Lactation Disorders

作者｜文心  CNS疾病是公认的药物治疗贡献度最低和临床未满足需求最高的疾病领域之一。据WHO预测，20年内，CNS疾病将成为第二致死源。 虽然中枢神经系统疾病（CNS）领域的患病人数并不亚于肿瘤及心血管疾病，然而，中枢神经系统药物研发成功率仅为6%，不足其他药物研发成功率的一半。  在21世纪，政府主导的资助为CNS药物重新发展起来悄悄的积蓄着力量。据统计，美国国立卫生研究院（NIH）在21世纪投入80多亿美元进行神经学研究，是90年代的近10倍。在至少最近五年，CNS的交易活动一直在增加，并且没有减弱的迹象，这种趋势不仅在绝对意义上呈上升趋势，而且相对于其他治疗领域也是如此。 目前全球已经有一些嗅觉灵敏的biotech公司开始进入中枢神经系统（CNS）领域。比如，在5月13日，武田宣布与AC Immune就针对Aβ的疫苗产品ACI-24.060，达成了一项高达22亿美元的全球独家选择权和许可协议。同一天，艾伯维和Gilgamesh宣布达成一项超20亿美元的合作和许可选择协议，以开发下一代精神疾病疗法。 本文，就让我们一起来了解CNS领域的前世今生、市场需求、研发痛点、国内外现状、市场前景与研发现状。   01   CNS领域的前世今生 1895年，Ehrlich博士在研究染料时意外发现了“血脑屏障”现象。五年后，“血脑屏障”这一概念被正式提出，并进入了验证阶段。经过近20年的研究，对于脑部和外周组织间存在血脑屏障这一事实得到了广泛认可。只是，当时尚未有人知道形成该屏障的原因。时间进入20世纪60年代，随着电子显微镜出现，人类得以观察血脑屏障这一现象。日后，血脑屏障的发现和研究，让入脑药物的开发有了可能。 在1980年代之前，CNS药物的发现具有偶然性。在1980年代至1990年代，由于受体理论和分子结构分析技术的进步，在精神疾病领域取得了一些进展，尤其是在抑郁症方面。 然而，在1990年代至2000年代，CNS药物领域并没有取得重大的实质性进展。原因是缺乏对疾病机制的认识，导致开发的药物只能缓解临床症状，无法治愈疾病的根本原因。例如，阿尔茨海默病领域的Aricept只能对症治疗，帕金森病领域的Levodopa只是多巴胺替代物，其他CNS疾病也是类似情况。在此期间，许多临床试验以失败告终，辉瑞、礼来、阿斯利康等大型药厂削减了对CNS药物的投资，甚至退出了这个领域，这是CNS药物开发的最低谷时期。 在21世纪，政府主导的资助为CNS药物的发展提供了动力。据统计，美国国立卫生研究院（NIH）在21世纪投入了80多亿美元用于神经学研究，是90年代的近10倍。NIH的资金增长极大地促进了对基础神经科学的理解扩展，这是其他治疗领域所没有的增长。 CNS疾病给患者和社会带来了巨大的负担，需求仍然未得到满足。随着政府支持、风险投资和新技术的共同作用，CNS药物领域开始进入收获期。与肿瘤药物领域相比，CNS药物领域的竞争相对较少，存在较多的空白点，这也意味着在CNS药物项目上更容易取得创新突破，并为投资者带来超额收益的机会。 在2009年至2018年的风险投资和首次公开募股中，美国神经病学公司仅次于癌症公司。辉瑞、诺华、强生、大冢等大公司也重新回到CNS领域，设立风险基金，广泛投资该领域的生物科技公司，这些公司往往具有原创性的新疗法。 CNS领域的交易活动至少在过去五年内一直在增加，并且没有减弱的迹象。不仅从绝对意义上呈上升趋势，相对于其他治疗领域也是如此。从2012年到2016年的五年间，CNS药物的投资额比前五年增长了10亿美元，增速超过整个风险投资领域的33%。 技术进步也是推动CNS领域发展的重要因素。一系列创新技术正在扩展到CNS领域，可能促进多种疗法的开发，包括RNA技术、腺相关病毒基因治疗和CRISPR。 在2010年至2019年的十年间，FDA共批准了45种CNS药物上市，其中以多发性硬化症、偏头痛、精神分裂症、癫痫和抑郁症为主，合计占比超过50%。 通过以上多种因素的分析，许多企业坚信当前CNS药物开发已经进入一个新的阶段。   02   CNS领域的市场需求 进入21世纪，全球人口年龄结构已逐渐呈现倒金字塔形态，尤其在发达国家，中枢神经系统（CNS）疾病已成为重大卫生和社会挑战。随着人口老龄化、生活水平提高和饮食习惯变化，CNS疾病的用药比重逐年攀升，阿尔茨海默症（AD）和肌萎缩性脊髓侧索硬化症（ALS）等成为药物治疗贡献度最低且临床需求最高的疾病领域之一。据WHO预测，未来20年内，CNS疾病有望成为第二大致死源。 图1 大多数中枢神经系统疾病患病人数不亚于肿瘤及心血管疾病患者，药物市场空间足够大。但以FDA批准的药物、药物有效性角度看，仍存在大量未满足的临床需求。Japan Health Sciences Foundation通过调查研究发现，多数中枢神经系统疾病的临床有效性不足，存在大量未满足临床需求。 然而，与肿瘤、自身免疫性疾病等领域相比，CNS领域的药物研发进展显得相对缓慢。以阿尔茨海默病和帕金森病为例，现有治疗手段仅能减缓疾病进展，而抑郁症患者自杀比例高，精神分裂的治疗效果也不尽如人意，临床需求存在大量未被满足的空间。 在我国，作为世界上老年人口最多的国家，我们面临着约4000万失能、部分失能老年人的挑战，同时抑郁症患病率达到2.1%，焦虑障碍患病率达4.98%。然而，在全球中枢神经药物消费总额中，我国仅占3%，远低于美国的49%、欧洲的26%和日本的9%。这一数据凸显出我国中枢神经药物行业与国外相比仍处于起步阶段，中国中枢神经系统（CNS）用药市场存在大量未满足的临床需求。特别是在阿尔兹海默症、帕金森氏病、治疗酒精依赖、治疗阿片依赖、多发性硬化症等细分领域，存在巨大的市场空白等待填补。 图2   03   CNS领域的研发痛点 相较于肿瘤与心血管等慢性病领域拥有着如此大的市场需求的背后不仅取决于人类疾病谱的改变，其更深入的逻辑是CNS的药物研究堪“研发黑洞”引无数药企竞折腰。 CNS药物的开发困难似乎已经成为一种共识。从机制不明，到动物模型难验证、临床开发难，每一项都是CNS药物开发的拦路虎： 3.1 血脑屏障和血脑脊液屏障的阻碍 BBB 是高度选择性的屏障，将大脑与身体的其他部分隔开。出于这个原因，血脑屏障是发现有效治疗中枢神经系统相关疾病的新药的主要障碍，能够进入神经中枢的药物分子非常有限。 在药物设计中，增加药物分子的亲脂性则会影响其水溶性，造成给药困难，一些抗体药/多肽/核酸药需要设计专门的跨BBB载体才能发挥作用。 不仅如此，进入大脑中的药物浓度也无法进行直接的测量，药物浓度与临床终点的联系过于复杂，这也给造成了CNS新药开发造成了困难。 图3 3.2 大部分的CNS疾病缺乏明确的致病机理 任何一种疾病药物的成功研发，都是建立在对疾病机制有着深刻了解的基础上。但CNS疾病是缓慢的退行性的疾病，大部分的发病机制并不明确，这一方面限制了药物研发只能对疾病的症状进行治疗，另一方面也导致了实验设计困难的问题。 3.3 实验设计困难，缺乏可以对疾病进行可观量化和评估的疾病标志物 疾病机制的缺失导致临床试验设计的困难，进而影响下一步的效果。根据 1990 年至 2012 年间不同 CNS 适应症的试验，III 期失败率为 53%，缺乏疗效是主要原因 (46%)。CNS疾病的表征不够明显，有些甚至没有明显的器质病变，病人自己报告效果带有高度的主观性，得出的数据也难以对疾病进行可观的测量和评估。 3.4 缺乏有效的疾病模型 许多CNS药物在临床前的表现不错，但临床却以失败告终，这和疾病模型的表面效度和结构效度较差有关。耶鲁大学医学院2016年的一篇文章就指出，大多数导致中枢神经系统临床失败的模型过于宽松，比如AD 和 ALS 模型可能会测量错误的事物（或在错误的时间测量正确的事物），导致其与人类疾病相关性差。 3.5 毒副作用大 比如治疗抑郁症的药物，会引起高血压、自杀倾向等副作用，这对于进入市场销售的影响很大，导致收益过低。一些公司的药物效果不错，但是毒副作用过大，最终也导致了试验的失败。塔夫茨大学药物开发研究中心曾对1995—2007年期间的274种CNS药物和1168种非 CNS 药物临床进行研究分析，发现FDA最终批准上市的CNS药物的成功率不到非 CNS 药物批准率的一半（分别为6.2% 和 13.3%）。 此前，史上最多引用次数的Nature论文作者承认造假一事，也正是拜CNS药物研发黑洞所赐。 图4 通信作者已承认其2006年发表于《Nature》杂志的、关于阿尔茨海默病的具有划时代意义的论文中存在图像篡改等学术不端行为。该研究曾指出淀粉样蛋白Aβ中的一种特定形式——Aβ56，可能与阿尔茨海默病有密切关联，并显示该蛋白在基因改造后呈现阿尔茨海默病样症状的小鼠体内含量随认知能力下降而增加，且注射Aβ56的大鼠出现记忆缺陷。 长期以来，科学界致力于通过清除大脑中的淀粉样蛋白来对抗阿尔茨海默病，但多数实验药物未获成功。Aβ56的发现曾被视为治疗该疾病的新希望，引发了广泛关注并获得了大量研究资金。然而，后续研究中，科学家们对Aβ56的可靠性和存在性提出了质疑。 2021年底，范德比尔特大学的神经科学家在调查阿尔茨海默病相关研究时，发现这篇发表于2006年 Nature 论文，似乎存在着多处图像篡改问题。而此文通讯作者则是在全面调查后承认该文的学术不端行为。   04   CNS领域的国内外现状 CNS疾病主要包括：阿尔茨海默症(AD)、抑郁症、精神分裂症等疾病。下面我们将盘点一下上述代表性CNS的市场药物现状以及代表公司。 4.1 阿尔茨海默症(AD) 抗AD药物已成为国际CNS药物市场上销量增长最快的一类药物。但与其它抗精神病药物相比，AD治疗药物的数量并不多。阿尔茨海默病的新药开发，也是谈及CNS药物时无法避开的话题。在过去几年中，该领域一直饱受阿尔茨海默病药物后期失败的困扰。 2021年6月7日，FDA宣布加速审批渤健/卫材治疗早期阿尔茨海默病（AD）患者的新药Aduhelm（阿杜卡玛单抗）上市，但该药的治疗效果仍存在大量争论。随后，2024年1月31日，渤健表示将停止销售和开发Aduhelm，将重心转移到最新获批的阿尔茨海默病单抗疗法Leqembi（Lecanemab; 仑卡奈单抗）之上。 回顾2024年度AD管线报告，包括了2024年1月1日之前所有正在评估AD药物疗法的临床试验数据，结果显示，2024年AD管线中有164项试验，评估了127种药物。其中，有48项试验处于第3期试验阶段（32种药物），90项试验处于第2期试验阶段（81种药物），26项试验处于第1期试验阶段（25种药物）。在164项试验中，有34%（56项）评估了疾病修饰性生物制剂，41%（68项）测试了疾病修饰性小分子药物，10%（17项）评估了认知增强剂，14%（23项）测试了治疗神经精神症状的药物。 图5 近日，FDA的外周和中枢神经系统药物咨询委员会（PCNS）全票通过了推举礼来公司开发的Donanemab用于治疗早期阿尔茨海默病患者。在6月10日的会议上，委员会以11票全票通过，认为Donanemab的疗效显著，其益处大于风险。这一决定为FDA正式批准Donanemab铺平了道路，并为AD治疗领域带来了新的希望。专家委员会认为，尽管Donanemab在早期AD患者中展现出显著疗效，但仍需进一步研究以确定其最佳使用时长及对不同Tau蛋白水平患者的长期疗效。Donanemab的推荐批准及其初步研究结果为AD治疗带来了新的希望。科学界和医药界将继续关注并推进这方面的研究，为AD患者带来更有效的治疗方案。 图6 此外，Roche 及其子公司 Genentech研发的皮下注射型Gantenerumab 已经进入 III 期临床试验阶段，着重研究其在早期阿尔茨海默症患者中的疗效和安全性。2023年，基于二期临床(NCT01767311), Gantenerumab 已被 FDA 列为突破性疗法。 4.2 抑郁症 抑郁症的主要治疗方法有抗抑郁药物、心理治疗及电休克治疗。在美国和中国，SSRI（五羟色胺再摄取抑制剂）类及SNRI（去甲肾上腺素再摄取抑制剂）类药物经常被用来通过提高5-羟色胺及去甲肾上腺素的神经递质水平来治疗抑郁症。其他常见疗法包括三环类抗抑郁药（TCA），主要影响去甲肾上腺素及5-羟色胺这两种化学信使（神经递质）的水平，去甲肾上腺素和多巴胺再摄取抑制剂（NDRI），抑制神经递质去甲肾上腺素及多巴胺的再摄取，及去甲肾上腺素和特异性5-羟色胺能再摄取抑制剂（NaSSA），通过阻隔α2-肾上腺素受体及部分5-羟色胺受体而起作用。然而，抗抑郁药物对最多40%的重度抑郁症患者无效。因此，患者需要在抗抑郁药物类别之间转换，或增加当前治疗的剂量。倘若患者对两种或以上不同的抗抑郁药物治疗均无反应，则可能发展成为难治性抑郁症（TRD），TRD治疗方案十分有限。 4.3 精神分裂症 ①典型抗精神病药物 20世纪50年代出现了以氯丙嗪和氟哌啶醇为代表的抗精神病药物，由于其抗精神病作用与阻滞多巴胺 D2受体有关。此类药物临床的共同特点是，对精神分裂症的阳性症状有肯定的疗效，但对阴性症状疗效较差，且影响认知功能，不良反应较多，可能引起锥体外系运动障碍，对心血管及肝脏毒性较大，用药剂量越大，所引起的不良反应越明显。因此临床上这类药的使用率越来越低，渐被新一代抗精神病药所代替。 ②非典型抗精神病药物 20 世纪 60 年代末出现了氯氮平，因与多种受体有亲和力而被称为非典型抗精神病药。受氯氮平的启发，人们开发了一系列的非典型抗精神病新药，如利培酮、奥氮平、喹硫平、齐拉西酮、帕利哌酮、伊潘立等。阿立哌唑是首个上市的三代抗精分药物，峰值年销售曾达到93亿美金。卡利拉嗪是2015年最新上市的非典型类药物，2020年年销售额已达9.51亿美金。