Osteoarthropathy, Primary Hypertrophic

点击上方的 行舟Drug ▲ 添加关注对“以患者为中心”的罕见疾病药物研发的审评考虑来源《罕见病研究》2024, 3(2):168-174作者唐凌，艾星，赵田，杨志敏国家药品监督管理局药品审评中心摘要罕见病患者的临床需求远未被满足，目前仍有许多罕见病缺乏有效的治疗药物，同时罕见病的药物研发又面临着比常见多发疾病更大的挑战。近年来，“以患者为中心”的药物研发理念已被广泛采纳。国家药品监督管理局药品审评中心陆续发布了《以患者为中心的临床试验实施技术指导原则》等多项相关指导原则，以推进“以患者为中心”的药物研发模式。在罕见病药物研发领域，落实“以患者为中心”的药物研发理念，关注患者视角，倾听患者声音，将是帮助药物研发企业、研究者、监管机构深入了解罕见病和患者需求，提高罕见病药物研发精准度与研发效率的有效途径。未来，国家药品监督管理局药品审评中心将持续关注“以患者为中心”的理念融入罕见病药物研发领域，切实提高罕见病患者在药物研发过程中的参与度，发挥患者观点对药物研发的指导作用。关键词罕见病；以患者为中心；药物临床研发；审评审批_正文_罕见病是一类患病率极低、患者总数较少的疾病的统称。由于其诊断率较低，难以统计患者的准确数量，因此罕见病患者的治疗和管理面临极大挑战。据估计，全球已知的罕见病超过7000种[1]，中国罕见病患者人数约为2000万以上。在这些罕见病患者中，80%患有先天遗传性疾病，其中50%为儿童患者[2]。2015年8月18日，国务院正式发布了《国务院关于改革药品医疗器械审评审批制度的意见》[3]，标志着药品审评审批全面改革计划的启动。此后，相继发布了《关于深化审评审批制度改革鼓励药品医疗器械创新的意见》[4]和《关于优化药品注册审评审批有关事宜的公告》[5]等一系列纲领性文件。这些文件的出台，旨在以罕见病目录为指导，推动中国罕见病药物研发的创新进程，引领罕见病的诊断、治疗、药物研发和保障体系的发展。自2015年起，中国在罕见病研发领域取得了显著进步。近年发布的《中国新药注册临床试验进展年度报告》显示[6⁃7]，中国罕见疾病药物临床试验的数量和适应证领域均呈逐年增长的态势，这表明中国在罕见病研发领域的努力正在取得积极成果，为罕见病患者带来了更多的治疗选择和希望。目前仍有许多罕见病缺乏有效的治疗药物。由于罕见病的发病率和患病率极低，病情复杂，临床医师对罕见病的认知相对有限，这使得罕见病的药物研发面临着比常见多发疾病更大的挑战。此外，新药的研发需要进行临床试验，但罕见病受试者的招募往往面临诸多困难，这无疑增加了研发的难度。1以“患者为中心”的药物研发理念美国食品药品监督管理局（Food and Drug Ad⁃ministration，FDA）已启动“罕见疾病治愈加速器”（Rare Disease Cures Accelerator）[8]项目。FDA旨在通过该项目以促成一种合作方法并建立一个通用的标准化平台，从而更好地表征罕见病，将患者观点纳入临床结局评价措施。加速器将建立如通用数据平台等技术支持，以支持在罕见病患者中进行临床试验，并致力于创建与罕见病有关的标准化临床结局评价和终点。在罕见病药物研发领域落实“以患者为中心”的药物研发理念，关注患者视角，倾听患者声音，是帮助药物研发企业、研究者、监管机构深入了解罕见病和患者需求的有效途径。罕见病对患者的生理、心理及生活质量产生的深远影响，患者的个体偏好、治疗预期及需求，以及治疗可能带来的改善或负担，唯有患者自身能够深刻体会。然而，这些重要信息在以往常常被医务人员、研究者、申请方或监管机构所忽视或了解不全面。因此，如何将患者观点、感受融入罕见病药物研发领域，切实提高罕见病患者在药物研发过程中的参与度，并发挥患者观点对药物研发的指导作用，是当前值得各方深入思考和探讨的问题。近些年，“以患者为中心”的药物研发理念逐渐得到了各方广泛的认同与重视。在药物研发的全过程中，必须深入倾听患者的真实感受，充分关注患者的观点和需求，并以此作为研发方向的指导，才能更有效地实现新药研发的核心目标，即满足患者的实际治疗需求。为了进一步推广和实施这一理念，国家药品监督管理局药品审评中心（以下简称“国家药审中心”）陆续发布了《以患者为中心的临床试验实施技术指导原则》《以患者为中心的临床试验设计技术指导原则》《以患者为中心的临床试验获益⁃风险评估技术指导原则》[9]，以及《组织患者参与药物研发的一般考虑指导原则》[10]等多项相关指导原则，为药品研发工作提供了明确的指引。文章内容由凡默谷小编查阅文献选取，排版与编辑为原创。如转载，请尊重劳动成果，注明【来源：凡默谷公众号】。2对罕见病领域落实“以患者为中心”药物研发理念的考虑基于一般药物研发规律和监管需求，药物研发阶段可分为5个阶段，以覆盖药物研发的全生命周期：①项目启动阶段，即药物研发立项启动阶段；②临床试验申请前阶段，即药物启动临床研发阶段；③关键性临床试验前阶段，即药物计划开展针对罕见疾病适应证的关键研究前阶段；④药物上市许可申请前沟通交流/审评阶段，即药物针对罕见病适应证的上市申请前与监管机构进行沟通交流和上市申请审评阶段；⑤上市后阶段，即药物所申请的罕见病适应证获批上市后的阶段。2.1 项目启动阶段项目启动阶段对于药物的早期开发具有重要意义。在此阶段，邀请患者参与的主要目的在于深入了解患者尚未被满足的临床需求，并根据患者意见，明确研究中需评估的关键内容，进而指导后续临床研发策略的制定。与患者群体的互动及定性/定量数据的收集，有助于精准定位罕见疾病患者的临床需求，为后续开展针对性和系统性的临床研究奠定基础。结合中国实际情况，在项目启动阶段，除了关注药物研发相关问题，还需在患者群体互动中重视整个生态系统的建设，如患者教育体系等。这包括在患者互动过程中，宣传教育临床研究的基本概念、数据解读的基础知识，强调医疗专业人士参与评估的必要性，以及实施患者互动相关的合规措施等。这些举措将为患者群体和治疗领域的长期健康发展，以及各方效率提升奠定坚实基础。在临床开发项目的启动阶段，通常会收集患者观点和患者体验数据（patient experience date，PED）以提供指导。这些数据通常包括以下几个方面：①患者诊治现状（如就诊路径、常见漏诊误诊、专科/多学科诊疗的可及性）、当前患者的治疗选择（如超适应证用药、非处方药、替代和支持疗法等）；②未被满足的临床需求（如疾病症状，以及对患者及其家庭广泛的影响）；③疾病改善程度对患者生活质量产生的影响；④疾病症状和当前治疗/标准治疗所造成的负担，以及对相关治疗的满意度情况；⑤疾病自然史、疾病异质性、疾病亚型、发病率、患病率等信息（如不同患者的不同表现、疾病亚组间差异、疾病周期中的不同表现，不同阶段患者对于治疗的反应，合并症和并发症等）；⑥患者对风险（如药物不良反应）、治疗不确定性（如是否能从治疗中获益）的接受程度，以及对不同类型的治疗方式和给药方式的偏好性。2.2 临床试验申请前阶段鉴于罕见病患者数量较少，开展临床试验面临较大困难。因此，在药物研发过程中，秉持“以患者为中心”的药物研发理念有助于优化和完善临床试验方案，提高招募效率，以及提前预警临床试验实施中可能出现的问题。在临床试验申请前阶段，“以患者为中心”的药物研发理念体现在将PED纳入目标药物特征（target product profile，TPP）、临床研发计划（clinical development plan，CDP），以及早期探索性研究方案设计的概念中，并开展临床报告结局（clinical outcome assessments，COA）的开发。TPP明确指明药物开发的目标，是制定CDP的基石。而CDP则为实现TPP所规划的目标提供了具体路线图，这些都将指导和应用于关键性临床试验的设计与执行。2.2.1 应以患者为中心确立目标药物特征建议从药物研发管理视角出发，设定合理的TPP，以患者为核心，秉持“以终为始”的原则，推动临床研发管理理念与工具的发展，将其作为主线和目标，全程指导与规划罕见病药物的临床研发与研究。