Cariprazine hydrochloride

4月22日，百时美施贵宝（BMS）公布了3期ARISE临床试验的顶线结果。该研究评估了Cobenfy（占诺美林/曲司氯铵）作为辅助疗法在症状控制不佳的成人精神分裂症患者中的安全性和有效性。研究结果显示，与安慰剂联合非典型抗精神病药相比，Cobenfy辅助治疗在第6周时使阳性和阴性症状量表（PANSS）总分降低2.0分，但未达到主要终点的统计学显著性阈值（P=0.11）。初步分析表明，在特定患者亚组中，Cobenfy辅助治疗显示出优于安慰剂的症状改善趋势。值得注意的是，事后亚组分析揭示了显著的应答差异：以利培酮为基础治疗的患者与使用其他非利培酮类抗精神病药（包括帕利哌酮、阿立哌唑、齐拉西酮、鲁拉西酮和卡利拉嗪）的患者相比，表现出不同的治疗效果。ARISE试验（KAR-012）是一项为期6周、随机、双盲、安慰剂对照的多中心门诊研究，旨在评估Cobenfy对当前抗精神病药疗效不佳的成人精神分裂症患者（18-65岁）的辅助治疗效果。研究纳入标准包括：保持稳定的背景治疗，且筛选期PANSS总分≥70分。研究设置的主要终点为第6周时PANSS总分较基线的变化，次要终点包括：个人与社会功能量表（PSP）评分临床总体印象-严重度量表（CGI-S）评分PANSS Marder因子分应答率（定义为PANSS总分改善≥30%）用药偏好评估完成ARISE试验的合格受试者可进入为期52周的开放标签扩展研究（OLE），以进一步评估该疗法的长期安全性和耐受性特征。占诺美林/曲司氯铵是BMS去年收购的产品，是失败产品二次定位、成功盘活的经典案例。关于占诺美林的故事[1]Karuna成立于2009年，于2024年5月被百时美施贵宝耗资140亿美元收购。Karuna之所以如此值钱，是因为它成功盘活了一个“废弃”的高潜力药物占诺美林。占诺美林是一个选择性乙酰胆碱M1和M4受体激动剂，是礼来与诺和诺德开发的一个抗阿尔茨海默病（AD）药物。上世纪八九十年代，科学家认为AD与乙酰胆碱通路有关，并成功开发了多奈哌齐、卡巴拉汀、加兰他敏等产品。虽然临床试验证实占诺美林对AD有效，但因严重的胃肠道和心血管不良反应，临床试验在1998年被终止。在临床试验中，科学家发现占诺美林对AD“异常行为”有影响，如幻觉、妄想等，这让他们联想到该药物有望用于治疗精神分裂症。本世纪初，丹麦科学家就通过阿扑吗啡诱导建模，在动物试验中评估了占诺美林在对抗精神分裂方面的活性，而且礼来公司还开展了早期的临床试验初步证明了疗效，但因严重的不良反应，项目开发也相继终止。2012年，Karuna以“10万美元首付款+最高5400万美元里程碑付款+销售提成”的方式向礼来购买了占诺美林的全球开发权益，包括礼来持有的专利、监管文件和试验数据。随后，Karuna将占诺美林与M受体阻断剂曲司氯铵联用，巧妙地解决了占诺美林的不良反应问题。他们认为占诺美林的不良反应是因激动外周M受体引起，只要找到一种不能进入中枢的M受体阻断剂与之搭配使用，外周M受体激动引起的不良反应就能抵消。经过大量的筛选，科学家最终选择了曲司氯铵。一开始，Karuna几乎无法融资，硬着头皮在70名健康者中进行了一期临床试验，结果发现KarXT（占诺美林+曲司氯铵的固定剂量组合物）组的不良反应发生率相比占诺美林单药组下降了53%。这样的数据非常让人兴奋，2018年，Karuna在A轮融资中成功筹集了4200万美元，六个月后又在B轮融资中成功筹集到8000万美元。同年，Karuna的股票挂牌上市。2019年11月，KarXT的二期临床试验达到了预期的终点，Karuna的股价飞速上涨，市值从3亿多美元飞升至20多亿美元。2020~2024年间，Karuna在国际顶级期刊上发表了多篇文章，披露的临床数据非常惊艳。作为精神分裂症全新机制的疗法，市场潜力巨大，分析师认为该产品在2028年的销售额有望达到28亿美元。2024年5月，百时美施贵宝以140亿美元的天价收购了Karuna，而KarXT在2024年9月获得了FDA批准。[1] 内容摘自《探寻跨国药企的成功基因》，该书将在下半年出版发行药事纵横投稿须知：稿费已上调，欢迎投稿

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol Myers Squibb (NYSE: BMY) today announced topline results from the Phase 3 ARISE trial evaluating the efficacy and safety of Cobenfy (xanomeline and trospium chloride) as an adjunctive treatment to atypical antipsychotics in adults with inadequately controlled symptoms of schizophrenia. In the Phase 3 trial, adjunctive Cobenfy treatment demonstrated a 2.0-point reduction in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo with an atypical antipsychotic at Week 6, which did not reach the threshold for statistical significance for the primary endpoint (P = 0.11). Preliminary analyses suggest that Cobenfy as an adjunctive treatment to an atypical antipsychotic was associated with improvements in symptoms of schizophrenia compared to placebo plus an atypical antipsychotic for certain patients. In a post-hoc subgroup analysis there was a notable difference in response between subjects treated with risperidone as a background therapy compared with the remaining subjects treated with other background antipsychotics (non-risperidone). The initial analyses showed: PANSS, PSP and CGI-S Change from Baseline by Treatment Group Endpoint Cobenfy + APD Placebo + APD LSMD (95% CI) p-value mITT Population, N 190 196 Primary Endpoint Change in PANSS Total Score LS Mean (SE) -14.3 (1.01) -12.2 (0.98) -2.0 (-4.5, 0.5) 0.11 Key Secondary Endpoint Change in PSP Score LS Mean (SE) 5.3 (0.75) 5.9 (0.73) -0.6 (-2.4, 1.2) 0.52* Secondary Endpoint Change in CGI-S LS Mean (SE) -0.6 (0.06) -0.5 (0.06) -0.1 (-0.3, 0.04) 0.14* Post-Hoc Subgroup Analysis Risperidone Change in PANSS Total Score LS Mean (SE) (N=60) -11.3 (2.13) (N=69) -12.3 (2.10) 1.1 (-3.7, 5.9) 0.66* Non-Risperidone Change in PANSS Total Score LS Mean (SE) (N=130) -15.1 (1.18) (N=127) -11.7 (1.17) -3.4 (-6.3, -0.5) 0.03* APD = Antipsychotic background drug; PANSS = Positive and Negative Syndrome Scale; PSP = Personal and Social Performance Scale; CGI-S = Clinical Global Impressions Severity Scale; mITT = modified intent-to-treat; SE = Standard Error; LSMD = Least Squares Mean Difference; Non-Risperidone group includes paliperidone, aripiprazole, ziprasidone, lurasidone and cariprazine. *p-value is nominal, not adjusted for multiplicity Cobenfy’s safety and tolerability profile as an adjunctive treatment was consistent with previous monotherapy trials. Further analysis will follow, and the company will plan