5-HT1A receptor agonists(Serotonin 1a (5-HT1a) receptor agonists), 5-HT2A receptor antagonists(Serotonin 2a (5-HT2a) receptor antagonists), D2 receptor agonists(Dopamine D2 receptor agonists)

Therapeutic Areas

Other DiseasesNervous System Diseases

Active Indication

Depressive DisorderAgitation in DementiaAgitation+ [8]

Inactive Indication

Anxiety DisordersAttention Deficit and Disruptive Behavior DisordersAttention Deficit Disorder With Hyperactivity+ [9]

Originator Organization

Otsuka Pharmaceutical Co., Ltd.

Active Organization

Lundbeck Australia Pty Ltd.Otsuka Pharmaceutical Netherlands B.V.Hainan Zhongwang Medical Technology Development Co., Ltd.

+ [21]

Inactive Organization

Otsuka Beijing Research Institute

Drug Highest PhaseApproved

First Approval Date

US (10 Jul 2015),

Depressive Disorder, MajorSchizophrenia

RegulationPriority Review (US), Fast Track (US)

Structure/Sequence

Molecular FormulaC25H27N3O2S

InChIKeyZKIAIYBUSXZPLP-UHFFFAOYSA-N

CAS Registry913611-97-9

197

Clinical Trials associated with Brexpiprazole

CTR20244144

/ RecruitingNot Applicable

健康受试者空腹和餐后单次口服布瑞哌唑片的随机、开放、单剂量、两序列、两制剂、两周期、双交叉设计的生物等效性试验

[Translation] A randomized, open-label, single-dose, two-sequence, two-formulation, two-period, double-crossover bioequivalence study of a single oral dose of brexpiprazole tablets in healthy subjects after fasting or after meals

主要研究目的：研究空腹和餐后状态下单次口服受试制剂布瑞哌唑片（规格：2mg，宁波大红鹰药业股份有限公司生产）与参比制剂布瑞哌唑片（REXULTI®，规格：2mg，Otsuka Pharmaceutical Co Ltd持证）在健康受试者体内的药代动力学，评价空腹和餐后状态口服两种制剂的生物等效性。次要研究目的：评价健康受试者在空腹和餐后状态下，单次口服布瑞哌唑片受试制剂和参比制剂后的安全性。

[Translation]

The main purpose of the study is to study the pharmacokinetics of the test preparation brepirazole tablets (specification: 2 mg, produced by Ningbo Dahongying Pharmaceutical Co., Ltd.) and the reference preparation brepirazole tablets (REXULTI®, specification: 2 mg, licensed by Otsuka Pharmaceutical Co Ltd) in healthy subjects after a single oral administration in the fasting and fed state, and to evaluate the bioequivalence of the two preparations after oral administration in the fasting and fed state. Secondary purpose of the study is to evaluate the safety of the test preparation and reference preparation of brepirazole tablets in healthy subjects after a single oral administration in the fasting and fed state.

Start Date04 Dec 2024

Sponsor / Collaborator

Ningbo Dahongying Pharmaceutical Co. Ltd.

CTR20244115

/ Active, not recruitingNot Applicable

研究健康受试者餐后单次口服受试制剂布瑞哌唑片（北京仁众药业有限公司，规格：2mg）与参比制剂布瑞哌唑片（商品名：Rexulti®；大塚製薬株式会社，规格：2mg）在吸收程度和速度方面是否存在差异，评价受试制剂和参比制剂在餐后状态下给药时的生物等效性，观察受试制剂和参比制剂在健康受试者中的安全性

[Translation] Study on the single oral administration of test preparation Bripipiprazole Tablets (Beijing Renzhong Pharmaceutical Co., Ltd., specification: 2 mg) and reference preparation Bripipiprazole Tablets (trade name: Rexulti®; manufactured by Otsuka) to healthy subjects after a meal Co., Ltd., specification: 2 mg), whether there is any difference in the degree and speed of absorption, evaluate the bioequivalence of the test preparation and the reference preparation when administered in the postprandial state, and observe the health effects of the test preparation and the reference preparation. Safety in subjects

[Translation]

Study on the single oral administration of test preparation Bripipiprazole Tablets (Beijing Renzhong Pharmaceutical Co., Ltd., specification: 2 mg) and reference preparation Bripipiprazole Tablets (trade name: Rexulti®; manufactured by Otsuka) to healthy subjects after a meal Co., Ltd., specification: 2 mg), whether there is any difference in the degree and speed of absorption, evaluate the bioequivalence of the test preparation and the reference preparation when administered in the postprandial state, and observe the health effects of the test preparation and the reference preparation. Safety in subjects

Start Date02 Dec 2024

Sponsor / Collaborator

Beijing Renzhong Pharmaceutical Co., Ltd.

CTR20244117

/ Active, not recruitingNot Applicable

研究健康受试者空腹单次口服受试制剂布瑞哌唑片（北京仁众药业有限公司，规格：2mg）与参比制剂布瑞哌唑片（商品名：Rexulti®；大塚製薬株式会社，规格：2mg）在吸收程度和速度方面是否存在差异，评价受试制剂和参比制剂在空腹状态下给药时的生物等效性，观察受试制剂和参比制剂在健康受试者中的安全性

[Translation] Study healthy subjects taking a single fasting oral administration of the test preparation Bripipiprazole Tablets (Beijing Renzhong Pharmaceutical Co., Ltd., specification: 2 mg) and the reference preparation Bripipiprazole Tablets (trade name: Rexulti®; Otsuka Manufacturing Co., Ltd. Co., Ltd., specification: 2mg), whether there is any difference in the extent and speed of absorption, evaluate the bioequivalence of the test preparation and the reference preparation when administered in the fasting state, and observe the effects of the test preparation and the reference preparation on healthy subjects safety among

[Translation]

Study healthy subjects taking a single fasting oral administration of the test preparation Bripipiprazole Tablets (Beijing Renzhong Pharmaceutical Co., Ltd., specification: 2 mg) and the reference preparation Bripipiprazole Tablets (trade name: Rexulti®; Otsuka Manufacturing Co., Ltd. Co., Ltd., specification: 2mg), whether there is any difference in the extent and speed of absorption, evaluate the bioequivalence of the test preparation and the reference preparation when administered in the fasting state, and observe the effects of the test preparation and the reference preparation on healthy subjects safety among

Start Date30 Nov 2024

Sponsor / Collaborator

Beijing Renzhong Pharmaceutical Co., Ltd.