2.2.2 应以患者为中心制定临床研发计划CDP的内容包括从临床试验阶段Ⅰ至关键阶段Ⅲ的设计，如研究终点、样本量、观察时长，以及期中与最终分析的时间线等。在临床试验设计中落实“以患者为中心”的理念，应持续了解患者需求，在遵循科学原则的基础上，将PED纳入早期探索性研究及后续关键临床试验设计要素的考量，从而充分体现患者的临床获益，并关注其在临床试验中的体验。药物研发企业应在药物研发初期即与患者保持密切沟通，并在整个研发生命周期中不断汲取患者意见。药物研发企业可以根据药品特性（预期仅用于治疗罕见病，或可用于治疗罕见病和非罕见病），规划启动罕见病适应证的开发时机，遵循科学原则，优化临床研发策略，提高研发效率[10]。2.2.3 重视临床报告结局的开发根据报告者的身份，COA可分为患者报告结局、临床医生报告结局、观察者报告结局及表现结局。在开发和应用COA时，需关注COA作为有效性终点的定位，选择符合要求的COA。COA是评估药物治疗益处与风险的核心依据之一，因此确保准确、可靠、全面地监测临床结局至关重要。拟在后期关键研究中应用的COA工具应在早期研发阶段完成探索和验证[10]。脊髓性肌萎缩症（spinal muscular atrophy，SMA）是一种主要发生在婴幼儿时期的致残致死的罕见神经肌肉疾病。2021年6月16日，中国国家药品监督管理局正式批准了罗氏制药的创新药物利司扑兰口服溶液用散（risdiplam powder for oral solution，EvrysdiⓇ，艾满欣Ⓡ），用于治疗2月龄及以上患者的SMA。该产品是全球首个SMA口服药，也是首个在中国获批治疗SMA的口服药物，为中国SMA患者和家庭提供全新的治疗选择。通常用于评估治疗结果的测量方法，并未捕捉到SMA患者进行日常生活活动（activities of daily living，ADL）所需的辅助量。为评价治疗对维持SMA患者独立进行日常活动能力的意义，罗氏制药开发了一种患者和护理者报告的结果测量方法，即SMA独立性量表（SMA independence scale，SMAIS）。SMAIS旨在评估与ADL相关的独立性水平[11]。为了确保SMAIS的全面及易于患者理解，罗氏制药对SMA患者及其照顾者进行电话访谈，以了解患者及家庭的角度所关注的SMA12种主要症状及其影响，同时了解评估SMAIS在临床试验环境中作为结果衡量指标的适宜性。最终经两个阶段的开发和评估，形成了SMAIS，用于≥12岁SMA患者的报告结果测量，以及≥2岁患儿护理者的观察者报告结果测量[12]。一项在2~25岁2型和3型SMA患者应用利司扑兰的随机、双盲、安慰剂对照研究（SUNFISH）中，应用SMAIS对患者完成日常活动（如用手、叉子或勺子吃饭，刷牙，写字/用笔等）的独立能力进行评价，研究结果显示，在利司扑兰治疗12个月后，患者自评和照护者评估的SMAIS评分改善，进一步体现了药物的治疗临床价值。2.2.4 以患者为中心设计和实施临床试验申请人可根据需求，选择性地将患者体验或意见纳入临床试验方案、临床试验知情同意书、研究者手册等文件，并将患者关注的研究问题、对潜在适应证的反馈、临床试验方案风险评估等关键内容纳入研究设计。整体研究设计应充分体现患者在身心感受、功能和生存状态等方面的临床获益，采用易于接受的试验设计。在保证科学性的基础上，通过优化临床试验设计、引入新技术、新方法或新型试验模式，提高临床试验便利性、减轻受试者负担，进而降低脱落率、提升临床试验受试者代表性和依从性，为研发和监管决策提供依据。在临床研发过程中去中心化临床试验（decentralized clinical trials，DCT）也值得特别关注。罕见疾病药物临床研发存在诸多挑战。由于罕见疾病单病种人数少，患者居住分散，加剧了临床试验招募难度；试验流程复杂、访视方式多样、临床试验周期长、终点指标复杂、儿童等人群需要特殊保护等，进一步加大了罕见疾病药物临床试验难度。此外，一些罕见疾病患者疾病症状严重，行动不便，限制了患者到研究中心参与临床试验的意愿和能力。因此，探索更有利于患者参与的临床试验新模式将有助于提高罕见疾病药物研发效率。随着数字健康技术（digital health technologie，DHT）的进步，业界积极探索在临床研发中应用DCT模式，成为临床试验各方提升试验效能的关键举措。DCT是指在传统临床试验中心以外地点通过远程医疗和移动/本地医疗来执行部分或全部试验相关活动的临床试验。DCT可通过完全远程模式或者混合模式，结合应用DHT，为罕见病药物临床试验提供更加灵活、可及的新方法、新路径。部分国外监管机构已对DCT给予政策指导。例如，美国FDA于2023年5月及EMA于2022年12月发布的两篇指南[13⁃14]均对DCT的科学规范实施提出全方位建议。在中国，国家药审中心于2023年11月发布《在罕见疾病药物临床研发中应用去中心化临床试验的技术指导原则》[15]的征求意见稿，该指导原则聚焦于罕见疾病药物研发特点，对罕见疾病药物临床研发过程中如何应用及科学开展DCT提出建议及参考。开展“以患者为中心”的DCT，并在罕见病研究领域予以推广，将有助于患者更便利地参与药物临床试验，减少地域限制；有助于最大限度地保障患者参加药物临床试验的权利；有利于减轻受试者负担，增加受试者的代表性和多样性，提高受试者的参与度和依从性。这些优势，既保障了患者权益，增强了对受试者的保护，同时，对于本身患者少、临床试验招募困难的罕见疾病药物临床试验更是非常重要的助力。2.3 关键性临床试验前阶段关键性临床试验应在前期探索研究基础上，确保科学可靠，保障受试者安全和隐私，并提高受试者参与便利度、减轻负担，实施更加接近真实诊疗场景的临床试验。根据前期患者参与临床试验的体验，优化关键试验设计，确定评估工具，如采用COA作为临床试验终点支持监管决策。在关键研究开展前，药物研发单位应充分考虑罕见疾病特点及患者的特殊困难和风险，优化试验设计和流程，减轻患者负担。研究人群应具代表性，除此之外，研发企业还应关注药物用法用量的合理性，加强特殊人群给药方案研究。在采用对照研究设计时，应选择临床实践中可及的、最优的治疗手段作为对照。罕见疾病药物关键临床研究样本量应根据统计学原则，基于主要终点统计假设确定。选择敏感的主要终点指标、灵活的试验设计，有助于减少样本量，提高药物研发效率[10，16]。“以患者为中心”的有效性评价，应关注试验药物对客观指标（如生存时长）的改善，同时关注患者感受、功能状态和生存状态的获益。可采用电子化手段采集PED，或使用COA工具进行安全性、有效性评价。2.4 药物上市许可申请前沟通交流/审评阶段在本阶段，“以患者为中心”的理念体现在利用PED及患者对药物的评估，助力药物获益/风险的监管决策。在与监管机构的沟通阶段及上市申请评审过程中，药物研发企业应充分吸纳患者意见，将患者的理解、建议和评价纳入药物说明书、风险管理计划等文件，以支持上市注册申请及全生命周期的获益/风险评估；在需要开展上市后研究时，还需将患者意见纳入研究设计中。（1）在药物上市申请及审评过程中，药物研发企业和监管机构可邀请患者参与对药物的获益/风险评估。为此，药物研发企业需整理并归纳前期收集的数据，如疾病相关的患者经验数据，包括疾病自然史、疾病负担、患者诊疗现状、未被满足的临床需求，以及患者对治疗和结局的偏好；药物相关的患者经验数据，如生活质量评估等，并提供关键临床试验期间与药物体验、获益/风险相关的数据，如患者对药物获益/风险的认知；患者对药物风险的可接受程度；患者对药物说明书的理解与反馈等，供监管部门参考。（2）在药品说明书的编制过程中，应纳入患者意见。药品说明书是法定文件，载明药品重要信息，是选用药品的法定指南，也是患者获取药物信息（包括有效性/获益、安全性/风险）的主要途径。因此，说明书需符合患者阅读习惯，客观地提供患者关注和所需了解的药品信息。在说明书编制过程中，倾听患者声音，将有助于制定更符合患者需求的说明书。