Buprenorphine

Data show rapid initiation with once-monthly SUBLOCADE significantly improves retention in opioid use disorder (OUD) patients, especially among fentanyl-positive participants. Study also administered second SUBLOCADE injection a week later vs. standard 28 days, enabling patients to achieve and maintain target medication levels more quickly. Data show rapid initiation with once-monthly SUBLOCADE significantly improves retention in opioid use disorder (OUD) patients, especially among fentanyl-positive participants. Study also administered second SUBLOCADE injection a week later vs. standard 28 days, enabling patients to achieve and maintain target medication levels more quickly. Presented at the 2024 Canadian Society of Addiction Medicine (CSAM) conference, this study highlights the potential of rapid initiation to transform the treatment of opioid use disorder. Presented at the 2024 Canadian Society of Addiction Medicine (CSAM) conference, this study highlights the potential of rapid initiation to transform the treatment of opioid use disorder. Data supporting the subcutaneous administration of SUBLOCADE to alternative injection sites including the thigh, upper arm, and buttocks vs current subcutaneous abdominal injection site, were also presented at CSAM. Data supporting the subcutaneous administration of SUBLOCADE to alternative injection sites including the thigh, upper arm, and buttocks vs current subcutaneous abdominal injection site, were also presented at CSAM. SUBLOCADE has received Priority Review designation from the U.S. Food and Drug Administration (FDA) to expand the label to include rapid initiation one hour after a single transmucosal buprenorphine dose as well as inclusion of alternative injection sites. SUBLOCADE has received Priority Review designation from the U.S. Food and Drug Administration (FDA) to expand the label to include rapid initiation one hour after a single transmucosal buprenorphine dose as well as inclusion of alternative injection sites. RICHMOND, Va., Nov. 19, 2024 -- Indivior PLC (Nasdaq/LSE: INDV) last week shared results from a randomized, open-label sub-study in opioid-dependent participants seeking treatment, (NCT04995029) that demonstrates rapid initiation (RI) with SUBLOCADE® (buprenorphine extended-release injection) for the treatment of OUD significantly improves treatment retention compared to standard initiation (SI). RI with SUBLOCADE in a single day may reduce barriers to treatment and improve patient retention especially those who frequently inject opioids or use fentanyl without increasing the risk of precipitated opioid withdrawal (POW) symptoms. The data were presented at the 2024 Canadian Society of Addiction Medicine (CSAM) conference in Hamilton, Ontario, Canada. “These findings underscore the potential for rapid initiation to transform opioid use disorder treatment,” said Dr. Christian Heidbreder, Ph.D., Chief Scientific Officer at Indivior. “Rapid initiation may improve patient retention