100 Clinical Results associated with Brexpiprazole

100 Translational Medicine associated with Brexpiprazole

100 Patents (Medical) associated with Brexpiprazole

519

Literatures (Medical) associated with Brexpiprazole

16 Jan 2025·Current Neuropharmacology

Partial Dopamine D2/3 Agonists and Dual Disorders: A Retrospective-Cohort Study in a Real-World Clinical Setting on Patients with Schizophrenia Spectrum Disorders and Cannabis Use Disorder

Article

Author: Trovini, Giada ; Amici, Emanuela ; Lombardozzi, Ginevra ; Giovanetti, Valeria ; Fagiolini, Andrea ; De Filippis, Sergio ; Perrini, Filippo ; Kotzalidis, Georgios D. ; Pagano, Ilaria

Introduction/Objective::

Schizophrenia with substance use disorder is a complex clinical condition that may increase treatment resistance. Cannabis use disorder is frequently associated with psychosis and the causal link has still to be defined. Partial D2/3 agonists may ensure limbic dopamine release normalization while avoiding reduced frontocortical dopamine release, which would contribute to negative symptoms. We aimed to observe the clinical course of patients with schizophrenia comorbid with cannabis use disorder while being treated with oral or long-acting injectable D2/3 partial agonists.

Methods::

We observed 96 young adults with schizophrenia/schizoaffective disorder comorbid with cannabis use disorder during 18 months of treatment with aripiprazole long-acting injectable or oral aripiprazole or brexpiprazole. The assessment comprised Clinical Global Impressions-Severity, Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Barratt Impulsiveness Scale, and Visual Analog Scale for Craving.

Results::

Included were 17 women and 79 men (mean age = 26.89 ± 4.74 years). The sample responded favorably to treatment as assessed by all clinical scales, save for the impulsiveness scale which showed no significant change. The four treatment samples responded well without differences, but employing a general linear model, long-acting injectable aripiprazole and brexpiprazole were better and similar on all clinical and craving scales compared to oral aripiprazole and to other antipsychotics. Long-acting injectable aripiprazole fared better than brexpiprazole on general psychopathology, negative symptoms, and craving, while the reverse was true for global severity. However, the sample size imbalance did not allow for drawing strong conclusions. We found no significant treatment resistance in our 96-patient sample.

Conclusion::

Partial D2/3 agonists may treat comorbid schizophrenia/schizoaffective disorder and cannabis use disorder, improving the symptoms of both disorders and substance craving.

02 Jan 2025·Expert Review of Neurotherapeutics

A critical review of brexpiprazole oral tablets as the first drug approved to treat agitation symptoms associated with dementia due to Alzheimer’s disease

Review

Author: Cummings, Jeffrey ; Zhong, Kate

INTRODUCTION:

Agitation is a common and disruptive syndrome in dementia due to Alzheimer's disease (AD). Brexpiprazole was recently approved for this agitation of AD dementia and is the only therapy approved for this indication.

AREAS COVERED:

The authors review the chemistry, pharmacokinetics, mechanism of action, and pharmacodynamics of brexpiprazole. Phase 2/3 and Phase 3 studies of brexpiprazole for the treatment of agitation in dementia due to AD are described. These studies demonstrated efficacy and safety for the 2 mg/d and 3 mg/d doses. Agitation reduction from baseline was significantly greater in the active treatment groups compared to the participants on placebo as measured by the Cohen-Mansfield Agitation Inventory, the primary outcome. Treatment benefit was demonstrated on the Clinician Global Impression - Severity, the key secondary outcome. Safety and tolerability were comparable in drug and placebo arms of the studies.

EXPERT OPINION:

Approval by the Food and Drug Administration (FDA) of brexpiprazole for the treatment of agitation in dementia due to AD is an important milestone and regulatory precedent. This is the first approval for the treatment of any neuropsychiatric syndrome of AD. Brexpiprazole has a 'black box' warning for its use in psychosis caused by dementia due to an observed increase in mortality when using this class of antipsychotic agents in patients with dementia. Post-marketing surveillance will be key to understanding the safety profile of brexpiprazole. Brexpiprazole may be prioritized over the 'off label' use of other potential treatments for agitation.

01 Dec 2024·Neuropsychopharmacology reports

Correction to “Brexpiprazole: A new option in treating agitation in Alzheimer's dementia‐Insights from transgenic mouse models”

103

News (Medical) associated with Brexpiprazole

10 Jan 2025

·www.businesswire.com

Otsuka Announces FDA Plans to Host an Advisory Committee Meeting to Discuss the sNDA for Brexpiprazole in Combination with Sertraline for the Treatment of Adults with Post-Traumatic Stress Disorder (PTSD)