（3）上市后研究应注重患者需求。鉴于罕见疾病药物的临床急需性，以及其关键临床试验中获得的临床数据往往有限，罕见疾病药物上市后，可能需要开展确证性临床试验（针对附条件上市的药物）和/或其他上市后研究（如在真实世界中进一步收集安全性、有效性的研究）。在设计上市后研究时，可邀请患者参与讨论，了解患者对上市后研究的看法。2.5 上市后阶段药物在获得上市批准时，其安全性和有效性的数据通常是在严格控制的环境下，基于有限数量的患者样本所得到的。由于罕见疾病药物在临床研究中的特殊性，通常需要在药物上市后进一步积累相关的安全性及有效性数据，以便为药物的获益/风险再评估及药品说明书的更新提供更为充分的依据和信息。上市后阶段的核心目标在于深入理解真实世界中患者对药品的实际体验，将PED纳入获益/风险重新评估，并根据评估结果优化药品使用，实现患者获益的最大化和风险的最小化。此类数据可以通过药物研发企业回应特定上市后要求的研究收集，也可以通过药物研发企业、研究者或患者组织自愿发起的各种研究（如访谈、问卷调查、患者偏好研究等）获取。同时，药物研发企业还可通过上市后研究、不良事件报告、医学文献、同类药物获得的新数据等途径进行上市后安全性监测。上市后收集的PED和安全性数据有助于更全面地反映药品在真实临床使用环境中的获益/风险特征，包括支持风险管理计划的修订和完善，更新药品安全性特征及风险最小化措施；可结合上市后证据收集，调整药物适应证描述（如扩大或缩小至特定亚人群），优化给药方案，完善用药说明和注意事项，更新安全性信息及临床疗效相关数据；根据患者对药物的实际体验和需求，制订后续研究计划；以及利用真实世界数据申请新适应证等。3结语近年来，中国国家药审中心针对罕见病用药审评工作，采取了一系列扎实有效的措施，并取得了积极的成效。罕见病用药的上市批准数量逐年上升，这充分展示了中国在罕见病药物研发和审评方面的决心和行动。为了更好地推动罕见病药物的研发，国家药审中心不断完善和支持罕见病药物研发的审评标准体系。这一体系的建设旨在确保罕见病药物的质量和安全，同时也为药物研发企业提供了明确的指导。通过制定和发布多个罕见病用药技术指导原则，国家药审中心为业界提供了详细的政策解读和实践指南，使得罕见病药物的研发工作更加有据可依。此外，国家药审中心还在逐步探索建立一种“全方位”的技术服务模式，该模式以患者为核心，旨在推动科学监管理念的落实。这一模式将药审中心、医疗机构、研究人员和患者等多方紧密联系在一起，共同为罕见病患者的健康护航。通过这一模式，中国有望进一步提高罕见病用药的审评效率，加快罕见病药物的研发和上市进程，为罕见病患者带来更多的治疗选择。在药物研发领域，患者的感受和需求一直以来都是核心关注点。为了更好地实现新药研发的目标，即满足患者的治疗需求，国家药审中心积极倡导并推行“以患者为中心”的药物研发理念。在此背景下，国家药审中心相继发布了一系列指导原则，旨在引导药物研发过程更加贴近患者需求。未来，国家药审中心将进一步推进“以患者为中心”的罕见疾病药物研发试点工作。通过此举，国家药审中心希望以罕见疾病为突破口，深入落实“以患者为中心”的药物研发理念。为了实现这一目标，国家药审中心将积极促进监管机构、药物研发单位、患者等多方参与罕见疾病药物研发的沟通与合作。中国国家药审中心在推动罕见病用药审评工作方面，已经取得了显著的成果，并在不断完善和优化相关体系。在未来，国家药审中心将继续推动“以患者为中心”的罕见病药物研发，致力于提高罕见病用药的可及性，为罕见病患者提供更多、更好的治疗药物和方案。作者贡献详见《罕见病研究》2024, 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//   • 谈判药品的竞品会降低药价到与谈判药品相同甚至更低； • 100%受访人表示IRA会对商业市场的药价产生间接影响； • 生物类似药和最低成本疗法对保险公司更具吸引力； • 保险公司可能从市场上撤回医疗保险处方药计划（PDP）和医保优势计划（MA）。 编译｜陈小娟 随着《通胀削减法案》（IRA）通过，美国政府获得了与制药公司直接谈判药品价格的能力。自2026年起，首批10款价格谈判的全球畅销处方药将降价38%～79%，平均降价63%。除了1款产品降价38%，其余9款产品降价幅度都超过50%。 IRA根据药品上市时间不同，将谈判的最低降价幅度划分为三个等级，分别是：上市9~12年的下降25%、上市12~16年的下降35%、上市16年以上的下降60%。而在本次谈判的10款药品中，美国医疗保险和医疗补助服务中心（CMS）获得的降价幅度均超过了IRA规定的强制性最低降价幅度。这明显超出了医疗保险公司的预期。在参与科睿唯安（Clarivate）调研的30家保险公司高管中，只有1家预计所有10种药物的降价幅度都将超过其对应的强制性最低降价幅度。 CMS在首次谈判中获得大幅降价  来源|CMS 到2027年，CMS每年将谈判20种额外的药品，包括通常由医生管理的复杂而昂贵的Medicare Part B（补充性医疗保险）药物，如可输注的生物制剂。 IRA还改革了Medicare Part D（医疗保险处方药计划）的支付规则，对患者、药企、保险公司和Medicare基金要承担的各层责任比例做了重新设定。这将对药企与保险公司和药品福利管理公司（PBM）的垂直整合体产生不利影响，最明显的是巨灾保险部分的高成本药物成分分担翻了两番。与此同时，患者将受益于2000美元的新自付费用上限。 对付款人的影响 为了更好地了解IRA对健康保险公司和制药行业的影响，科睿唯安于2024年3月和4月对美国30家保险公司的医药学和医疗总监（下称“付款人”）进行了调查，他们来自国家和地区健康计划、拥有综合保险部门的医疗服务提供者和PBM。调查发现，CMS药价谈判影响的不只是直接谈判的药品，这些药品的竞争对手也会因此降低价格。 在所有治疗领域，大多数接受调查的付款人预计，如果他们想要保留目前的覆盖范围和管理，谈判药物的竞争对手需要与谈判药物的净价相同或者更低，这一影响对肿瘤药物稍微小一点。付款人还表示，他们可能会通过降低覆盖率来处罚那些没有充分调整价格的药物，包括实施阶梯疗法，这意味着患者将被要求尝试成本较低的谈判药物。 对商业市场药价的影响 尽管IRA中对价格控制和保险公司的规定仅适用于医疗保险市场，但参与调查的付款人表示，IRA可能会对商业市场的药价产生一些间接影响。当被问及医疗保险价格下降将如何影响商业净价时，没人预计商业净价会保持不变；1/3的受访者预计谈判药品的商业净价会上涨，因为制药企业将通过减少商业回扣来补偿IRA；2/3的受访者预计谈判药品的商业净价会下降。 有趣的是，来自大型国家计划的付款人比来自小型区域计划的付款人更有可能预计商业净价会下降，后者由于其成员的总购买力较低，往往杠杆作用较小。无论计划规模如何，IRA都可能使商业净价谈判复杂化，因为保险公司和制药企业预计都将在商业市场寻求抵消IRA的财务影响。 对患者获得创新药的影响 调查结果还表明，IRA下具有挑战性的付款人环境，可能会使制药企业“确保患者能够获得强有力治疗”的努力复杂化。该法案可能会促进更多地使用各种保险公司利用管理策略（utilization management tactics）。其中，鼓励服用生物类似药这一策略占比最高，63%的受访者选了该策略。受访者还表示，他们将利用医疗指南，如美国国家综合癌症网络（NCCN）发布的指南，鼓励在具有相同临床评分的类似药中使用成本最低的治疗方法。 生物类似药和最低成本疗法对付款人更具吸引力 对保险公司提供医疗保险计划意愿的影响 为了应对IRA带来的挑战，1/3的受访人表示，他们可能会从市场上撤回医疗保险处方药计划（PDP）；近1/5的受访人表示，预计将从市场上撤回一些医保优势计划（Medicare Advantage，MA）。人们认为，IRA对PDP的不利影响更大，因为PDP只涵盖了D部分，而MA计划涵盖了B部分和D部分，后者能分散增加的D部分财务风险。 