这类药物对精神分裂症有比较好的疗效，在阳性症状方面的治疗作用比较强，较少或不会引起锥体外系反应，较少因催乳素水平升高而导致内分泌不良反应，如月经紊乱、溢乳等，具有一定的临床优势。   05   盘点国内外主要CNS研发企业（部分）   06   市场前景与研发策略 CNS治疗领域孕育着巨大的市场机会，资本市场对CNS药物研发的关注度持续提升。根据弗若斯特沙利文统计，2019年全球CNS药物市场规模为1245亿美元，为第四大药物市场。 未来15年，全球CNS药物市场预计保持稳定增长，2034年达到1721亿美元。2019年中国CNS药物市场规模为296亿美元。未来15年，中国CNS药物预计实现快速增长，2034年达到571亿美元。按2019年我国药品销售收入计，中枢神经系统疾病治疗领域市场份额占当年医药市场份额的12.5%。从CNS结构性研发成功率来看，AD药物成功率较低，而其他适应症研发风险并不算高，这也指导CNS研发企业管线布局在整体风险控制上的考量；同时，表型筛选结合靶点筛选对于神经系统药物开发是一个有效突破的开发策略。 目前的主流研发策略大致可以分为TDD和PDD两类。机制优先策略，基于靶点的药物发现（target-baseddrug,TDD）。TDD的出发点针对特定靶点，发现能够改变其功能、表达、活性的药物。化合物优先策略，基于表型的药物发现（phenotypic drugdiscovery,PDD）。PDD因为机制不可知论，其出发点是生物学试验，通过转化医学标志物来作为结果输出。FDA是明确允许在没有已知靶点的情况下开展临床试验的。但随着发展，新机制的发现速度已经跟不上药物研发的速度，导致很多药企管线拥挤在一个靶点/机制上。对于一些没有明确机制的疾病，要想通过机制优先策略再到药物研发似乎不太现实，这之间有一道无法跨越的沟壑。 图7 最近十年，PDD重回药物研发者的视野。PDD以靶点不可知论为前提，获得药物活性分子和通过全新机制的创新疗法。特别是对疾病如AD，PD，ALS，其机制尚不清楚，尽管通过特异性蛋白找到相关编码基因，但仍不清楚这些基因是如何引起特性的神经损伤和死亡，PDD则直接跨过了机制不清楚的障碍，发现有效药物。 局部来看，以精神分裂症为代表的适应症目前有一定靶点依据和疗效，但对于精分的阴性症状和认知症状改善不佳，同时现有药物有一定副作用问题，因此仍存在疗效提升的临床需求。对于抑郁症患者，目前的治疗手段为三环类抗抑郁药，有效性不足，尚需新的机制有更好的疗效。对于成瘾治疗，现有的治疗方法主要是阿片类药物，复吸率仍然较高，尚需从成瘾环路调控策略出发而非靶点策略的治疗方式。以阿尔茨海默症为代表的神经退行性疾病，全球范围内患病人数约5000万，FDA近20年仅批准针对Aβ靶点的aducanumab上市，新靶点新机制亟需突破。2024年AD管线中临床试验数量、以及在研药物和新化学实体数量的减少等信息提示，近年来针对疾病修饰疗法(DMT)和精神症状治疗的成功开发，并未增加AD管线的活跃度。更多地使用生物标志物，更精确的靶标识别，以及更完善的试验执行等，可能会增加AD药物开发的成功案例，并吸引更多对这一亟需新疗法领域的兴趣和投资。   写在最后   在当今心血管疾病、肿瘤等慢性疾病的治疗药物发展渐入饱和之际，人们再次将目光投向了CNS领域。与曾经的“研发黑洞”不同的是，科学技术的突破，研究基础的累积和资本的光顾使得CNS领域焕发的“第二生机”。 目前仍有多款CNS药物处于临床试验阶段，各大Biotech的加入也使得CNS药物研发正处于爆发的前夜，在科学家的不懈努力和资本助力下，未来不仅在精神分裂症等需要提升治疗效果的适应症上，甚至是AD、ALS等较难攻克的疾病，一定会被人类所征服，而生物制药再次进军CNS领域的举措也必将有所收获！  主要参考文献  1.Japan Health Sciences Foundation 2.https://www.nature.com/articles/nature04533 3.2023年医药行业专题报告 抑郁症流行病学 德邦证券 4.中国CNS及精神类药物汇总比较（数据更新至2022年）来源：药融云 5.https://www.cn-healthcare.com/articlewm/20230718/content-1580229.html 6.https://www.drugtimes.cn/2020/09/08/49de1cc5ee/ 7.Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023 Aug 8;330(6):512-527. doi: 0.1001/jama.2023.13239. 8. Cummings J,et al.Alzheimer's disease drug development pipeline:2024. Alzheimer's & Dementia: Translational Research & Clinical Interventions. First published: 24 April 2024   BiG 十周年预告   6月26-29日，苏州，将召开BiG十周年庆典，此次会议将首次分为国内和国际篇章，以原创科学和临床需求为出发点，讨论创新技术平台和创新疗法（PROTACT/分子胶、双抗/ADC、siRNA/ASO、CGT、AI制药）的重大进展和发展前景，十年一药曙光现，大浪淘沙始见金！ ▼ 论坛4:  自免与CNS：从临床需求，寻找下一个重磅炸弹 策划：申华琼、郭秋杉 B2圣托里尼厅 上半场：当双抗、细胞疗法进军自免 14:00-14:30 自免领域，CAR-T及细胞疗法临床进展 徐沪济：海军军医大学长征医院大内科主任兼风湿科主任/清华大学医学院教授  14:30-14:55 双抗在自免领域中的开发进展 占一帆：华奥泰生物首席科学家 14:55-15:20 TIL细胞疗法，开发现状和未来展望 郭晓宁：毕诺济生物联合创始人/CEO 15:20-16:00 Panel：当细胞疗法进军自免，能否成为下一个重磅炸弹？ 郭秋杉：上海生物医药基金合伙人、BiG青委（主持） 徐沪济：海军军医大学长征医院大内科主任兼风湿科主任/清华大学医学院教授  王   俊：纽约大学助理教授 倪夕祥：恩瑞恺诺生物创始人、董事长 韩   露：北恒生物联合创始人/CEO 郭晓宁：毕诺济生物联合创始人/CEO 16:00-16:15 Break 下半场：多位视角下，CNS创新药的临床研发 16:15-16:45 临床视角：CNS领域创新疗法临床进展 16:45-17:10 AD重磅新药-Donanemab 的命运解析：审评结果及FDA专家委员会看点 王亚宁：上海瑞宁康生物医药创始人/CEO 17:10-18:00  Panel：CNS创新药临床研发，挑战与机会 申华琼：纽欧申医药创始人/CEO、BiG理事（主持） 王亚宁：上海瑞宁康生物医药创始人/CEO MNC代表 公开会议报名参会  会议门票：审核制(免费)； 含主论坛+分论坛，不含餐；优先biotech/Pharma、临床、院校科学家、投资机构。 咨询BiG 商务合作：Lisa 18662346610（同微信） 参会/会员：Kathy 17621909690（同微信） 媒体合作：静 渝   18335445068（同微信） 秘书长：李 圆   18521514899（同微信） 共建Biomedical创新生态圈！ 如何加入BiG会员？

Results from Long-Term Safety Study and Data from Healthcare Resource Utilization Research Offer Insights into Treatment Experiences for People Living with Schizophrenia or Bipolar I Disorder DUBLIN, May 14, 2024 /PRNewswire/ -- Alkermes plc (Nasdaq: ALKS) today announced the presentation of research related to its psychiatry franchise products—LYBALVI® (olanzapine and samidorphan) and ARISTADA® (aripiprazole lauroxil)—at four scientific conferences this spring. These meetings take place during Mental Health Awareness Month in May, an important moment in the year to raise awareness about mental health conditions, support people living with these complex diseases, and honor the work of healthcare providers. The meetings include: American Psychiatric Association (APA) Annual Meeting, May 4-8, New York City International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Annual Meeting, May 5-8, Atlanta American Society of Clinical Psychopharmacology (ASCP) Annual Meeting, May 28-31, Miami Beach Psych Congress Elevate, May 30–June 2, Las Vegas "Each year, the spring scientific meetings bring together critical stakeholders from across the field of psychiatry to share insights and advance patient care; Alkermes is honored to have our research selected for presentation at these important events," said Craig Hopkinson, M.D., Chief Medical Officer and Executive Vice President of Research & Development at Alkermes. "These data from across our psychiatry product franchise demonstrate our commitment to expanding the body of evidence for our medicines and advancing understanding of their real-world impact. We look forward to presenting our findings and engaging in robust discussion with the community around our shared purpose in supporting patients living with schizophrenia and bipolar I disorder." Highlights of the upcoming presentations include: Findings from an international, multicenter, phase 3, open-label extension study assessing the long-term safety, tolerability and durability of treatment effect of LYBALVI in patients who received up to four years of treatment. Results from a real-world study of treatment patterns and healthcare resource utilization among patients with schizophrenia before and after initiating ARISTADA using the ARISTADA INITIO® initiation regimen. The full list of Alkermes' presentations by meeting is as follows: APA Poster 5749: Long-term Safety and Efficacy of Olanzapine/Samidorphan: Results of a 4-Year Open-Label Study ISPOR Poster RWD194: Healthcare Resource Utilization Following 6 Months of Treatment With Olanzapine/Samidorphan: Real-World Assessment