PRINCETON, N.J. & TOKYO--( BUSINESS WIRE )--Otsuka America Pharmaceutical, Inc., (OAPI) and Otsuka Pharmaceutical, Co., Ltd. (Otsuka) announce that the U.S. Food and Drug Administration (FDA) plans to host a Psychopharmacologic Drugs Advisory Committee (PDAC) meeting to seek input on issues related to the Supplemental New Drug Application (sNDA) for brexpiprazole in combination with sertraline for the treatment of adults with post-traumatic stress disorder (PTSD). The FDA’s decision to host a PDAC meeting does not reflect a final decision on the approvability. A final date for the meeting has yet to be set by the FDA, but it is currently anticipated to occur during the first half of 2025. This decision means that the Prescription Drug User Fee Act (PDUFA) target action date, originally planned for February 8, 2025, will be delayed. About Post-Traumatic Stress Disorder PTSD is one of the most common mental health disorders in the United States, with approximately five percent of the population affected during a given year i, ii, iii, iv . Most patients (>80%) with PTSD in the United States are in the civilian population v, vi . It may occur in people who have experienced or witnessed a traumatic event, series of events or set of circumstances. An individual may experience an event that is emotionally or physically harmful or life-threatening and which may affect mental, physical, social, and/or spiritual well-being. Examples of traumatic events include physical/sexual assault, natural disasters, serious accidents, terrorist acts, war/combat, historical trauma, intimate partner violence and bullying vii, viii . Symptoms of PTSD are generally grouped into four symptom clusters: intrusion (re-experiencing), avoidance, negative cognitions and mood, and marked alterations in arousal and reactivity ix . Individual symptom type and intensity can fluctuate over time and between individuals. The average time from index trauma to symptom presentation is typically 2.2 years, and the average time from index trauma to PTSD diagnosis is typically 8.7 years. To meet the criteria for PTSD diagnosis, symptoms must last longer than one month, and they must be severe enough to interfere with aspects of daily life, such as relationships or work. Symptoms also must not be due to medications, substance use, or another medical condition. Guideline-recommended first-line treatment includes psychotherapy (e.g., cognitive behavioral therapy) and first line pharmacotherapy options include certain antidepressants x . About brexpiprazole Brexpiprazole was approved in the U.S. by FDA in 2015, as an adjunctive therapy to antidepressants in adults with major depressive disorder (MDD) and as a treatment for schizophrenia in adults. Most recently, brexpiprazole was approved in the U.S. for the treatment of agitation associated with dementia due to Alzheimer's disease, in May 2023. Brexpiprazole was also approved by Health Canada for schizophrenia and adjunctive treatment of MDD in 2017 and 2019, respectively, and for agitation associated with dementia due to Alzheimer's disease in 2024. It was approved by the European Medicines Agency in 2018 for the treatment of schizophrenia and the Ministry of Health, Labour and Welfare in Japan for the treatment of schizophrenia and MDD in 2018 and 2023, respectively. In 2024, Japan’s Ministry of Health, Labour and Welfare also approved brexpiprazole for the treatment of excessive motor activity or physically/verbally aggressive behavior due to rapid changes in mood, irritability, and/or outbursts associated with dementia due to Alzheimer’s disease. Brexpiprazole was discovered by Otsuka and is being co-developed by Otsuka and Lundbeck. The mechanism of action of brexpiprazole is unknown. Brexpiprazole has high receptor binding affinity to norepinephrine, serotonin and dopamine receptors. It is an antagonist at norepinephrine α1B and α2C receptors and serotonin 5-HT 2A receptors, as well as a partial agonist at serotonin 5-HT 1A and dopamine D2 receptors xi, xii . INDICATIONS and IMPORTANT SAFETY INFORMATION for REXULTI ® (brexpiprazole) INDICATIONS: REXULTI is a prescription medicine used: along with antidepressant medicines to treat major depressive disorder (MDD) in adults to treat schizophrenia in adults and children ages 13 years and older to treat agitation that may happen with dementia due to Alzheimer’s disease REXULTI should not be used as an “as needed” treatment for agitation that may happen with dementia due to Alzheimer’s disease. It is not known if REXULTI is safe and effective in children with MDD. It is not known if REXULTI is safe and effective in children under 13 years of age with schizophrenia. IMPORTANT SAFETY INFORMATION: Increased risk of death in elderly people with dementia-related psychosis. Medicines like REXULTI can raise the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). REXULTI is not approved for the treatment of people with dementia-related psychosis without agitation that may happen with dementia due to Alzheimer’s disease. Increased risk of suicidal thoughts and actions. REXULTI and antidepressant medicines may increase suicidal thoughts and actions in pediatric patients and young adult patients, especially within the first few months of treatment or when the dose is changed. Depression and other mental illnesses are the most important causes of suicidal thoughts and actions. All patients on antidepressants and their families or caregivers should closely watch for new or worsening depression symptoms, especially sudden changes in mood, behaviors, thoughts, or feelings. Report any change in these symptoms immediately to the doctor. Do not take REXULTI if you are allergic to brexpiprazole or any of the ingredients in REXULTI. REXULTI may cause serious side effects, including: Cerebrovascular problems, including stroke, in elderly people with dementia-related psychosis that can lead to death. Neuroleptic malignant syndrome (NMS) is a serious condition that can lead to death. Call your healthcare provider or go to the nearest hospital emergency room right away if you have some or all of the following signs and symptoms of NMS: high fever; changes in your pulse, blood pressure, heart rate, and breathing; stiff muscles; confusion; increased sweating Uncontrolled body movements (tardive dyskinesia). REXULTI may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop taking REXULTI. Tardive dyskinesia may also start after you stop taking REXULTI. Problems with your metabolism such as: high blood sugar (hyperglycemia) and diabetes. Increases in blood sugar can happen in some people who take REXULTI. Extremely high blood sugar can lead to coma or death. Your healthcare provider should check your blood sugar before you start, or soon after you start REXULTI and then regularly during long term treatment with REXULTI. Call your healthcare provider if you have any of these symptoms of high blood sugar during treatment with REXULTI: feel very thirsty feel very hungry feel sick to your stomach need to urinate more than usual feel weak or tired feel confused, or your breath smells fruity increased fat levels (cholesterol and triglycerides) in your blood. Your healthcare provider should check the fat levels in your blood before you start, or soon after you start REXULTI, and then periodically during treatment with REXULTI. weight gain. You and your healthcare provider should check your