来自IRA的压力可能会使1/3的PDP计划退出市场 对制药行业的总体影响 科睿唯安在调查报告中指出，IRA的影响可能超出参与医疗保险价格谈判药物的范围。大多数受访人预计，谈判药品的竞争对手将调整其价格，使其与谈判药品的价格相同或更低。100%的受访者表示，他们预计医疗保险药品价格谈判将影响商业市场上付款人和制药企业之间的净价谈判。 保险公司对IRA的主要担忧是，在Medicare Part D重新设计的巨灾保险部分，他们承担了60%的支付比例；其次是2000美元的患者自付上限，这一新规进一步增加了他们的开支。保险公司面临的其他令人担忧的情况包括合规成本上升、商业市场回扣减少，以及由于保费涨幅每年都被限制在6%以内而导致的财务限制。这些对付款人的打击，将以更强硬的价格谈判立场和更多的利用管理策略传递至整个制药行业。 参考资料： Clarivate：Pharma’s pain from the Inflation Reduction Act will be felt well beyond the first 10 brands facing price cuts https://clarivate.com/blog/pharmas-pain-from-the-inflation-reduction-act-will-be-felt-well-beyond-the-first-10-brands-facing-price-cuts/ 编辑 | 姚嘉 yao.jia@PharmaDJ.com  总第2219期 访问研发客网站，深度报道和每日新闻抢鲜看 www.PharmaDJ.com

MONTPELLIER, France--( BUSINESS WIRE )--Regulatory News: Sensorion (FR0012596468 – ALSEN) a pioneering clinical-stage biotechnology company which specializes in the development of novel therapies to restore, treat and prevent within the field of hearing loss disorders, today announces the detailed results of its clinical programs (SENS-501 and SENS-401), which were unveiled on September 20, 2024, during a symposium hosted by the Company and an oral presentation at the 36th World Congress of Audiology, held in Paris, France. Nawal Ouzren, Chief Executive Officer of Sensorion, said: “ Sensorion is making tremendous progress across its hearing care franchise of innovative therapies for the restoration, prevention and treatment of hearing loss disorders. Notably, we have made significant advances in our gene therapy clinical trial, Audiogene, for the restoration of hearing in very young patients born with severe to profound hearing loss caused by mutations in the gene encoding for otoferlin. This program received regulatory approval in January 2024, and we are today confident that we will have treated the first cohort of patients by year end 2024, with one patient already injected and two additional patients already screened. I am very thankful to the parents of these patients for their trust and also to the study investigators participating in this study for their dedication. I am also very pleased with the progress made with SENS-401 portfolio. We have reported the final results, including the positive secondary efficacy endpoints, of our Phase 2a clinical trial for the preservation of residual hearing, developed in collaboration with Cochlear Limited. Our second Phase 2a clinical trial of SENS-401, in the prevention of Cisplatin-Induced Ototoxicity, is progressing as planned and I am looking forward to the completion of the recruitment in H1 2025. Sensorion is more than ever striving to advance its innovative programs to potentially transform the quality of hearing of patients living with hearing disorders, a significant global unmet medical need .” - SENS-501 (OTOF-GT) / Audiogene Sensorion announced that the first patient in the Audiogene trial has been injected in Q3 2024 in Australia by the team of Professor Catherine Birman, Otorhinolaryngologist, and Director of the Sydney Cochlear Implant Centre. Audiogene aims to evaluate the safety, tolerability, and efficacy of intra-cochlear injection of SENS-501 for the treatment of OTOF gene-mediated hearing impairment in paediatric patients aged 6 to 31 months at the time of gene therapy treatment. Targeting the first years of life, the time period when the auditory