of Patients With Schizophrenia or Bipolar I Disorder Poster RWD103: Treatment Patterns and Healthcare Resource Utilization Following Initiation of Aripiprazole Lauroxil Using a 1-Day Initiation Regimen ASCP Poster T47: Key Characteristics of the Long-Acting Injectable Atypical Antipsychotic Aripiprazole Lauroxil for the Treatment of Adults with Schizophrenia Poster T49: Long-Term Safety and Efficacy of Olanzapine/Samidorphan: Results of a 4-Year Open-Label Study Poster T52: Treatment Patterns and Healthcare Resource Utilization Following Initiation of Aripiprazole Lauroxil Using a 1-Day Initiation Regimen Psych Congress Elevate Poster #59: Treatment Patterns and Healthcare Resource Utilization Following Initiation of Aripiprazole Lauroxil Using a 1-Day Initiation Regimen Poster #30: Long-term Safety and Efficacy of Olanzapine/Samidorphan: Results of a 4-Year Open-Label Study Poster #60: Healthcare Resource Utilization Following 6 Months of Treatment With Olanzapine/Samidorphan: Real-World Assessment of Patients With Schizophrenia or Bipolar I Disorder About LYBALVI® (olanzapine and samidorphan) LYBALVI® (olanzapine and samidorphan) is a once-daily, oral atypical antipsychotic drug approved in the U.S. for the treatment of adults with schizophrenia and for the treatment of adults with bipolar I disorder, as a maintenance monotherapy or for the acute treatment of manic or mixed episodes, as monotherapy or an adjunct to lithium or valproate. LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist, in a single bilayer tablet. LYBALVI is available in fixed dosage strengths composed of 10 mg of samidorphan and 5 mg, 10 mg, 15 mg or 20 mg of olanzapine. IMPORTANT SAFETY INFORMATION for LYBALVI® (olanzapine and samidorphan) Boxed Warning: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. LYBALVI is not approved for the treatment of patients with dementia-related psychosis. Contraindications: LYBALVI is contraindicated in patients who are using opioids or are undergoing acute opioid withdrawal. If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for these products. Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis, including stroke, transient ischemia attack, and fatalities. See Boxed Warning. Precipitation of Severe Opioid Withdrawal in Patients who are Physiologically Dependent on Opioids: LYBALVI can precipitate opioid withdrawal in patients who are dependent on opioids, which can lead to an opioid withdrawal syndrome, sometimes requiring hospitalization. LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Prior to initiating LYBALVI, there should be at least a 7‑day opioid-free interval from last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. Explain the risks associated with precipitated withdrawal and the importance of giving an accurate account of last opioid use to patients and caregivers. Vulnerability to Life-Threatening Opioid Overdose: Attempting to overcome opioid blockade with high or repeated doses of exogenous opioids could lead to life-threatening or fatal opioid intoxication, particularly if LYBALVI therapy is interrupted or discontinued, subjecting the patient to high levels of unopposed opioid agonist as the samidorphan blockade wanes. Inform patients of the potential consequences of trying to overcome the opioid blockade and the serious risks of taking opioids concurrently with LYBALVI or while transitioning off LYBALVI. In emergency situations, if a LYBALVI-treated patient requires opioid treatment as part of anesthesia or analgesia, discontinue LYBALVI. Opioids should be administered by properly trained individual(s) and patient should be continuously monitored in a setting equipped and staffed for cardiopulmonary resuscitation. Patients with a history of chronic opioid use prior to treatment with LYBALVI may have decreased opioid tolerance if LYBALVI therapy is interrupted or discontinued. Advise patients that this decreased tolerance may increase the risk of opioid overdose if opioids are resumed at the previously tolerated dosage. Neuroleptic Malignant Syndrome, a potentially fatal reaction. Signs and symptoms include hyperpyrexia, muscle rigidity, delirium, autonomic instability, elevated creatine phosphokinase, myoglobinuria (and/or rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation, intensive symptomatic treatment, and close monitoring. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a potentially fatal condition reported with exposure to olanzapine, a component of LYBALVI. Symptoms include a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Discontinue if DRESS is suspected. Metabolic Changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Any patient treated with LYBALVI should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required anti-diabetic treatment despite discontinuation of the suspect drug. Measure weight and assess fasting glucose and lipids when initiating LYBALVI and monitor periodically. Tardive Dyskinesia (TD): Risk of developing TD (a syndrome of potentially irreversible, involuntary, dyskinetic movements) and the likelihood it will become irreversible increases with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses, or after discontinuation. Given these considerations, LYBALVI should be prescribed in a manner that is most likely to reduce the risk of tardive dyskinesia. If signs and symptoms of TD appear, drug discontinuation should be considered. Orthostatic Hypotension and Syncope: Monitor orthostatic vital signs in patients who are vulnerable to hypotension, patients with known cardiovascular disease, and patients with cerebrovascular disease. Falls: LYBALVI may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls, and consequently, fractures or other injuries. Assess patients for risk