weight before you start and often during treatment with REXULTI. Unusual and uncontrollable (compulsive) urges. Some people taking REXULTI have had strong unusual urges, to gamble and gambling that cannot be controlled (compulsive gambling). Other compulsive urges include sexual urges, shopping, and eating or binge eating. If you or your family members notice that you are having new or unusual strong urges or behaviors, talk to your healthcare provider. Low white blood cell count. Your healthcare provider may do blood tests during the first few months of treatment with REXULTI. Decreased blood pressure (orthostatic hypotension) and fainting. You may feel dizzy, lightheaded or pass out (faint) when you rise too quickly from a sitting or lying position. Falls. REXULTI may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries. Seizures (convulsions). Problems controlling your body temperature so that you feel too warm. Do not become too hot or dehydrated during treatment with REXULTI. Do not exercise too much. In hot weather, stay inside in a cool place if possible. Stay out of the sun. Do not wear too much clothing or heavy clothing. Drink plenty of water. Difficulty swallowing that can cause food or liquid to get into your lungs. Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities. Do not drive a car, operate machinery, or do other dangerous activities until you know how REXULTI affects you. REXULTI may make you feel drowsy. Before taking REXULTI, tell your healthcare provider about all of your medical conditions, including if you: have or have had heart problems or a stroke have or have had low or high blood pressure have or have had diabetes or high blood sugar or a family history of diabetes or high blood sugar. have or have had high levels of total cholesterol, LDL cholesterol, or triglycerides, or low levels of HDL cholesterol have or have had seizures (convulsions) have or have had kidney or liver problems have or have had a low white blood cell count are pregnant or plan to become pregnant. REXULTI may harm your unborn baby. Taking REXULTI during your third trimester of pregnancy may cause your baby to have abnormal muscle movements or withdrawal symptoms after birth. Talk to your healthcare provider about the risk to your unborn baby if you take REXULTI during pregnancy. Tell your healthcare provider if you become pregnant or think you are pregnant during treatment with REXULTI. There is a pregnancy exposure registry for women who are exposed to REXULTI during pregnancy. If you become pregnant during treatment with REXULTI, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . are breastfeeding or plan to breastfeed. It is not known if REXULTI passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with REXULTI. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. REXULTI and other medicines may affect each other causing possible serious side effects. REXULTI may affect the way other medicines work, and other medicines may affect how REXULTI works. Your healthcare provider can tell you if it is safe to take REXULTI with your other medicines. Do not start or stop any medicines during treatment with REXULTI without first talking to your healthcare provider. The most common side effects of REXULTI include weight gain, sleepiness, dizziness, common cold symptoms, and restlessness or feeling like you need to move (akathisia). These are not all the possible side effects of REXULTI. For more information, ask your healthcare provider or pharmacist. You are encouraged to report side effects of REXULTI (brexpiprazole). Please contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 ( www.fda.gov/medwatch ). Please read FULL PRESCRIBING INFORMATION , including BOXED WARNING , and MEDICATION GUIDE for REXULTI . About Otsuka Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: Otsuka–people creating new products for better health worldwide. Otsuka researches, develops, manufactures, and markets innovative products, with a focus on pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health. In pharmaceuticals, Otsuka is a leader in the challenging areas of mental, renal, and cardiovascular health and has additional research programs in oncology and on several under-addressed diseases including tuberculosis, a significant global public health issue. These commitments illustrate how Otsuka is a “big venture” company at heart, applying a youthful spirit of creativity in everything it does. Otsuka established a presence in the U.S. in 1973 and today its U.S. affiliates include Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Otsuka America Pharmaceutical, Inc. (OAPI). These two companies’ 2,250 employees in the U.S. develop and commercialize medicines in the areas of mental health and nephrology, using cutting-edge technology to address unmet healthcare needs. OPDC and OAPI are indirect subsidiaries of Otsuka Pharmaceutical Co., Ltd., which is a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan. The Otsuka group of companies employed 34,400 people worldwide and had consolidated sales of approximately USD 14.2 billion in 2023. All Otsuka stories start by taking the road less traveled. Learn more about Otsuka in the U.S. at www.otsuka-us.com and connect with us on LinkedIn and Twitter at @OtsukaUS . Otsuka Pharmaceutical Co., Ltd.’s global website is accessible at https://www.otsuka.co.jp/en/ . ______________________ i Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen H -U. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012;21(3):169-184. ii Lehavot K, Katon JG, Chen JA, Fortney JC, Simpson TL. Post-traumatic Stress Disorder by Gender and Veteran Status [published correction appears in Am J Prev Med. 2019 Oct;57(4):573]. Am J Prev Med. 2018;54(1):e1-e9. iii Lancaster CL, Teeters JB, Gros DF, Back SE. Posttraumatic Stress Disorder: Overview of Evidence-Based Assessment and Treatment. J Clin Med. 2016;5(11):105. iv U.S. Department of Veterans Affairs. How Common Is PTSD in Adults? Last updated: Feb. 3, 2023. Last accessed: April 30, 2024. Available at: https://www.ptsd.va.gov/understand/common/common_adults.asp v Davis LL, Schein J, Cloutier M, et al. The Economic Burden of Posttraumatic Stress Disorder in the United States From a Societal Perspective. J Clin Psychiatry. 2022;83(3):21m14116. vi Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication [published correction appears in Arch Gen Psychiatry. 2005 Jul;62(7):768. Merikangas, Kathleen R [added]]. Arch Gen Psychiatry. 2005;62(6):593-602. vii American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 2013 viii American Psychiatric Association. What is Posttraumatic Stress Disorder (PTSD)? Last updated: November 2022. Last accessed: August 28, 2024. Available at: https://www.psychiatry.org/patients-families/ptsd/what-is-ptsd . ix Wang PS, Berglund P, Olfson M, Pincus HA, Wells KB, Kessler RC. Failure and delay in initial treatment contact after first onset of mental disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):603-613. x U.S. Department of Veterans Affairs. VA/DoD Clinical Practice Guidelines. Management of Posttraumatic Stress Disorder and Acute Stress Disorder. Provider Summary 2023. Version 4.0. www.healthquality.va.gov/guidelines/MH/ptsd/VA-DoD-CPG-PTSD-Provider-Summary.pdf xi REXULTI® (brexpiprazole). Prescribing Information. FDA. xii Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther. 2014;350(3):589-604.