system plasticity is optimal, will maximize the chances of these young children with pre-lingual hearing loss to acquire normal speech and language. The design of the study consists of two cohorts of two doses followed by an expansion cohort at the selected dose. While the safety will be the primary endpoint for the dose escalation cohort, the auditory brainstem response (ABR) will be the primary efficacy endpoint of the dose expansion cohort. Audiogene will also assess the clinical safety, performance, and usability of the administration device system developed by Sensorion. According to the inclusion criteria, the first patient enrolled in Audiogene suffers from profound to severe hearing loss caused by mutations of the gene encoding for otoferlin. The administration of the gene therapy product was uneventful and well tolerated by the patient. Initial safety data indicate that no serious or adverse events were detected in the child following administration of SENS-501. The medical condition of the child (upper respiratory infection unrelated to SENS-501 injection) at the time of efficacy assessment (ABR Month 1) did not allow to get reliable hearing sensitivity. From early observations, changes in the child's behaviour and vocalisations were noted. Sensorion continues the recruitment of patients in Audiogene Phase 1/2 study and announces that two additional patients have been screened. The Company anticipates the completion of the first cohort of patients (three patients) by the end of 2024 as well as the publication of initial efficacy data by year-end 2024. The recruitment completion of the second cohort (3 patients) is planned by the end of the first half of 2025. Professor Catherine Birman, ENT, Otorhinolaryngologist, and Director of the Sydney Cochlear Implant Centre, declared : “ I am very excited to participate in this groundbreaking gene therapy trial that may have the potential to transform the lives of the babies carrying the OTOF gene mutation. I am grateful to the family of the first patient to receive the gene therapy for placing their trust in this innovative approach and potentially paving the way for the use of gene therapies in the field of hearing loss. I am looking forward to following the progress of the first patient in the follow-up period and further recruitment of patients in Audiogene assessing SENS-501 efficacy .” - SENS-401 / Cochlear Implantation Sensorion’s Phase 2a clinical study of SENS-401 for the preservation of residual hearing loss after cochlear implantation is now completed with the last patient having completed the follow-up period. Overall, 16 patients were treated with SENS-401 and 8 were in the control group. The Company reported the analysis of the final results during its symposium, held at the World Congress of Audiology, on September 20, 2024. As a reminder, the study is a multicenter, randomized, controlled, open-label trial designed to assess the presence of SENS-401 in the perilymph after 7 days of repeated oral administration in adult participants over 18 years old undergoing cochlear implantation. On March 11, 2024, Sensorion confirmed the presence of SENS-401 in the perilymph at levels compatible with potential therapeutic efficacy in 100% of the patients sampled, 7 days after the start of the treatment. These results demonstrated that SENS-401 administered