to speak with regulators about potential next steps. "Adjunctive treatment trials in schizophrenia present significant clinical and methodological challenges," said Husseini Manji, MD, FRCPC, Co-Chair, UK Government Mental Health Goals Program and Professor, Department of Psychiatry, Oxford University. "When patients are already receiving treatment, demonstrating additional statistical benefit becomes inherently more difficult. However, it’s common for individuals to continue to experience persistent symptoms, and prescribers have adopted an approach to address this significant unmet need through adjunctive use. Although Cobenfy did not demonstrate a statistically significant improvement as an adjunctive treatment in this trial, the data are encouraging, showing a noteworthy improvement for the majority of patients in the trial, as well as a tolerable safety profile. These findings warrant additional follow up and may provide valuable direction in our ongoing search for complementary approaches to address these persistent treatment gaps." "Historically, the development of an effective, adjunctive treatment for schizophrenia has been difficult due to inherent challenges like variable patient response, stringent trial design requirements, and the complexities of demonstrating incremental benefits beyond established antipsychotics," said Samit Hirawat, MD, executive vice president, chief medical officer and head of development at Bristol Myers Squibb. "Despite the complex and challenging nature of adjunctive studies, we wanted to pursue research in this area to help more patients struggling with this condition. While the primary endpoint in this trial did not meet statistical significance, we need to complete our analysis and will plan to engage with the medical community and regulators to discuss these results and potential next steps. Cobenfy monotherapy has shown positive efficacy and safety in four pivotal studies, and provides a meaningful, differentiated treatment for people living with schizophrenia.” There is a robust clinical development program advancing for this important medicine across multiple neuropsychiatric conditions, including symptoms associated with Alzheimer's disease and autism spectrum disorder, bipolar disorder and other areas of significant clinical need. Bristol Myers Squibb will complete a full evaluation of the Phase 3 trial data and intends to present detailed results at an upcoming medical conference. Bristol Myers Squibb thanks the patients, investigators and clinical trial sites who participated in the ARISE clinical trial. About the Phase 3 ARISE Trial The ARISE clinical trial (KAR-012) is a Phase 3, 6-week, randomized, double-blind, placebo-controlled, multicenter, outpatient study evaluating Cobenfy (xanomeline and trospium chloride) as an adjunctive treatment in adults with schizophrenia who have inadequate response to their current antipsychotic treatment. The trial enrolled adults aged 18 to 65 years with schizophrenia who were on stable background therapy at the time of enrollment, with a Positive and Negative Syndrome Scale (PANSS) score of ≥70 at screening and randomization. The primary objective is to assess the efficacy of Cobenfy as an adjunctive treatment to one of several atypical antipsychotics compared to placebo with an atypical antipsychotic as measured by change from baseline in PANSS total score at Week 6. The study also evaluated several secondary endpoints, including changes in Personal Social Performance (PSP), Clinical Global Impression-Severity (CGI-S), PANSS Marder Positive and Negative symptom factor scores, categorical response (defined as the proportion of subjects achieving ≥30% improvement in PANSS total score at Week 6), and Preference of Medication (POM). Following completion of the ARISE study, eligible participants may continue in a 52-week open-label extension (OLE) study to evaluate the long-term safety and tolerability of adjunctive Cobenfy treatment. About Schizophrenia Schizophrenia is a persistent and often disabling mental illness impacting how a person thinks, feels and behaves. There are three symptom domains of schizophrenia, which include positive