Drug Approval

30 Dec 2024

·medcitynews.com

Axsome Aims for FDA Filing in Alzheimer’s Agitation Despite Mixed Bag of Phase 3 Data - MedCity News

Agitation caused by Alzheimer’s disease currently has one FDA-approved therapy, but that drug brings serious safety risks. An Axsome Therapeutics drug has mixed results from its latest slate of clinical tests in this indication, but company executives say the balance weighs in favor of the therapy and they’re planning to take the data to the FDA. The Axsome drug, Auvelity, is already approved as a treatment for major depressive disorder. The preliminary results announced Monday are from two tests of the pill as a treatment for Alzheimer’s agitation. In one of the studies, the drug met the main goal by showing a statistically significant delay in the time to relapse. This study also met a key secondary goal of preventing relapse of Alzheimer’s agitation. The data are less clear for the second Phase 3 test that posted preliminary data Monday. While the drug showed numerical improvement on the trial’s main goal, Axsome said these results were not enough to be statistically significant. Nevertheless, the company points to statistical significance achieved in two previous Phase 3 tests in Alzheimer’s agitation. With three pivotal clinical trials achieving statistically significant results and one showing numerical improvement, the company said it is readying a new drug application it expects to file with the FDA in the second half of 2025. presented by Health IT Transforming Patient Care: The Role of AI-Powered Assistants The progress in artificial intelligence (AI) is reshaping patient care, across various dimensions, from facilitating faster discharge to curating treatment plans and suggesting lifestyle changes. By IT Medical Auvelity initially won FDA approval in 2023 as a treatment for depression, specifically major depressive disorder. This drug is a combination of two older medications, the depression drug buproprion and dextromethorphan, a medication that crosses the blood-brain barrier to target NMDA receptors. Dextromethorphan is commonly used in cough drugs; its targeting and blocking of NMDA receptors suppresses activity in the brain that causes coughing. NMDA receptors are found throughout the central nervous system and play key roles in functions such as learning and memory. Axsome has been testing whether blocking these receptors can also treat the agitation caused by Alzheimer’s. The first drug specifically approved for treating Alzheimer’s agitation was Rexulti, from partners Lundbeck and Otsuka Pharmaceutical. Rexulti, which is thought to work by affecting serotonin receptors, was initially approved in 2015 as a treatment for both major depressive disorder and schizophrenia. The following year, Rexulti was approved as a maintenance treatment for schizophrenia. The drug’s label was expanded to Alzheimer’s agitation in 2023. Rexulti, across all of its approved indications, generated 3.8 billion Danish krone (about $530 million) in revenue in the first nine months of 2024, a 15% increase compared to the same period in the prior year. In its financial reports, Lundbeck attributes the revenue growth to prescriptions for Alzheimer’s agitation. The drug has also received approvals in this indication in Australia, Israel, Malaysia, Singapore, and Switzerland. In depression, Axsome’s Auvelity competes in a crowded market of branded and generic medications. The drug accounted for $198.7 million in revenue for the first nine months of 2024, according to the company’s most recent financial report. Alzheimer’s agitation represents a large market where Rexulti would be Auvelity’s only competitor. But the Axsome drug has the opportunity to offer a safety edge. presented by Market Trends to Watch for Health Systems and Their Specialty Pharmacies The future looks bright for the integrated specialty pharmacy model – for health systems, providers, and most importantly, for patients. By Jake Gaffey, MBA, Chief Strategy Officer at Shields Health Solutions Rexulti’s label carries a black box warning for higher risks of suicidal thoughts and behaviors, which is consistent with other atypical antipsychotics. Across Auvelity’s Phase 3 studies, Axsome says its drug was safe and well tolerated in the elderly study participants. Furthermore, Auvelity was not associated with increased risk of falls, cognitive decline, or sedation and there were no deaths reported in patients who received the study drug. The black box warning for Rexulti is a significant limiting factor for use of the drug in elderly patients, William Blair analyst Myles Minter wrote in a note sent to investors on Monday. Axsome’s Auvelity could differentiate itself with a different mechanism of action that does not introduce the same dangerous safety risks as Rexulti. “We remain bullish on approval prospects and believe Axsome maintaining breakthrough therapy designation despite Rexulti’s approval highlights that the FDA recognizes there remains a high unmet need here despite approved therapy, which should bode well for Axsome from a regulatory perspective,” Minter said. The outstanding question is whether the clinical data are sufficient. Given the clinical trial that fell short of statistical significance, Minter said the FDA will need to show regulatory flexibility toward the Axsome drug. There’s precedent for neuropsychiatry drugs overcoming the failure of a pivotal study to win FDA approval based on the totality of data. One example noted by Minter is Rexulti, whose development program in Alzheimer’s agitation resulted in two positive studies and one negative study. To Leerink Partners analyst Marc Goodman, the results posted Monday create the most confusion for Auvelity’s prospects in Alzheimer’s agitation. Of the four Phase 3 tests of Auvelity in this indication, two were randomized, placebo-controlled studies and two were withdrawal studies. In withdrawal studies, all patients receive the study drug at first. But after a period of time, patients who show response to treatment are randomly assigned to either continue receiving the study drug or complete the trial on a placebo. Of the two clinical trials posting data Monday, the withdrawal study is the one that met its goal. Goodman said it’s unclear how the FDA will view the Auvelity withdrawal studies. He added that Leerink expects an FDA advisory committee will be convened to discuss the balance of the drug’s efficacy and safety, and the positive safety data may sway the vote. Public domain image by Flickr user SciTechTrend