when using LYBALVI. Leukopenia, Neutropenia, and Agranulocytosis (including fatal cases): Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count or history of leukopenia or neutropenia. Discontinue LYBALVI if clinically significant decline in WBC occurs in the absence of other causative factors. Dysphagia: Use LYBALVI with caution in patients at risk for aspiration. Seizures: Use LYBALVI with caution in patients with a history of seizures or with conditions that lower the seizure threshold. Potential for Cognitive and Motor Impairment: Because LYBALVI may cause somnolence, and may impair judgment, thinking, or motor skills, caution patients about operating hazardous machinery, including motor vehicles, until they are certain that LYBALVI does not affect them adversely. Body Temperature Dysregulation: Use LYBALVI with caution in patients who may experience conditions that increase core body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics). Anticholinergic (Antimuscarinic) Effects: Olanzapine, a component of LYBALVI, was associated with constipation, dry mouth, and tachycardia. Use LYBALVI with caution with other anticholinergic medications and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions. In postmarketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications. Hyperprolactinemia: LYBALVI elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Risks Associated with Combination Treatment with Lithium or Valproate: If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for a description of the risks for these products. Interference with Laboratory Tests for Opioid Detection: LYBALVI may cause false positive results with urinary immunoassay methods for detecting opioids. Use an alternative analytical technique (e.g., chromatographic methods) to confirm positive opioid urine drug screen results. Most Common Adverse Reactions observed in clinical trials were: Schizophrenia (LYBALVI): weight increased, somnolence, dry mouth, and headache Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite, and tremor Bipolar I Disorder, Manic or Mixed Episodes, adjunct to lithium or valproate (olanzapine): dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia Concomitant Medication: LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Concomitant use of LYBALVI is not recommended with strong CYP3A4 inducers, levodopa and dopamine agonists. Reduce dosage of LYBALVI when using with strong CYP1A2 inhibitors. Increase dosage of LYBALVI with CYP1A2 inducers. Use caution with diazepam, alcohol, other CNS acting drugs, or in patients receiving anticholinergic (antimuscarinic) medications. Monitor blood pressure and reduce dosage of antihypertensive drug in accordance with its approved product labeling. Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with LYBALVI. Inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYBALVI during pregnancy. Renal Impairment: LYBALVI is not recommended for patients with end-stage renal disease (eGFR of <15 mL/minute/1.73 m2). To report SUSPECTED ADVERSE REACTIONS, contact Alkermes at 1-888-235-8008 or FDA at 1-800-FDA-1088 or Please click here for full Prescribing Information, including Boxed Warning, for LYBALVI. About ARISTADA® (aripiprazole lauroxil) Extended-Release Injectable Suspension, for Intramuscular Use ARISTADA is an injectable atypical antipsychotic approved in four dose strengths and three dosing durations for the treatment of schizophrenia in adults (441 mg, 662 mg or 882 mg monthly, 882 mg once every six weeks and 1064 mg once every two months). Once in the body, ARISTADA converts to aripiprazole. About ARISTADA INITIO® (aripiprazole lauroxil) Extended-Release Injectable Suspension, for Intramuscular Use ARISTADA INITIO, in combination with a single 30 mg dose of oral aripiprazole, is indicated for the initiation of ARISTADA when used for the treatment of schizophrenia in adults. The first ARISTADA dose may be administered on the same day as the ARISTADA INITIO regimen or up to 10 days thereafter. IMPORTANT SAFETY INFORMATION for ARISTADA INITIO® and ARISTADA® Contraindication: Known hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis. Cerebrovascular Adverse Reactions, Including Stroke: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, have been reported in placebo-controlled trials of elderly patients with dementia-related psychosis treated with risperidone, aripiprazole, and olanzapine. ARISTADA INITIO and ARISTADA are not approved for the treatment of patients with dementia-related psychosis. Potential for Dosing and Medication Errors: Medication errors, including substitution and dispensing errors, between ARISTADA INITIO and ARISTADA could occur. ARISTADA INITIO is intended for single administration in contrast to ARISTADA which is administered monthly, every 6 weeks, or every 8 weeks. Do not substitute ARISTADA INITIO for ARISTADA because of differing pharmacokinetic pro Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex may occur with administration of antipsychotic drugs, including ARISTADA INITIO and ARISTADA. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. Tardive Dyskinesia (TD): The risk of developing TD (a syndrome of abnormal, involuntary movements) and the potential for it to become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic increase. The syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing antipsychotics should be consistent with the need to minimize TD. Discontinue ARISTADA if clinically appropriate. TD may remit, partially or completely, if antipsychotic treatment is withdrawn. Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include: Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with oral aripiprazole. Patients with diabetes should be regularly monitored for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug. Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Pathological Gambling and Other Compulsive Behaviors: Compulsive or uncontrollable urges to gamble have been reported with use of aripiprazole. Other compulsive urges less frequently reported include sexual urges, shopping, binge eating and other impulsive or compulsive behaviors which may result in harm for the patient and others if not recognized. Closely monitor patients and consider dose reduction or stopping aripiprazole if a patient develops such urges. Orthostatic Hypotension: Aripiprazole may cause orthostatic hypotension which can be associated with dizziness, lightheadedness, and tachycardia. Monitor heart rate and blood pressure, and warn patients with known cardiovascular or cerebrovascular disease and risk of dehydration and syncope. Falls: Antipsychotics including ARISTADA INITIO and ARISTADA may cause somnolence, postural hypotension or motor and sensory instability which may lead to falls and subsequent injury. Upon initiating treatment and recurrently, complete fall risk assessments as appropriate. Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics. Monitor complete blood count in patients with pre-existing low white blood cell count (WBC)/absolute neutrophil count or history of drug-induced leukopenia/neutropenia. Discontinue ARISTADA INITIO and/or ARISTADA at the first sign of a clinically significant decline in WBC and in severely neutropenic patients. Seizures: Use with caution in patients with a history of seizures or with conditions that lower the seizure threshold. Potential for Cognitive and Motor Impairment: ARISTADA INITIO and ARISTADA may impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are certain therapy with ARISTADA INITIO and/or ARISTADA does not affect them adversely. Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Advise patients regarding appropriate care in avoiding overheating and dehydration. Appropriate care is advised for patients who may exercise strenuously, may be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or are subject to dehydration. Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use; use caution in patients at risk for aspiration pneumonia. Concomitant Medication: ARISTADA INITIO is only available at a single strength as a single-dose pre-filled syringe, so dosage adjustments are not possible. Avoid use in patients who are known CYP2D6 poor metabolizers or taking strong CYP3A4 inhibitors, strong CYP2D6 inhibitors, or strong CYP3A4 inducers, antihypertensive drugs or benzodiazepines. Depending on the ARISTADA dose, adjustments may be recommended if patients are 1) known as CYP2D6 poor metabolizers and/or 2) taking strong CYP3A4 inhibitors, strong CYP2D6 inhibitors, or strong CYP3A4 inducers for greater than 2 weeks. Avoid use of ARISTADA 662 mg, 882 mg, or 1064 mg for patients taking both strong CYP3A4 inhibitors and strong CYP2D6 inhibitors. (See Table 4 in the ARISTADA full Prescribing Information.) Commonly Observed Adverse Reactions: In pharmacokinetic studies the safety pro ARISTADA INITIO was generally consistent with that observed for ARISTADA. The most common adverse reaction (≥5% incidence and at least twice the rate of placebo reported by patients treated with ARISTADA 441 mg and 882 mg monthly) was akathisia. Injection-Site Reactions: In pharmacokinetic studies evaluating ARISTADA INITIO, the incidences of injection site reactions with ARISTADA INITIO were similar to the incidence observed with ARISTADA. Injection-site reactions were reported by 4%, 5%, and 2% of patients treated with 441 mg ARISTADA (monthly), 882 mg ARISTADA (monthly), and placebo, respectively. Most of these were injection-site pain and associated with the first injection and decreased with each subsequent injection. Other injection-site reactions (induration, swelling, and redness) occurred at less than 1%. Dystonia: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first days of treatment and at low doses. Pregnancy/Nursing: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare provider of a known or suspected pregnancy. Inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARISTADA INITIO and/or ARISTADA during pregnancy. Aripiprazole is present in human breast milk. The benefits of breastfeeding should be considered along with the mother's clinical need for ARISTADA INITIO and/or ARISTADA and any potential adverse effects on the infant from ARISTADA INITIO and/or ARISTADA or from the underlying maternal condition. Please see full Prescribing Information, including Boxed Warning, for ARISTADA INITIO, and full Prescribing Information, including Boxed Warning, for ARISTADA. About Alkermes plc Alkermes plc is a global biopharmaceutical company that seeks to develop innovative medicines in the field of neuroscience. The company has a portfolio of proprietary commercial products for the treatment of alcohol dependence, opioid dependence, schizophrenia and bipolar I disorder, and a pipeline of clinical and preclinical candidates in development for neurological disorders, including narcolepsy. Headquartered in Ireland, Alkermes also has a corporate office and research and development center in Massachusetts and a manufacturing facility in Ohio. For more information, please visit Alkermes' website at . LYBALVI®, ARISTADA® and ARISTADA INITIO® are registered trademarks of Alkermes Pharma Ireland Limited, used by Alkermes, Inc. under license. Alkermes Contacts: For Investors: Sandy Coombs, +1 781 609 6377 For Media: Marisa Borgasano, +1 781 609 6659 View original content to download multimedia: SOURCE Alkermes plc Company Codes: NASDAQ-NMS:ALKS