and meet the immediate needs brought on by synthetic opioids in real-world settings, offering a practicable path to stabilization and long-lasting, meaningful recovery.” Conducted across multiple sites, this non-inferiority study included 729 participants (mean age 42, average opioid use of 15 years), stratified by fentanyl presence in urine screens, with an observed 78% fentanyl-positive rate. Patients randomized to RI received a single dose of 4 mg transmucosal buprenorphine (TM-BUP), followed by a SUBLOCADE injection within 1 hour. The primary endpoint was treatment retention at injection 2, administered 1 week after injection 1 comparing it to the current standard regimen of 28 days. Those in the SI group received daily TM-BUP doses over ≥7 days before injection, and if non-inferiority was met, superiority was assessed. Among the participants, RI was superior to SI in retention rates at injection 2, with a 12% improvement overall and 15% in the fentanyl-positive group. The shorter dose interval between BUP-XR injection 1 and 2 was designed to achieve and maintain buprenorphine plasma concentrations more quickly at target levels of 2 ng/mL. The overall Treatment Emergent Adverse Events (TEAE) profile up to Injection 2 was comparable for RI and SI. There were no unexpected safety findings. Data supporting the subcutaneous administration of SUBLOCADE to alternative injection sites including the thigh, upper arm, and buttocks were also presented at CSAM (NCT04995029). SUBLOCADE has received Priority Review designation granted by the U.S. Food and Drug Administration (FDA) for a labeling supplement, which would expand the label to include rapid initiation one hour after a single transmucosal buprenorphine dose and also expands from the current subcutaneous abdominal injection site for induction and maintenance to alternative injection sites including the thigh, upper arm, and buttocks. With a Prescription Drug User Fee Act (PDUFA) action date set for February 7, 2025, this Prior Approval Supplement (PAS) submission, if approved, could allow healthcare providers a flexible approach to initiate treatment rapidly, supporting better retention outcomes for OUD patients, particularly those testing positive for fentanyl. A Priority Review designation means that the FDA's goal is to take action on an application within 6 months (compared to 10 months under standard review). If approved, this label change could translate into significant improvements in OUD treatment with SUBLOCADE. +++ This press release has been issued by Indivior Inc. and the content has not been approved or authorized by the Canadian Society of Addiction Medicine. +++ About SUBLOCADE® SUBLOCADE ® (buprenorphine extended-release) injection, for subcutaneous use, CIII INDICATION AND HIGHLIGHTED SAFETY INFORMATION INDICATION SUBLOCADE is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days. SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support. HIGHLIGHTED SAFETY INFORMATION WARNING: RISK OF SERIOUS HARM OR DEATH WITH INTRAVENOUS ADMINISTRATION; SUBLOCADE RISK EVALUATION AND MITIGATION STRATEGY Serious harm or death could result if administered intravenously. SUBLOCADE forms a solid mass upon contact with body fluids and may cause occlusion, local tissue damage, and thrombo-embolic events, including life threatening pulmonary emboli, if administered intravenously. Serious harm or death could result if administered intravenously. SUBLOCADE forms a solid mass upon contact with body fluids and may cause occlusion, local tissue damage, and thrombo-embolic events, including life threatening pulmonary emboli, if administered intravenously. Because of the risk of serious harm or death that could result from intravenous self-administration, SUBLOCADE is only available through a restricted program called the SUBLOCADE REMS Program. Healthcare settings and pharmacies that order and dispense SUBLOCADE must be certified in this program and comply with the REMS requirements. Because of the risk of serious harm or death that could result from intravenous self-administration, SUBLOCADE is only available through a restricted program called the SUBLOCADE REMS Program. Healthcare settings and pharmacies that order and dispense SUBLOCADE must be certified in this program and comply with the REMS requirements. CONTRAINDICATIONS SUBLOCADE should not be administered to patients who have been shown to be hypersensitive to buprenorphine or any component of Indivior's proprietary buprenorphine gel depot delivery system. WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse: SUBLOCADE contains buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids. Monitor patients for conditions indicative of diversion or progression of opioid dependence and addictive behaviors. Respiratory Depression: Life threatening respiratory depression and death have occurred in association with buprenorphine. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with SUBLOCADE. Opioids can cause sleep-related breathing disorders e.g., central sleep apnea (CSA), sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. Consider decreasing the opioid using best practices for opioid taper if CSA occurs. Strongly consider prescribing naloxone at SUBLOCADE initiation or renewal because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose. Educate patients and caregivers on how to recognize respiratory depression and how to treat with naloxone if prescribed. Risk of Serious Injection Site Reactions: The most common injection site reactions are pain, erythema and pruritus with some involving abscess, ulceration, and necrosis. The likelihood of serious injection site reactions may increase with inadvertent intramuscular or intradermal administration. Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal syndrome is an expected and treatable outcome of prolonged use of opioids during pregnancy. Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid. Risk of Opioid Withdrawal With Abrupt Discontinuation: If treatment with SUBLOCADE is discontinued, monitor patients for several months for withdrawal and treat appropriately. Risk of Hepatitis, Hepatic Events: Monitor liver function tests prior to and during treatment. Risk of Withdrawal in Patients Dependent on Full Agonist Opioids: Verify that patient is clinically stable on transmucosal buprenorphine before injecting SUBLOCADE. Treatment of Emergent Acute Pain: Treat pain with a non-opioid analgesic whenever possible. If opioid therapy is required, monitor patients closely because higher doses may be required for analgesic effect. ADVERSE REACTIONS Adverse reactions commonly associated with SUBLOCADE (in ≥5% of subjects) were constipation, headache, nausea, injection site pruritus, vomiting, increased hepatic enzymes, fatigue, and injection site pain. For more information about SUBLOCADE, the full Prescribing information including BOXED WARNING, and Medication Guide, visit www.sublocade.com. About Opioid Use Disorder (OUD) Opioid Use Disorder (OUD) is a chronic disease in which people develop a pattern of using opioids that can lead to negative consequences.1 OUD may affect the parts of the brain that are necessary for life-sustaining functions.1,2 Important Cautionary Note Regarding Forward-Looking Statements This press release contains certain statements that are forward-looking. Forward-looking statements include, among other things, express and implied statements regarding: Indivior PLC’s expectations regarding the timing of approval for the PAS for rapid induction and injection sites, and the potential impact on OUD treatments and Sublocade from such; and other statements containing the words "believe," "anticipate," "plan," "expect," "expectations," "intend," "estimate," "forecast," “strategy,” “target,” “guidance,” “outlook,” “potential,” "project," "priority," "may," "will," "should," "would," "could," "can," the negatives thereof, and variations thereon and similar expressions. By their nature, forward-looking statements involve risks and uncertainties as they relate to events or circumstances that may or may not occur in the future. Actual results may differ materially from those expressed or implied in these forward-looking statements due to a number of factors, including: failure or delay in obtaining approval of the PAS and the acceptance by HCPs and their patients of the perceived benefits of such PAS changes. For information about some of the risks and important factors that could affect our future results and financial condition, see "Risk Factors" in Indivior's Annual Report on Form 20-F for the fiscal year 2023 and its other filings with the U.S. Securities and Exchange Commission. We have based the forward-looking statements in this press release on our current expectations and beliefs concerning future events. Forward-looking statements contained in this press release apply only at the date of this press release and, except as required by law, we undertake no