Phase 3Drug ApprovalClinical ResultFinancial StatementBreakthrough Therapy

19 Dec 2024

·www.otsuka.co.jp

JAMA Psychiatry Publishes Results of Otsuka and Lundbeck's Phase 3 Trial of Brexpiprazole in Combination with Sertraline in Treatment of Post-Traumatic Stress Disorder (PTSD) in Adults

RSS Brexpiprazole in combination with sertraline demonstrated a statistically significant reduction in overall PTSD symptoms compared to sertraline plus placebo, as measured by change in CAPS-5 total score from Week 1 to Week 101 The safety profile of brexpiprazole in combination with sertraline was consistent with that of brexpiprazole in approved indications1 Otsuka and Lundbeck submitted an sNDA for brexpiprazole in combination with sertraline for the treatment of adults with PTSD in April 2024. The sNDA is currently under FDA review with a PDUFA target date of February 8, 2025 PTSD is a highly prevalent, trauma-based neuropsychiatric disorder that impacts approximately 13 million U.S. adults in a given year, and nearly 6 in 100 people will be diagnosed with PTSD in their lifetime2-6 Otsuka Pharmaceutical Co., Ltd. (Otsuka) announces that its US subsidiary Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Lundbeck Pharmaceuticals LLC (Lundbeck) today announced that the full results of a Phase 3 trial of brexpiprazole in combination with sertraline for the treatment of PTSD in adults have been published in JAMA Psychiatry. The results showed that in adults with PTSD, treatment with brexpiprazole in combination with sertraline resulted in statistically significant greater improvement of PTSD symptoms vs treatment with sertraline plus placebo, as measured by change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score from Week 1 to Week 10.1 "About 6% of the United States population will have PTSD at some point in their lives, but around only half will seek treatment," said Lori Davis, M.D., clinical professor of psychiatry in the Department of Psychiatry and Behavioral Neurobiology, University of Alabama School of Medicine, who served as lead author on the JAMA Psychiatry manuscript. "The Phase 3 results are an important and encouraging step forward in the hopes of providing PTSD patients with a new therapeutic option in the future." About the Phase 3 Trial The Phase 3 randomized, double-blind, active-controlled, parallel-arm trial (NCT04124614) evaluated the efficacy, safety, and tolerability of brexpiprazole in combination with sertraline for the treatment of PTSD. The trial included 416 adult outpatients who were randomized to receive either brexpiprazole (2-3 mg/day) with sertraline (150 mg/day) or sertraline (150 mg/day) with a placebo. The primary endpoint was the change in CAPS-5 total score from randomization (Week 1) to Week 10. Patients receiving brexpiprazole with sertraline showed a statistically significant greater improvement in CAPS-5 total score (-19.2) compared to those receiving sertraline with placebo (-13.6), with a least squares (LS) mean difference of -5.59 (95% CI: -8.79 to -2.38; P<.001). Additionally, both secondary endpoints, the change in the Clinical Global Impression- Severity of Illness score (CGI-S) randomization (week 1) to week 10 and the change in the Brief Inventory of Psychosocial Function (B-IPF) from baseline (Day 0) to week 12, were also met.1 "The clinical trial results demonstrate the potential of brexpiprazole in combination with sertraline as a treatment option for patients with PTSD, a condition that affects millions within the United States," said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka Pharmaceutical Development & Commercialization, Inc. "The combination of brexpiprazole and sertraline demonstrated meaningful improvements in PTSD symptoms." The safety profile of brexpiprazole in combination with sertraline was consistent with that of brexpiprazole in approved indications. The proportion of treated participants who discontinued due to adverse events was 3.9% (8/205) for brexpiprazole + sertraline and 10.2% (20/196) for sertraline + placebo.1 The adverse events occurring in >=5% for brexpiprazole in combination with sertraline (n=205) compared to sertraline and placebo (n=196) were nausea (12.2% vs 11.7%), fatigue (6.8% vs 4.1%), weight increase (5.9% vs 1.5%), and somnolence (5.4% vs. 2.6%), respectively.1 "The outcome of this trial provides us with an opportunity to help patients with PTSD," said Johan Luthman, executive vice president and head of Research & Development at Lundbeck. "With these promising results, we are committed to working closely with the FDA to help bring brexpiprazole in combination with sertraline to the healthcare professionals serving the PTSD patient community." About CAPS-5 The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a structured interview designed to assess PTSD diagnostic status and symptom severity as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The CAPS-5 consists of 30 items, with a higher score indicating a worse outcome.1 The CAPS-5 includes 20 DSM-5 PTSD-symptom items that are each scored from 0 (absent) to 4 (extreme/incapacitating). The total score is calculated by summing the 20 items, and symptom cluster scores by summing specific items: Intrusion (items 1-5); Avoidance (items 6-7); Negative cognitions and mood (items 8-14); and Arousal and reactivity (items 15-20).1 The CGI-S is a 7-point categorical scale, originally developed for mental disorders, but now applied to various illnesses, that requires a clinician to rate the severity of a patient's illness at the time of assessment, relative to the clinician's experience