DUBLIN, April 8, 2024 /PRNewswire/ -- Alkermes plc (Nasdaq: ALKS) today announced the oral presentation of clinical data at the 2024 Congress of the Schizophrenia International Research Society (SIRS), which took place April 3-7, 2024 in Florence, Italy. Analyses were presented from a phase 3, open-label extension study assessing the long-term safety, tolerability and durability of treatment effect of LYBALVI® (olanzapine and samidorphan) in patients who received up to four years of treatment. LYBALVI is approved in the U.S. for the treatment of adults with schizophrenia, and for the treatment of adults with bipolar I disorder, as a maintenance monotherapy or for the acute treatment of manic or mixed episodes, as monotherapy or as adjunct to lithium or valproate. René Kahn, M.D., Ph.D., Icahn School of Medicine at Mount Sinai, presented the data in an oral presentation during the "New Pharmacological Treatments and Assessments" session. New analyses were presented related to the subset of participants in the study who reached at least two years of treatment and the subset of participants who reached four years of treatment, providing information as to the long-term safety profile and durability of treatment effect of LYBALVI at specific points in time. Key findings are as follows: Patient Disposition: 523 participants received at least one dose of LYBALVI in this global, open-label extension study. Depending on geography and enrollment date, patients had the opportunity to receive up to two to four years of treatment in this study. 188 (35.9%) participants completed the study, as defined in the protocol, having received between two to four years of treatment and attended their final study visit. There were 451 patients who had the opportunity to receive at least two years of LYBALVI treatment, of which 242 (53.7%) did so. There were 335 patients who had the opportunity to receive four years of LYBALVI treatment, of which 109 (32.5%) did so. Changes in Weight, Waist Circumference, and Metabolic Parameters: For patients who contributed data to the two-year assessment, mean change from baseline in body weight was 0.84 kg and waist circumference was -0.56 cm. For patients who contributed data to the four-year assessment, the mean change from baseline in body weight was 2.65 kg and waist circumference was 1.37 cm. In addition, there were minimal changes in lipid and glycemic parameters over the treatment period. Adverse Events: The adverse event (AE) profile of LYBALVI was consistent with previous studies. Overall, 60% of participants reported at least one AE. The most common AEs reported (>5%) were weight increase, headache, anxiety, insomnia, somnolence, nausea and weight decrease. Most AEs were mild to moderate in severity. Symptoms: Patients' symptoms of schizophrenia or bipolar I disorder remained stable, as measured by the Clinical Global Impression of Severity (CGI-S) scale. For patients who contributed data to the two-year assessment, mean change from baseline in CGI-S score was -0.18. For patients who contributed data to the four-year assessment, mean change from baseline in CGI-S was -0.24. According to Dr. Kahn, "The study results, which include data from patients who received up to four years of treatment on LYBALVI, demonstrated that the combination of olanzapine and samidorphan delivered long-term tolerability, including across key weight and metabolic parameters, and sustained symptom control, further reinforcing LYBALVI's potential utility as a foundational maintenance treatment option for people living with schizophrenia or bipolar I disorder." About the Phase 3, Open-Label Extension Study Design This was an international, multicenter, phase 3, open-label extension study that assessed the long-term safety, tolerability and durability of treatment effect of LYBALVI for up to four years. Patients were eligible to enroll within seven days of completing one of three antecedent phase 3 clinical trials investigating LYBALVI: the 52-week ENLIGHTEN-1 and ENLIGHTEN-2 safety extension studies (rollover extensions of the ENLIGHTEN-1 and ENLIGHTEN-2 phase 3 pivotal randomized controlled trials in adults with schizophrenia); and the 12-week ENLIGHTEN-Early randomized controlled trial comparing LYBALVI to olanzapine in young adults with recent-onset schizophrenia, schizophreniform disorder, or bipolar I disorder. In this long-term extension study, the daily dose of LYBALVI (olanzapine 5-20 mg + samidorphan 10 mg) was selected to maintain consistency with patients' therapeutic dose of either LYBALVI or olanzapine received in their antecedent study, with dose adjustments determined by the investigator. Depending on geography and the time of enrollment into the long-term extension study, patients had the opportunity to receive at least two and up to four years of additional LYBALVI therapy. A total of 524 patients enrolled in the study, and 523 received ≥1 dose of LYBALVI. At baseline, the overall population was mostly male (61.6%) and White (72.7%), with a mean age of 35.1 years. Safety assessments included changes from baseline in body weight and waist circumference and the incidence of adverse events. Changes in lipid (high-density lipoprotein [HDL], low-density lipoprotein [LDL], and total cholesterol and triglycerides) and glycemic (glucose) parameters were evaluated in a fasting state. Changes in glycemic (glycosylated hemoglobin [HbA1c]) parameters also were evaluated. Durability of treatment was assessed using the Clinical Global Impression of Severity (CGI-S) scale. About Schizophrenia and Schizophreniform Disorder Schizophrenia is a serious brain disorder marked by positive symptoms (hallucinations and delusions, disorganized speech and thoughts, and agitated or repeated movements) and negative symptoms (depression, blunted emotions and