orally crossed the labyrinth barrier and confirmed that the primary endpoint was met. The study design also included a number of secondary endpoints, notably the change of hearing threshold from baseline to the end of the treatment period in the implanted ear at several frequencies. Study entry criteria required patients to have a pure tone audiometry (PTA) threshold of 80 dB or better (i.e., ≤80 dB) at 500 Hz, defined as indicating a minimal level of residual hearing. The final results show that after 7 weeks of treatment with SENS-401 (and 6 weeks after cochlear implantation), the reduction in residual hearing loss was systematically better at all frequencies in the treated group with SENS-401. This protective effect was also observed 8 weeks after cessation of treatment (14 weeks post-cochlear implantation). The results show that solely the SENS-401 treated patients showed a complete hearing preservation (40% of patients) compared to the control group (0% of patients). Additionally, these data validate the favourable safety profile of SENS-401 in treated patients, in line with previous studies of 125 patients exposed to SENS-401. These positive results strongly support the continuation of the clinical development of SENS-401 for hearing preservation in treated patients. Stephen O’Leary, Head of otorhinolaryngology, University of Melbourne said : “The final results of the SENS-401 Phase 2a study are very encouraging as they support the conclusion that the administration of SENS-401 preserves residual hearing in patients undergoing cochlear implantation. This represents a crucial step towards for cochlear implantation candidates as residual hearing is very important to maintain and improve the quality of hearing of such patients. Residual hearing loss usually occurs mainly in the first 6 months after surgery; thus, early action is crucial. These positive data encourage us to pursue the clinical development of SENS-401, in order to offer innovative therapeutic treatments to patients scheduled for cochlear implantation as the level of residual hearing preservation showed in the study means patients have a better chance of understanding speech against background noise and perceiving more natural sound quality with speech and sounds.” - SENS-401 (Cisplatin-Induced Ototoxicity, CIO) / NOTOXIS Sensorion is conducting another clinical study of SENS-401 in the prevention of Cisplatin-Induced Ototoxicity (CIO). NOTOXIS is a Phase 2a, multi-center, randomized, controlled and open-label study designed to assess the efficacy of SENS-401 in the prevention of CIO in adult subjects with neoplastic disease. The preliminary analyses presented were conducted on 16 patients (7 in the treated with SENS-401 group, and 9 in the control group). The preliminary results presented indicate that the incidence of ototoxicity in the control group is consistent with published data. Despite significant exposure to cisplatin in the treatment group, most participants showed only mild ototoxicity. The SENS-401 group received higher cumulative doses of cisplatin than the control group. The preliminary results suggest a potential trend toward an otoprotective effect of SENS-401 beyond a cisplatin dose of 300 mg/m2. SENS-401 showed a favourable safety profile with no new or unexpected serious adverse events after 23 weeks of twice-daily oral