with patients who have the same diagnosis.7 The B-IPF is an abridged, 7-item version of the Inventory of Psychosocial Functioning (IPF) which assesses PTSD-related functional impairment in the prior 30 days across the same domains that are assessed by the 80-item version of the IPF; each item on the B-IPF corresponds to one IPF functional domain.8 About Post-Traumatic Stress Disorder PTSD is one of the most common mental health disorders in the United States, with approximately five percent of the population affected during a given year.2, 4, 9, 10 Most patients (>80%) with PTSD in the United States are in the civilian population.4, 11 It may occur in people who have experienced or witnessed a traumatic event, series of events or set of circumstances. An individual may experience an event that is emotionally or physically harmful or life-threatening which may affect mental, physical, social, and/or spiritual well-being. Examples of traumatic events include physical/sexual assault, natural disasters, serious accidents, terrorist acts, war/combat, historical trauma, intimate partner violence and bullying.12, 13 Symptoms of PTSD are generally grouped into four symptom clusters: intrusion (re-experiencing), persistent avoidance of stimuli, negative alterations in cognitions and mood, and marked alterations in arousal and reactivity. Individual symptom type and intensity can fluctuate over time and between individuals. To meet the criteria for PTSD diagnosis, symptoms must last longer than one month, and they must be severe enough to interfere with aspects of daily life, such as relationships or work. Symptoms also must not be due to medications, substance use, or another medical condition.10, 12 The average time from index trauma to symptom presentation is 2.2 years, and the average time from index trauma to PTSD diagnosis is 8.7 years.14 About Brexpiprazole Brexpiprazole was approved in the U.S. by the FDA in 2015, as an adjunctive therapy to antidepressants in adults with major depressive disorder (MDD) and as a treatment for schizophrenia in adults. Most recently, brexpiprazole was approved in the U.S. for the treatment of agitation associated with dementia due to Alzheimer's disease, in May 2023. Brexpiprazole was also approved by Health Canada for schizophrenia and adjunctive treatment of MDD in 2017 and 2019, respectively, and for agitation associated with dementia due to Alzheimer's disease in 2024. It was approved by the European Medicines Agency in 2018 for the treatment of schizophrenia and the Ministry of Health, Labour and Welfare in Japan for the treatment of schizophrenia and MDD in 2018 and 2023, respectively. Brexpiprazole was discovered by Otsuka and is being co-developed by Otsuka and Lundbeck. The mechanism of action of brexpiprazole is unknown. Brexpiprazole has high receptor binding affinity to norepinephrine, serotonin and dopamine receptors. It is an antagonist at norepinephrine α1B and α2C receptors and serotonin 5-HT2A receptors, as well as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors.15, 16 References 1. Davis LL, Behl S, Lee D, et al. Brexpiprazole and Sertraline Combination Treatment in Posttraumatic Stress Disorder. JAMA Psychiatry. Published online December 18, 2024. doi:10.1001/jamapsychiatry.2024.3996 2. U.S. Department of Veterans Affairs. How Common Is PTSD in Adults? Accessed September 2024. www.ptsd.va.gov/understand/common/common_adults.asp. 3. US Census Bureau. (2022). National Population by Characteristics: 2020-2022. Retrieved from www.census.gov/data/tables/time-series/demo/popest/2020s-national-detail.html. 4. Lehavot K, Katon JG, Chen JA, Fortney JC, Simpson TL. Post-traumatic Stress Disorder by Gender and Veteran Status [published correction appears in Am J Prev Med. 2019 Oct;57(4):573]. Am J Prev Med. 2018;54(1):e1-e9. 5. Goldstein RB, Smith SM, Chou SP, et al. The epidemiology of DSM-5 posttraumatic stress disorder in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions-III. Soc Psychiatry Psychiatr Epidemiol. 2016;51(8):1137-1148. 6. Schein J, Houle C, Urganus A, et al. Prevalence of post-traumatic stress disorder in the United States: a systematic literature review. Curr Med Res Opin. 2021;37(12):2151-2161. 7. Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37. 8. U.S. Department of Veterans Affairs. Inventory of Psychosocial Functioning (IPF). Accessed December 2024. https://www.ptsd.va.gov/professional/assessment/functioning-other/ipf_psychosocial_function.asp 9. Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen H -U. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012;21(3):169-184. 10. Lancaster CL, Teeters JB, Gros DF, Back SE. Posttraumatic Stress Disorder: Overview of Evidence-Based Assessment and Treatment. J Clin Med. 2016;5(11):105. 11. Davis LL, Schein J, Cloutier M, et al. The Economic Burden of Posttraumatic Stress Disorder in the United States From a Societal Perspective. J Clin Psychiatry. 2022;83(3):21m14116. 12. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 2013 13. American Psychiatric Association. What is Posttraumatic Stress Disorder (PTSD)? Last updated: November 2022. Last accessed: August 28, 2024. Available at: www.psychiatry.org/patients-families/ptsd/what-is-ptsd. 14. Davis LL, Urganus A, Gagnon-Sanschagrin P, et al. Patient journey of civilian adults diagnosed with posttraumatic stress disorder-A chart review study. Curr Med Res Opin. 2024;40(3):505-516. 15. Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther. 2014;350(3):589-604. 16. REXULTI® (brexpiprazole). Prescribing Information. FDA. Reference ID: 4911319. May 2024.