obligation to update or revise any forward-looking statement, whether due to new information, future developments, or otherwise. About Indivior Indivior is a global pharmaceutical company working to help change patients' lives by developing medicines to treat substance use disorders (SUD). Our vision is that all patients around the world will have access to evidence-based treatment for the chronic conditions and co-occurring disorders of SUD. Indivior is dedicated to transforming SUD from a global human crisis to a recognized and treated chronic disease. Building on its global portfolio of OUD treatments, Indivior has a pipeline of product candidates designed to expand on its heritage in this category. Headquartered in the United States in Richmond, VA, Indivior employs over 1,000 individuals globally and its portfolio of products is available in over 30 countries worldwide. Visit www.indivior.com to learn more. Connect with Indivior on LinkedIn by visiting www.linkedin.com/company/indivior. Media Contacts: US Media: Cassie France-Kelly VP, Communications Indivior PLC Tel: +1(804) 724-0327 References  National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on Medication-Assisted Treatment for Opioid Use Disorder, Mancher, M., & Leshner, A. I. (Eds.). (2019). Medications for Opioid Use Disorder Save Lives. National Academies Press (US). Accessed October 30, 2023, from https://www-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/books/NBK538936/pdf/Bookshelf_NBK538936.pdf NIDA. 2022, March 22. Drugs and the Brain. Accessed October 30,2023, from https://nida-nih-gov.libproxy1.nus.edu.sg/publications/drugs-brains-behavior-science-addiction/drugs-brain

关注并星标CPHI制药在线 阿片类镇痛药是目前已知疗效最好的镇痛药之一，然而其便秘、耐受和成瘾等毒副作用严重限制了其临床应用。近年来，随着对阿片受体信号转导机制的深入认知和药物设计技术的不断进步，研究者们尝试了许多有前景、不同于传统的改造吗啡骨架结构的全新方法，致力于开发低毒高效的阿片类镇痛药。 01 偏向型 μ 受体激动剂 阿片类药物通过不同的细胞内信号途径产生不同的作用。研究发现，G蛋白偶联受体 (Gprotein-coupled receptor, GPCR)激活后，在其下游除了G蛋白依赖型通路外，还存在另一条由β-arrestin介导的信号通路，不同的配体可以不同程度地激活这两条通路，甚至只激活其中一条，这种现象称为“偏向性激活”。研究显示，G蛋白依赖型通路主要介导镇痛镇静，而β-arrestin 通路主要介导呼吸抑制、胃肠功能紊乱、药物耐受等。说明若某个阿片受体激动剂可以偏向性激动G蛋白信号通路，其镇痛疗效与毒副作用的平衡关系会更优，这为低毒高效阿片类镇痛新药的发现提供了理论基础。目前，丁丙诺啡、奥赛利定和PZM21 是比较有代表性的G蛋白偏向性激动剂。 丁丙诺啡是由英国Reckitt Benckiser公司基于吗啡骨架所设计的，于 1978 年获批上市。该药不仅能够有效治疗急性和慢性疼痛，还可通过替代疗法减轻阿片类药物的成瘾性。丁丙诺啡的镇痛疗效媲美吗啡，但其呼吸抑制等不良反应的发生率较吗啡更低。 奥赛利定，由美国 Trevena公司于2013 年研发。在细胞水平上，该药对G蛋白信号通路的激活能力与吗啡相近，但招募β-arrestin 2的能力远低于吗啡；在动物水平上，该药显示出略强于吗啡的镇痛效力，并且不易诱发呼吸抑制。2020年，奥赛利定获美国 FDA 批准上市，用于中重度急性疼痛的治疗，但该药仍会引发恶心、呕吐、便秘等不良反应。 PZM21是首个基于阿片受体晶体结构所设计的G蛋白偏向性激动剂。在细胞水平上，其偏向性与奥赛利定不相上下；在啮齿和灵长类动物水平上，其镇痛效力与吗啡、羟考酮相当且持续时间更久，并且没有成瘾性。但是，PZM21 仍未能避免便秘、耐药等不良反应。 此外，引入苯并二氧戊环取代 PZM21 分子结构中的羟基，该衍生物可表现出比母体更强的镇痛活性和更大的G蛋白信号通路偏向性。有研究通过对配体-受体复合物冷冻电镜结构的解析和对比，发现 PZM21 和奥赛利定分别为完全不激活和部分激活 β-arrestin 信号通路，而芬太尼和吗啡则是强效激活β-arrestin 信号通路，这阐释了偏向性激动剂招募 β-arrestin 的结构细节，为开发低毒高效的偏向性阿片类镇痛药夯实了结构基础。 近日，国内关于G蛋白偏向性阿片受体激动剂的临床研究取得重大突破。江苏恒瑞医药股份有限公司的泰吉利定（产品开发名为 SHR8554）是一种 μ 阿片受体的偏向性小分子激动剂，具有良好的镇痛作用、安全性和耐受性，于 2024 年 1 月 31 日获我国国家药品监督管理局批准上市，适用于腹部手术后的中重度疼痛，是国内首款自主研发的一类阿片类镇痛创新药。