背景:遗传性转甲状腺素蛋白淀粉样变性(ATTRv,也称为hATTR;ORPHA271861)和野生型ATTR淀粉样变性(ATTRwt;ORPHA330001)很少见,进步,具有异质性临床表现的系统性蛋白质错误折叠障碍。ATTRv和ATTRwt淀粉样变性的特征是淀粉样原纤维在包括心脏在内的多个器官中沉积,神经,眼睛,和软组织。尽管有可用的治疗选择,但由于其多系统性质和进展,ATTR淀粉样变性的管理是复杂的。发病率很高,患者有许多未满足的医疗需求。虽然当代ATTR淀粉样变性队列诊断较早,与前一个时代相比,疾病风险较低,死亡率较低,这些进展加上有效的疾病改善疗法的出现,使得未来前瞻性临床试验的设计和历史对照数据的解释受到了混淆.
方法:淀粉样变性论坛是美国食品和药物管理局药物评估和研究中心与非营利性淀粉样变性研究联盟之间的公私合作伙伴关系(www.arci.org)。本文总结了2023年6月21日淀粉样变性论坛关于在不断发展的治疗环境中推进ATTR淀粉样变性药物开发的程序。论坛重点讨论了应对这些挑战的临床试验设计要素,并从多个利益相关者的角度讨论了它们的优势和劣势(即,病人,赞助商,统计学家,临床医生,和监管机构)。
结论:鉴于ATTR淀粉样变性自然史的快速演变,历史控制数据的效用有限。利用当代现实世界的数据对于临床试验设计至关重要。从临床试验中产生的证据应解决临床相关问题。成功试验设计的关键因素必须通过最新的自然史数据来了解。预后因素,临床上有意义的阈值,并共享可用的临床试验数据。淀粉样变性论坛包括ATTR淀粉样变性患者社区,治疗它们的医生,以及共同准备支持进一步研究以开发新的有效疗法的赞助商和监管机构。
BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv, also referred to as hATTR; ORPHA 271861) and wild-type ATTR amyloidosis (ATTRwt; ORPHA 330001) are rare, progressive, systemic protein misfolding disorders with heterogeneous clinical presentations. ATTRv and ATTRwt amyloidosis are characterized by the deposition of amyloid fibrils in multiple organs including the heart, nerves, eyes, and soft tissues. The management of ATTR amyloidosis is complex because of its multisystemic nature and progression despite available treatment options. Morbidity is high and there are many unmet medical needs for patients. While contemporary ATTR amyloidosis cohorts are diagnosed earlier, have lower risk disease and lower mortality compared with the previous era, these advances coupled with the emergence of effective disease-modifying therapies have confounded the design of future prospective clinical trials and interpretation of historical control data.
METHODS: The Amyloidosis Forum is a public-private partnership between the US Food and Drug Administration Center for Drug Evaluation and Research and the nonprofit Amyloidosis Research Consortium ( www.arci.org ). This article summarizes proceedings from the 21 June 2023 Amyloidosis Forum on advancing drug development in ATTR amyloidosis in an evolving treatment landscape. The Forum focused on elements of clinical trial design to address these challenges and discussed their strengths and weaknesses from multiple stakeholder perspectives (i.e., patient, sponsor, statistician, clinician, and regulatory authorities).
CONCLUSIONS: Given rapid evolution of natural history in ATTR amyloidosis, the utility of historical control data is limited. Leveraging contemporary real-world data is essential for clinical trial design. Evidence generation from clinical trials should address clinically relevant questions. Key factors in successful trial design must be informed by up-to-date data on natural history, prognostic factors, clinically meaningful thresholds, and sharing available clinical trial data. The Amyloidosis Forum includes the community of patients with ATTR amyloidosis, the physicians who treat them, and the sponsors and regulators who collectively stand ready to support further studies in order to develop novel effective therapies.