Clinical ResultPhase 3Drug Approval

100 Deals associated with Brexpiprazole

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KEGG	Wiki	ATC	Drug Bank
D10309	Brexpiprazole	N05AX16	DB09128

R&D Status

Approved

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Indication	Country/Location	Organization	Date
Depressive Disorder	JP	Otsuka Holdings Co., Ltd.	22 Dec 2023
Agitation in Dementia	US	Otsuka Pharmaceutical Co., Ltd.	10 May 2023
Agitation	AU	Lundbeck Australia Pty Ltd.	19 May 2017
Alzheimer Disease	AU	Lundbeck Australia Pty Ltd.	19 May 2017
Depressive Disorder, Major	US	Otsuka Pharmaceutical Co., Ltd.	10 Jul 2015
Schizophrenia	US	Otsuka Pharmaceutical Co., Ltd.	10 Jul 2015

Developing

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Indication	Highest Phase	Country/Location	Organization	Date
Psychotic Disorders	NDA/BLA	CN	Shanghai Xinfeng Pharmaceutical Co., Ltd.	16 Aug 2024
Stress Disorders, Post-Traumatic	NDA/BLA	US	Otsuka Pharmaceutical Development & Commercialization, Inc.	25 Jun 2024
Borderline Personality Disorder	Phase 3	US	Otsuka Pharmaceutical Development & Commercialization, Inc.	13 Jan 2020
Autism Spectrum Disorder	Phase 3	US	Otsuka Pharmaceutical Development & Commercialization, Inc.	30 Oct 2019
Autism Spectrum Disorder	Phase 3	US	H. Lundbeck A/S	30 Oct 2019
Bipolar I disorder	Phase 3	US	H. Lundbeck A/S	14 Sep 2017
Bipolar I disorder	Phase 3	US	Otsuka Pharmaceutical Development & Commercialization, Inc.	14 Sep 2017
Bipolar I disorder	Phase 3	BG	Otsuka Pharmaceutical Development & Commercialization, Inc.	14 Sep 2017
Bipolar I disorder	Phase 3	BG	H. Lundbeck A/S	14 Sep 2017
Bipolar I disorder	Phase 3	PL	H. Lundbeck A/S	14 Sep 2017

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04124614 (Pubmed) Manual	Phase 3	Stress Disorders, Post-Traumatic	416	Brexpiprazole 2-3 mg + Sertraline 150 mg	pxtndymchc(izwqwxsdil) = cbpxgrirov ddpdbyomvf (geuryjsnod, 1.2) View more	Positive	18 Dec 2024
				Sertraline 150 mg + Placebo	pxtndymchc(izwqwxsdil) = jkzjazwvmb ddpdbyomvf (geuryjsnod, 1.2) View more
NCT03737474 (BLESS, Pubmed \| CNS Drugs)	Phase 2/3	Depressive Disorder, Major	247	Brexpiprazole 2 mg/day	qmcztvzfwk(hnxtqwudqr) = kuxzgilkrz lxuduoyxqm (iksrxxlkgr ) View more	Positive	01 Dec 2024
NCT03548584 \| NCT03594123 (Pubmed \| Alzheimers Dement)	Phase 3	Agitation in Dementia	-	Brexpiprazole 2 mg/day	aijhiewfow(fhexnmcwfu) = fbtermrgaw bpzmdoyihf (taecktdpne ) View more	Positive	01 Dec 2024
				Placebo	aijhiewfow(fhexnmcwfu) = hkjeajivas bpzmdoyihf (taecktdpne ) View more
NCT03620981 (CTgov)	Phase 2/3	Dementia due to Alzheimer's disease (disorder) \| Agitation	410	Placebo	fbkadiisbw(fymrzzhdfw) = krwdzqphst rcvdjajmht (uzffwmkzat, fqtiwkpxmo - mhivijzfkc) View more	-	14 Nov 2024
NCT03594123 (NCT03594123, Pubmed \| J Alzheimers Dis)	Phase 3	Dementia due to Alzheimer's disease (disorder)	259	Brexpiprazole 2 mg/day	rilulncopp(sikrempqfg) = przvlmfpzt mjxssuofax (xlveujohgc )	Positive	01 Nov 2024
NCT04186403 (CTgov)	Phase 2/3	Borderline Personality Disorder	201	Brexpiprazole	eeydpfirjr(wkidjeswsy) = bjayovzdip rgktoxebut (tkezwktqvs, yarogiucdb - wptcwqxkjp) View more	-	03 Oct 2024
NCT03724942 (CTgov)	Phase 3	Dementia due to Alzheimer's disease (disorder) \| Agitation	164	brexpiprazole (ROLLOVER BREX)	letxzizuln(xzkobpujsz) = qudvxwkwww shlnpabmqd (lzozvljmpq, kjqqcrnsea - ebduttkevf) View more	-	19 Sep 2024
				placebo (ROLLOVER PLACEBO)	letxzizuln(xzkobpujsz) = gqyswkhrtv shlnpabmqd (lzozvljmpq, loprbnoafb - qzlfgpccpj) View more
NCT03697603 (CTgov)	Phase 2/3	Depressive Disorder, Major	740	Placebo	dokkgqmusv(xyuvzbxyum) = ybehsabtmo tucytbydqx (nbzdyojoen, redyfqpmxh - ijtlhcbbzv) View more	-	09 Aug 2024
NCT04100096 (CTgov)	Phase 2	Borderline Personality Disorder	332	Brexpiprazole (Brexpiprazole 2-3 Milligrams Per Day)	xymwbjgqil(blheoxmuri) = pysgfrzoiw uyfnudmpst (qxxsvzybwj, pxlqqfarbp - awiwkqakfn) View more	-	18 Jul 2024
				Placebo (Placebo)	xymwbjgqil(blheoxmuri) = syeenaljzl uyfnudmpst (qxxsvzybwj, oixlgkhnme - budxducmur) View more
NCT04258839 (CTgov)	Phase 3	Autism Spectrum Disorder \| Irritable Mood	95	Brexpiprazole (Prior Brexpiprazole)	rtbgtgwzhq(azxispaihe) = auawubldda beysnzwwae (tkkjbfvhja, ykesegtsng - utpizaqprl) View more	-	30 May 2024
				placebo+brexpiprazole (Prior Placebo)	rtbgtgwzhq(azxispaihe) = ptxdxxzsfq beysnzwwae (tkkjbfvhja, wcdmncbsdr - dgbiduxvla) View more

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