exposure, a longer duration than previous studies. Safety results are consistent with previous studies involving a total of 125 patients exposed to SENS-401. Adverse events reported included constipation and nausea, as expected. These preliminary data suggest that the cumulative dose of cisplatin is a key factor in the severity of ototoxicity. So far, the data show no significant difference in ototoxicity between the 2 groups. Patients most exposed to cisplatin may benefit more from the otoprotective effect of SENS-401. Sensorion anticipates the patient recruitment completion in H1 2025. A more detailed analysis will be carried out on all patients at the end of the study. Professor Yann Nguyen, ENT Surgeon, Pitié Salpétrière Hospital, Paris, France, declared: “The results of the Phase 2a study of SENS-401 in the NOTOXIS program are encouraging. Ototoxicity is a debilitating condition in patients following cisplatin-based chemotherapy. Hearing loss caused by cisplatin is often diagnosed when it's too late, and it is permanent and irreversible. Therefore, it is paramount to pursue the development of a therapeutic solution, that has the potential to prevent cisplatin-induced ototoxicity without interfering with cisplatin efficacy. I am very satisfied with the drug safety profile and the otoprotective trend suggested by the preliminary data, and I am impatient to advance Sensorion’s small molecule further in this study.” A recording of the symposium held on September 20, 2024, at the World Congress of Audiology will be available on the Company’s website in the coming days. About SENS-501 SENS-501 (OTOF-GT) is an innovative gene therapy program developed to treat a specific form of congenital deafness linked to mutations in the OTOF (otoferlin) gene. This gene plays a key role in the transmission of auditory signals between the hair cells of the inner ear and the auditory nerve. When this gene is defective, affected individuals are born with severe to profound hearing loss. The aim of SENS-501 (OTOF-GT) is to restore hearing by introducing a functional copy of the OTOF gene directly into hair cells via viral vector technology (AAV). By replacing the defective gene, this therapy aims to restore the normal process of converting sound into electrical signals, enabling patients to regain their hearing ability. Currently in the pre-clinical research phase, this gene therapy program represents significant hope for families affected by this rare form of genetic deafness. SENS-501 (OTOF-GT) embodies a commitment to scientific innovation in the field of hearing, with the potential to dramatically improve the quality of life of patients suffering from genetic deafness. This gene therapy for patients suffering from otoferlin deficiency has been developed in the framework of RHU AUDINNOVE, a consortium composed of Sensorion with the Necker Enfants Malades Hospital, the Institut Pasteur, and the Fondation pour l’Audition. The project is partially financed by the French National Research Agency, through the “investing for the future” program (ref: ANR-18-RHUS-0007). About SENS-401 SENS-401 (Arazasetron), Sensorion’s clinical stage lead drug candidate, is an orally available small molecule that aims to protect and preserve inner ear tissue from damage responsible of progressive or sequelae hearing impairment. Sensorion currently develops