symptoms (e.g., hallucinations, delusions, disordered thinking and speech), negative symptoms (e.g., lack of motivation, lack of emotional expression/flat affect, social withdrawal) and cognitive dysfunction (e.g., impaired attention, deficits in memory, concentration and decision-making). The symptoms of schizophrenia can affect all areas of people’s lives, making it difficult to maintain employment, live independently and manage relationships. Schizophrenia affects nearly 24 million people worldwide, including 2.8 million people in the United States, and is one of the top 15 leading causes of disability worldwide. Bristol Myers Squibb: Transformational Research Advancing Neuroscience Bristol Myers Squibb is inspired by a single vision – transforming patients’ lives through science. Neurological and neuropsychiatric conditions represent some of the greatest challenges of our time, bringing life-altering hardships to patients, caregivers and families throughout the course of these devastating diseases. Our researchers are committed to the pursuit of breakthrough science to develop life-changing medicines that modify disease and treat symptoms to improve quality of life. We have established a diverse neuroscience portfolio, including assets across a wide range of therapeutic modalities and mechanisms in conditions such as Alzheimer’s disease, schizophrenia, multiple sclerosis and more. With industry-leading capabilities, including our in-house neuroimaging program, we seek bold solutions to improve the treatment landscape. Evolution is in our DNA at Bristol Myers Squibb. We are motivated by the rapid progress of scientific knowledge within neuroscience and have an unwavering commitment to advance the most promising innovations to deliver transformational results for patients. About Cobenfy™ (xanomeline and trospium chloride) Cobenfy™ (xanomeline and trospium chloride), formerly KarXT, is an oral medication for the treatment of schizophrenia in adults. Cobenfy combines xanomeline, a dual M1- and M4-preferring muscarinic receptor agonist, with trospium chloride, a muscarinic receptor antagonist that does not appreciably cross the blood-brain barrier, primarily confining its effects to peripheral tissues. While the exact mechanism of action of Cobenfy is unknown, its efficacy is thought to be due to the agonist activity of xanomeline at M1 and M4 muscarinic acetylcholine receptors in the central nervous system. INDICATION COBENFY™ (xanomeline and trospium chloride) is indicated for the treatment of schizophrenia in adults. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS COBENFY is contraindicated in patients with: urinary retention moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment gastric retention history of hypersensitivity to COBENFY or trospium chloride. Angioedema has been reported with COBENFY and trospium chloride. untreated narrow-angle glaucoma WARNINGS AND PRECAUTIONS Risk of Urinary Retention: COBENFY can cause urinary retention. Geriatric patients and patients with clinically significant bladder outlet obstruction and incomplete bladder emptying (e.g., patients with benign prostatic hyperplasia (BPH), diabetic cystopathy) may be at increased risk of urinary retention. COBENFY is contraindicated in patients with pre-existing urinary retention and is not recommended in patients with moderate or severe renal impairment. In patients taking COBENFY, monitor for symptoms of urinary retention, including urinary hesitancy, weak stream, incomplete bladder emptying, and dysuria. Instruct patients to be aware of the risk and promptly report symptoms of urinary retention to their healthcare provider. Urinary retention is a known risk factor for urinary tract infections. In patients with symptoms of urinary retention, consider reducing the dose of COBENFY, discontinuing COBENFY, or referring patients for urologic evaluation as clinically indicated. Risk of Use in Patients with Hepatic Impairment: Patients with hepatic impairment have higher systemic exposures of xanomeline, a component of COBENFY, compared to patients with normal hepatic function, which may result in increased incidence of COBENFY-related adverse reactions. COBENFY is contraindicated in patients with moderate or severe hepatic impairment. COBENFY is not recommended in patients with mild hepatic impairment. Assess liver enzymes prior to initiating COBENFY and as clinically indicated during treatment. Risk of Use in Patients with Biliary Disease: In clinical studies with COBENFY, transient increases in liver enzymes with rapid decline occurred, consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage. COBENFY is not recommended for patients with active biliary disease such as symptomatic gallstones. Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated during treatment. The occurrence of symptoms such as dyspepsia, nausea, vomiting, or upper abdominal pain should prompt assessment for gallbladder disorders, biliary disorders, and pancreatitis, as clinically indicated. Discontinue COBENFY in the presence of signs or symptoms of substantial liver injury such as jaundice, pruritus, or alanine aminotransferase levels more than five times the upper limit of normal or five times baseline values. Decreased Gastrointestinal Motility: COBENFY contains trospium chloride. Trospium chloride, like other antimuscarinic agents, may decrease gastrointestinal motility. Administer COBENFY with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Use COBENFY with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis. Risk of Angioedema: Angioedema of the face, lips, tongue, and/or larynx has been reported with COBENFY and trospium chloride, a component of COBENFY. In one case, angioedema occurred after the first dose of trospium chloride. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, discontinue COBENFY and initiate appropriate therapy and/or measures necessary to ensure a patent airway. COBENFY is contraindicated in patients with a history of hypersensitivity to trospium chloride. Risk of Use in Patients with Narrow-angle Glaucoma: Pupillary dilation may occur due to the anticholinergic effects of COBENFY. This may trigger an acute angle closure attack in patients with anatomically narrow angles. In patients known to have anatomically narrow angles, COBENFY should only be used if the potential benefits outweigh the risks and with careful monitoring. Increases in Heart Rate: COBENFY can increase heart rate. Assess heart rate at baseline and as clinically indicated during treatment with COBENFY. Anticholinergic Adverse Reactions in Patients with Renal Impairment: Trospium chloride, a component of COBENFY, is substantially excreted by the kidney. COBENFY is not recommended in patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <60 mL/min). Systemic exposure of trospium chloride is higher in patients with moderate and severe renal impairment. Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate and severe renal impairment. Central Nervous System Effects: Trospium chloride, a component of COBENFY, is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported with trospium chloride, including dizziness, confusion, hallucinations, and somnolence. Monitor patients for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how COBENFY affects them. If a patient experiences anticholinergic CNS effects, consider dose reduction or drug discontinuation. Most Common Adverse Reactions (≥5% and at least twice placebo): nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease. Use in Specific Populations: Moderate or Severe Renal Impairment: Not recommended Mild Hepatic Impairment: Not recommended COBENFY (xanomeline and trospium chloride) is available in 50mg/20mg, 100mg/20mg, and 125mg/30mg capsules. Please see U.S. Full Prescribing Information, including Patient Information. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, X, YouTube, Facebook and Instagram. Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, the possibility of unfavorable results from further clinical trials involving Cobenfy (xanomeline and trospium chloride) and whether Cobenfy for the additional indications described in this release will be successfully developed and commercialized. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2024, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news