with 181 participants randomized to placebo in RISE (55 of whom were subsequently randomized to TV-46000 q1m or q2m in SHINE), 363 participants randomized to TV-46000 q1m or q2m in RISE, and 109 de novo participants randomized to TV-46000 q1m or q2m in SHINE. Among the groups in the RISE and SHINE studies, affective and behavioral AEs that occurred in ≥ 2% of participants were schizophrenia, anxiety, psychotic disorder, and depression; all occurred in ≤ 4% of participants in any group. The most common central nervous system or neuromotor AEs were headache (range, 0-6%), insomnia (< 1-6%), akathisia (< 1-4%), extrapyramidal disorder (0-4%), dizziness (0-4%), and somnolence (< 1-4%). Common metabolic-related AEs were weight increase (1-6%), increased appetite (0-3%), and hyperglycemia (0-4%). No cardiovascular AEs occurred in ≥ 2% of participants in any group. No clinically meaningful trends were observed in the results of safety assessments and AEs associated with second-generation antipsychotic use, with the exception of an increase in prolactin levels.

Conclusions: The safety profile of TV-46000 is favorable and consistent with other currently approved oral and long-acting injectable risperidone formulations.

Registration: ClinicalTrials.gov, NCT03503318, 18 April 2018; and NCT03893825; 27 March 2019.

Plain language summary

Antipsychotic drugs used to treat adults with schizophrenia can cause certain side effects, including weight gain, movement disturbances, and cardiovascular changes. TV-46000 is a form of the antipsychotic risperidone that is given as an injection under the skin of the back of the upper arm or abdomen. It is given monthly or once every 2 months. This study used data from two clinical trials to look at rates of safety events that occur with certain antipsychotic drugs in participants taking TV-46000. Overall safety with TV-46000 was similar to other forms of risperidone. Most of the safety events happened at similar rates in placebo and TV-46000 groups. The safety events that happened at a higher rate with TV-46000 than placebo included weight gain and increased amounts of prolactin in the blood. Prolactin is normally associated with milk production after childbirth. Abnormally high levels of prolactin can lead to infertility in women and problems with erection in men as well as decreased bone mass. Participants stopped taking the drug because of safety events at similar rates in placebo and TV-46000 groups. On the basis of these results, the safety of TV-46000 was consistent with other forms of risperidone.

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Conflict of interest statement

Declarations. Sponsor: Teva Branded Pharmaceutical Products R&D LLC. Funding: This study was supported by Teva Branded Pharmaceutical Products R&D LLC. Conflict of interest: C.U. Correll has been a consultant and/or advisor to or has received honoraria from AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Eli Lilly, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Maplight, Mylan, Neumora Therapeutics, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Saladax, Sanofi, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, Viatris, and Xenon Pharmaceuticals; provided expert testimony for Janssen, Lundbeck and Otsuka; served on a Data Safety Monitoring Board for Compass Pathways, Denovo, IntraCellular Therapies, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; received grant support from Boehringer-Ingelheim, Janssen, and Takeda; received royalties from UpToDate; and is a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Medlink, Mindpax, Quantic, and Terran. H. Knebel, E. Harary, R. Eshet, O. Tohami, N. Sharon, and K.R. Franzenburg are employees and shareholders of Teva Pharmaceuticals. M. Suett is an employee and stockholder of Teva UK. J.M. Kane has been a consultant for or received honoraria from Alkermes, Boehringer Ingelheim, Cerevel, Click Therapuetics, HLS Therapuetics, Intra-Cellular Therapies, Janssen, Johnson & Johnson, Karuna Therapeutics, LB Pharmaceuticals, Lundbeck, Lyndra Therapeutics, Merck, Neurocrine Biosciences, Newron, Otsuka, Pierre Fabre, Reviva Pharmaceuticals, Roche, Saladax Biomedical, Sunovion, Takeda, and Teva Pharmaceuticals; has received grant support from Otsuka, Lundbeck, and Janssen and is a shareholder or option holder of Health Rhythms, Intracellular Therapies, LB Pharmaceuticals, Medincell, NW PharmaTech, North Shore Therapies and Vanguard Research Group. Data sharing statement: Qualified researchers may request access to patient-level data and related study documents, including the study protocol and statistical analysis plan. Requests will be reviewed for scientific merit, product approval status, and conflicts of interest. Patient-level data will be de-identified and study documents will be redacted to protect the privacy of trial participants and to protect commercially confidential information. Please email USMedInfo@tevapharm.com to make your request. Code availability: Not applicable. Consent for publication: Not applicable. Ethics approval: The protocol and subsequent amendments were approved before the start of the study by independent ethics committees (IECs)/institutional review boards (IRBs) according to national or local regulations. IEC/IRB organizations and approval numbers for the study include the following: Western IRB (20180568), Western IRB and WCG (ICO1-18-072), Copernicus Group (20190551), and Republic of Bulgaria/Ethics Committee for Clinical Trials (KEMI/CT-0412). This study was conducted in full accordance with the International Council for Harmonisation Good Clinical Practice Consolidated Guideline (E6) and any applicable national and local laws and regulations. Consent to participate: Participants provided informed consent or assent, as applicable, at screening, before any study-related procedures or assessments were performed. Author contributions: J.M.K., R.E., E.H., O.T., and N.S. conceived and designed the study. J.M.K., R.E., E.H., O.T., H.K., N.S., M.S., K.R.F., and C.U.C. acquired, analyzed, and interpreted the data. R.E., E.H., O.T., H.K., N.S., and C.U.C. verified the data. J.M.K., R.E., E.H., O.T., H.K., N.S., M.S., K.R.F., and C.U.C. accessed the data. J.M.K., R.E., E.H., O.T., H.K., N.S., M.S., K.R.F., and C.U.C. drafted the manuscript. J.M.K., R.E., E.H., O.T., H.K., N.S., M.S., K.R.F., and C.U.C. critically revised the manuscript for important intellectual content. N.S. did the statistical analysis. G.L.D. provided administrative, technical, or material support. J.M.K., R.E., E.H., O.T., H.K., N.S., M.S., K.R.F., and C.U.C. approved the final submitted version and agree to be accountable for the work.

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