绿叶制药集团有限公司的G蛋白偏向性阿片受体激动剂 LPM-3480392 已先后在中国和美国完成了腹部手术中重度疼痛的Ⅱ期临床试验（CTR20222358、NCT06204120），关于骨科手术术后中重度疼痛的Ⅱ期临床试验（CTR20233389）正在有序开展中。 02 混合阿片受体激动剂以及 “一药多靶”策略 多种药物联用的“鸡尾酒”疗法，在癌症、艾滋病和慢性疼痛等疾病治疗中均取得了良好成效。研发人员基于“鸡尾酒”疗法提出了“一药多靶”的多重药理学新理念，即作用于多个靶标的单一组分化合物，有助于平衡各靶标活性并产生协同作用。在痛觉相关的受体或信号通路中，μ阿片受体的调控效果最为显著。因此，阿片类“一药多靶”策略主要是围绕μ阿片受体开展的。根据靶标组合的不同，阿片类“一药多靶”药物主要分为下述两类。 ① 阿片受体家族不同亚型之间的组合，即：除靶向激动μ阿片受体以外，药物还作用于δ、κ 或 NOP 受体。研究发现，敲除 δ 受体可减轻 μ 受体激动剂的成瘾、耐受等副作用，以此为理论基础所设计的 μ 受体激动剂/δ 受体拮抗剂显示出更少的不良反应。有趣的是，μ/δ 受体双靶点激动剂同样显示出较好的镇痛潜力。此外，κ 和 NOP 受体也能够协同调节 μ 受体的生理效应。Cebranopadol 是一款极有代表性的“一药多靶”药物，由美国 Tris 公司开发。在细胞水平上，该药对多个阿片受体亚型都有较高的亲和力和激动活性（尤其是对μ和 NOP 受体），多靶点特性突出；在啮齿和灵长类动物水平上，该药的镇痛效力远高于吗啡，且不良反应更少。目前，该药在癌症疼痛、糖尿病周围神经病变、骨关节炎引发的慢性疼痛和药物滥用潜力评估等近10项临床试验中均取得了良好进展。 ② 阿片受体与非阿片受体的组合，除靶向激动μ阿片受体以外，药物还作用于非阿片系统的受体或信号通路，如神经肽FF（neuropeptide FF，NPFF）受体、神经激肽受体、胆囊收缩素受体等。以 NPFF 为例，有学者以阿片受体激动剂 morphiceptin 和 NPFF 类似物PFRTicNH2为母体设计了多靶点阿片肽药物 MCRT，该药显示出强效的镇痛活性和极少的不良反应；另有学者基于阿片受体激动剂和 NPFF 构建了 DN-9 等多个多靶点分子，其有效性和安全性均优于吗啡。 在已上市的阿片类镇痛药中，具有“一药多靶”特性的药物占有很大比例，包括地佐辛和他喷他多等十余种药物都属于此类。相比吗啡等专一性 μ 阿片受体激动剂，多靶点阿片类镇痛药的安全性普遍较好。例如地佐辛，其呼吸抑制等不良反应的发生率非常低且有封顶效应，因而备受医患关注，占据了我国麻醉镇痛药市场约60% 的份额。多靶点药物的设计策略为安全高效的新型阿片类镇痛药的研发提供了更多可能性。 03 外周阿片受体激动剂 众所周知，阿片受体在脑和脊髓之外的周围神经系统有着广泛的分布。透过血-脑屏障激活中枢神经系统的阿片受体，是阿片类药物发挥强效镇痛作用的关键，也是成瘾、过度镇静等副作用的根本原因。因此，“不上头”的外周阿片受体激动剂愈发受到关注。一种方法是研究本身不通过血脑屏障的药物，该研究集中于κ 受体激动剂，以asimadoline (EMD61753) 为代表，但 asimadoline 在镇痛方面表现差强人意，上市后主要用于肠易激综合征。再者，可采用纳米载体搭载阿片类药物，纳米载体无法通过血脑屏障，从而达到仅激动外周阿片受体的作用。法国学者开发出一种装载了亮氨酸脑啡肽 (leu-enkephalin, LENK) 的纳米药物，在动物模型中，该药成功的被血脑屏障阻隔，通过外周阿片受体实现炎症部位的长效止痛。另外，有学者设计出仅在特定 pH 环境中起作用的阿片受体激动剂，而炎性组织一般为酸性环境。该类药物以NFEPP 为代表，NFEPP 是基于芬太尼所设计的一种氟化衍生物。相比于芬太尼，该药不仅无法跨越血-脑屏障，氟原子的修饰作用还使其只有在酸性条件下才能与外周 μ 阿片受体结合，对呈现酸性微环境的病变组织实现靶向治疗。在结肠炎小鼠模型中，该药能够精准靶向炎症组织，有效缓解结肠疼痛，且完全不诱发成瘾、镇静、便秘等阿片样副作用。此外，研究人员基于 L-脑啡肽和角鲨烯的生物缀合物所开发的一种纳米载体镇痛药，通过制剂手段同样达到了不入脑而仅激活外周阿片受体的目的。 04 改变中枢分布动力学的阿片受体激动剂 有假说认为 μ 受体激动剂的成瘾作用与其进入中枢的速度有关，但镇痛效果只与中枢暴露水平有关，那么开发以较低速率穿过血脑屏障的新型阿片受体激动剂，有可能降低成瘾。NKTR-181是一种聚合物-药物偶联物，通过聚乙二醇侧链 (polyethylene glycol, PEG) 来降低 μ 阿片类激动剂穿过血脑屏障的速度，在降低阿片类镇痛药成瘾性和滥用的同时，并具有显著的镇痛效力。目前，在腰痛和慢性非癌性痛病人中完成 3 期临床试验，其治疗相关不良反应 (TEAEs) 发生率为72%，最常见的不良反应为便秘 (26%)，恶心 (12%)。遗憾的是，目前美国 FDA 并没有通过 NKTR-181的上市申请。 05 内源性阿片肽降解酶抑制剂 内源性阿片肽存在于与疼痛相关的中枢、外周神经系统以及外周损伤组织中。试验表明在炎性痛和神经病理性疼痛的动物模型中，通过抑制内源性阿片肽降解酶，可以增加疼痛相关部位内源性阿片肽的水平，达到镇痛作用。研究较多的是双重脑啡肽降解酶抑制剂 DENK，同时具有抑制氨基肽酶 N (aminopeptidase N, APN)和中性肽链内切酶 (neutral endopeptidase, NEP) 的作用。机体接受疼痛刺激时，会内生出脑啡肽，以达到“生理性”镇痛。DENK抑制剂通过在有大量脑啡肽及其降解酶的地方发挥作用，放大“生理性”镇痛，具有一定意义上的定向作用。与吗啡不同的是，在啮齿动物中给予高剂量 DENK 抑制剂，不会导致耐受、镇静、呼吸抑制、呕吐、便秘或依赖。DENK 是一类药物的总称，其中，PL265 可缓解啮齿动物角膜炎所致的眼痛和炎症，目前已进入临床试验阶段。 06 抑制阿片类药物成瘾作用的新靶点 研究者对线虫基因的900多种突变进行测试，以观察是否导致对阿片类药物敏感性的变化，发现 FRPR-13 基因可能有意义。同时，在哺乳动物中也发现了 FRPR-13 的同源基因，该基因编码 GPR139 蛋白。在小鼠中，GPR139 与μ受体共表达，可抑制G蛋白耦联受体信号转导。缺失 GPR139 的小鼠对吗啡诱导的奖赏和镇痛的敏感性增加。当研究人员给小鼠服用激活 GPR139 的药物时，小鼠表现出更加依赖阿片类药物；相反，抑制、消除 GPR139 则增强了阿片类药物的止痛效果。因此， GPR139 可能是提高阿片类药物安全性的有效靶点。 参考资料 [1]吴鸽,林沈娴,朱奇,等.阿片类药物是否穷途末路？[J].中国疼痛医学杂志,2021,27(03):212-215. [2]贺春波,王丹,杨淑佳,等.新型阿片类镇痛药的研发进展[J].中国药房,2024,35(17):2176-2180. END 【生物制药新锐说直播预告】 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~