social withdrawal).1 Schizophrenia affects approximately 1.1% of the U.S. population.2 Schizophreniform disorder exhibits symptoms similar to schizophrenia, but without sufficient duration for a diagnosis of schizophrenia (one to six months).1 About Bipolar I Disorder Bipolar disorder is a brain disorder that is marked by extreme changes in a person's mood, energy and ability to function. Individuals with this brain disorder may experience debilitating mood states, including extreme highs (mania) and extreme lows (depression). Bipolar I disorder is characterized by the occurrence of at least one manic episode, with or without the occurrence of a major depressive episode, and affects approximately 1% of the adult population in the United States in any given year.3 About LYBALVI® (olanzapine and samidorphan) LYBALVI ® (olanzapine and samidorphan) is a once-daily, oral atypical antipsychotic drug approved in the U.S. for the treatment of adults with schizophrenia and for the treatment of adults with bipolar I disorder, as a maintenance monotherapy or for the acute treatment of manic or mixed episodes, as monotherapy or an adjunct to lithium or valproate. LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist, in a single bilayer tablet. LYBALVI is available in fixed dosage strengths composed of 10 mg of samidorphan and 5 mg, 10 mg, 15 mg or 20 mg of olanzapine. INDICATIONS AND IMPORTANT SAFETY INFORMATION for LYBALVI® (olanzapine and samidorphan) INDICATIONS LYBALVI is indicated for the treatment of: Schizophrenia in adults Bipolar I disorder in adults Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate Maintenance monotherapy treatment IMPORTANT SAFETY INFORMATION Boxed Warning: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. LYBALVI is not approved for the treatment of patients with dementia-related psychosis. Contraindications: LYBALVI is contraindicated in patients who are using opioids or are undergoing acute opioid withdrawal. If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for the contraindications for these products. Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis, including stroke, transient ischemia attack, and fatalities. See Boxed Warning. Precipitation of Severe Opioid Withdrawal in Patients who are Physiologically Dependent on Opioids: LYBALVI can precipitate opioid withdrawal in patients who are dependent on opioids, which can lead to an opioid withdrawal syndrome, sometimes requiring hospitalization. LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Prior to initiating LYBALVI, there should be at least a 7‑day opioid-free interval from last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. Explain the risks associated with precipitated withdrawal and the importance of giving an accurate account of last opioid use to patients and caregivers. Vulnerability to Life-Threatening Opioid Overdose: Attempting to overcome opioid blockade with high or repeated doses of exogenous opioids could lead to life-threatening or fatal opioid intoxication, particularly if LYBALVI therapy is interrupted or discontinued, subjecting the patient to high levels of unopposed opioid agonist as the samidorphan blockade wanes. Inform patients of the potential consequences of trying to overcome the opioid blockade and the serious risks of taking opioids concurrently with LYBALVI or while transitioning off LYBALVI. In emergency situations, if a LYBALVI-treated patient requires opioid treatment as part of anesthesia or analgesia, discontinue LYBALVI. Opioids should be administered by properly trained individual(s) and patient should be continuously monitored in a setting equipped and staffed for cardiopulmonary resuscitation. Patients with a history of chronic opioid use prior to treatment with LYBALVI may have decreased opioid tolerance if LYBALVI therapy is interrupted or discontinued. Advise patients that this decreased tolerance may increase the risk of opioid overdose if opioids are resumed at the previously tolerated dosage. Neuroleptic Malignant Syndrome, a potentially fatal reaction. Signs and symptoms include hyperpyrexia, muscle rigidity, delirium, autonomic instability, elevated creatine phosphokinase, myoglobinuria (and/or rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation, intensive symptomatic treatment, and close monitoring. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a potentially fatal condition reported with exposure to olanzapine, a component of LYBALVI. Symptoms include a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Discontinue if DRESS is suspected. Metabolic Changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Any patient treated with LYBALVI should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required anti-diabetic treatment despite discontinuation of the suspect drug. Measure weight and assess fasting glucose and lipids when initiating LYBALVI and monitor periodically. Tardive Dyskinesia (TD): Risk of developing TD (a syndrome of potentially irreversible, involuntary, dyskinetic movements) and the likelihood it will become irreversible increases with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses, or after discontinuation. Given these considerations, LYBALVI should be prescribed in a manner that is most likely to reduce the risk of tardive dyskinesia. If signs and symptoms of TD appear, drug discontinuation should be considered. Orthostatic Hypotension and Syncope: Monitor orthostatic vital signs in patients who are vulnerable to hypotension, patients with known cardiovascular disease, and patients with cerebrovascular disease. Falls: LYBALVI may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls, and consequently, fractures or other injuries. Assess patients for risk when using