SENS-401 in a Phase 2 clinical trial for the prevention of Cisplatin-Induced Ototoxicity and has completed a Phase 2a study to prevent residual hearing loss in patients scheduled for cochlear implantation. SENS-401 has been granted Orphan Drug Designation by the EMA in Europe for the treatment of sudden sensorineural hearing loss, and by the FDA in the U.S. for the prevention of platinum-induced ototoxicity in pediatric population. About Sensorion Sensorion is a pioneering clinical-stage biotech company, which specializes in the development of novel therapies to restore, treat, and prevent hearing loss disorders, a significant global unmet medical need. Sensorion has built a unique R&D technology platform to expand its understanding of the pathophysiology and etiology of inner ear related diseases, enabling it to select the best targets and mechanisms of action for drug candidates. It has two gene therapy programs aimed at correcting hereditary monogenic forms of deafness, developed in the framework of its broad strategic collaboration focused on the genetics of hearing with the Institut Pasteur. SENS-501 (OTOF-GT) currently being developed in a Phase 1/2 clinical trial, targets deafness caused by mutations of the gene encoding for otoferlin and GJB2-GT targets hearing loss related to mutations in GJB2 gene to potentially address important hearing loss segments in adults and children. The Company is also working on the identification of biomarkers to improve diagnosis of these underserved illnesses. Sensorion’s portfolio also comprises clinical-stage small molecule programs for the treatment and prevention of hearing loss disorders. Sensorion’s clinical-stage portfolio includes one Phase 2 product: SENS-401 (Arazasetron) progressing in a planned Phase 2 proof of concept clinical study of SENS-401 in Cisplatin-Induced Ototoxicity (CIO) and, with partner Cochlear Limited, has completed in a study of SENS-401 in patients scheduled for cochlear implantation. A Phase 2 study of SENS-401 was also completed in Sudden Sensorineural Hearing Loss (SSNHL) in January 2022. www.sensorion.com Label: SENSORION ISIN: FR0012596468 Mnemonic: ALSEN Disclaimer This press release contains certain forward-looking statements concerning Sensorion and its business. Such forward looking statements are based on assumptions that Sensorion considers to be reasonable. However, there can be no assurance that such forward-looking statements will be verified, which statements are subject to numerous risks, including the risks set forth in the 2023 full year report published on March 14, 2024, and available on our website and to the development of economic conditions, financial markets and the markets in which Sensorion operates. The forward-looking statements contained in this press release are also subject to risks not yet known to Sensorion or not currently considered material by Sensorion. The occurrence of all or part of such risks could cause actual results, financial conditions, performance or achievements of Sensorion to be materially different from such forward-looking statements. This press release and the information that it contains do not constitute an offer to sell or subscribe for, or a solicitation of an offer to purchase or subscribe for, Sensorion shares in any country. 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