LYBALVI. Leukopenia, Neutropenia, and Agranulocytosis (including fatal cases): Perform complete blood counts in patients with a history of a clinically significant low white blood cell (WBC) count or history of leukopenia or neutropenia. Discontinue LYBALVI if clinically significant decline in WBC occurs in the absence of other causative factors. Dysphagia: Use LYBALVI with caution in patients at risk for aspiration. Seizures: Use LYBALVI with caution in patients with a history of seizures or with conditions that lower the seizure threshold. Potential for Cognitive and Motor Impairment: Because LYBALVI may cause somnolence, and may impair judgment, thinking, or motor skills, caution patients about operating hazardous machinery, including motor vehicles, until they are certain that LYBALVI does not affect them adversely. Body Temperature Dysregulation: Use LYBALVI with caution in patients who may experience conditions that increase core body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics). Anticholinergic (Antimuscarinic) Effects: Olanzapine, a component of LYBALVI, was associated with constipation, dry mouth, and tachycardia. Use LYBALVI with caution with other anticholinergic medications and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus or related conditions. In postmarketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications. Hyperprolactinemia: LYBALVI elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Risks Associated with Combination Treatment with Lithium or Valproate: If LYBALVI is administered with lithium or valproate, refer to the lithium or valproate Prescribing Information for a description of the risks for these products. Interference with Laboratory Tests for Opioid Detection: LYBALVI may cause false positive results with urinary immunoassay methods for detecting opioids. Use an alternative analytical technique (e.g., chromatographic methods) to confirm positive opioid urine drug screen results. Most Common Adverse Reactions observed in clinical trials were: Schizophrenia (LYBALVI): weight increased, somnolence, dry mouth, and headache Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite, and tremor Bipolar I Disorder, Manic or Mixed Episodes, adjunct to lithium or valproate (olanzapine): dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia Concomitant Medication: LYBALVI is contraindicated in patients who are using opioids or undergoing acute opioid withdrawal. Concomitant use of LYBALVI is not recommended with strong CYP3A4 inducers, levodopa and dopamine agonists. Reduce dosage of LYBALVI when using with strong CYP1A2 inhibitors. Increase dosage of LYBALVI with CYP1A2 inducers. Use caution with diazepam, alcohol, other CNS acting drugs, or in patients receiving anticholinergic (antimuscarinic) medications. Monitor blood pressure and reduce dosage of antihypertensive drug in accordance with its approved product labeling. Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with LYBALVI. Inform patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYBALVI during pregnancy. Renal Impairment: LYBALVI is not recommended for patients with end-stage renal disease (eGFR of <15 mL/minute/1.73 m2). To report SUSPECTED ADVERSE REACTIONS, contact Alkermes at 1-888-235-8008 or FDA at 1-800-FDA-1088 or . Please click here for full Prescribing Information , including Boxed Warning, for LYBALVI. About Alkermes plc Alkermes plc is a global biopharmaceutical company that seeks to develop innovative medicines in the field of neuroscience. The company has a portfolio of proprietary commercial products for the treatment of alcohol dependence, opioid dependence, schizophrenia and bipolar I disorder, and a pipeline of clinical and preclinical candidates in development for neurological disorders. Headquartered in Dublin, Ireland, Alkermes has a research and development center in Waltham, Massachusetts; a research and manufacturing facility in Athlone, Ireland; and a manufacturing facility in Wilmington, Ohio. For more information, please visit Alkermes' website at . Note Regarding Forward-Looking Statements Certain statements set forth in this press release constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, but not limited to, statements concerning the potential therapeutic and commercial value of LYBALVI for people living with schizophrenia or bipolar I disorder. The company cautions that forward-looking statements are inherently uncertain. Although the company believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, the forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those expressed or implied in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: whether clinical results for LYBALVI will be predictive of future clinical results or real-world results; whether LYBALVI could be shown to be ineffective or unsafe; and those risks and uncertainties described under the heading "Risk Factors" in the company's Annual Report on Form 10-K for the year ended Dec. 31, 2023 and in subsequent filings made by the company with the U.S. Securities and Exchange Commission (SEC), which are available on the SEC's website at . Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Except as required by law, the company disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release. LYBALVI ® is a registered trademark of Alkermes Pharma Ireland Limited, used by Alkermes, Inc. under license. References 1 American Psychiatric Association. Schizophrenia Spectrum and Other Psychiatric Disorders. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 2 Cloutier M. Journal of Clinical Psychiatry. 2016 Jun; 77(6): 764-71. 3 Merikangas et al. Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication. Arch Gen Psychiatry, 2007 May; 64(5): 543-552. SOURCE Alkermes plc