Maurer Mathew S, Soman Prem, Hernandez Adrian, Garcia-Pavia Pablo, Signorovitch James, Wei L J, Hanna Mazen, Ruberg Frederick L, Kittleson Michelle, Kazi Dhruv, Dorbala Sharmila, Hsu Kristen, Lousada Isabelle, Adigun Rosalyn, Dunnmon Preston, Kelly Jeffery, Gillmore Julian
Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
University of Pittsburgh Medical Center, UPMC Heart and Vascular Institute, Cardiac Amyloidosis Center, Pittsburg, PA, USA.
Adv Ther. 2024 Jul;41(7):2723-2742. doi: 10.1007/s12325-024-02891-0. Epub 2024 Jun 4.
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.
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).
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.
遗传性转甲状腺素蛋白淀粉样变性（ATTRv，也称为hATTR；孤儿病编号271861）和野生型ATTR淀粉样变性（ATTRwt；孤儿病编号330001）是罕见的、进行性的、全身性蛋白质错误折叠疾病，临床表现具有异质性。ATTRv和ATTRwt淀粉样变性的特征是淀粉样原纤维在包括心脏、神经、眼睛和软组织在内的多个器官中沉积。由于ATTR淀粉样变性的多系统性质和尽管有可用治疗方案仍会进展，其管理较为复杂。发病率很高，患者有许多未满足的医疗需求。虽然与过去相比，当代ATTR淀粉样变性队列的诊断更早、疾病风险更低且死亡率更低，但这些进展以及有效疾病修饰疗法的出现，给未来前瞻性临床试验的设计和历史对照数据的解释带来了困惑。
淀粉样变性论坛是美国食品药品监督管理局药物评价和研究中心与非营利性淀粉样变性研究联盟（www.arci.org）之间的公私合作项目。本文总结了2023年6月21日淀粉样变性论坛的会议记录，该论坛讨论了在不断演变的治疗格局中推进ATTR淀粉样变性药物开发的相关内容。该论坛聚焦于临床试验设计的要素以应对这些挑战，并从多个利益相关者的角度（即患者、申办方、统计学家、临床医生和监管机构）讨论了其优缺点。
鉴于ATTR淀粉样变性自然病程的快速演变，历史对照数据的效用有限。利用当代真实世界数据对于临床试验设计至关重要。临床试验产生的证据应解决临床相关问题。成功的试验设计的关键因素必须依据关于自然病程、预后因素、临床有意义的阈值的最新数据以及共享可用的临床试验数据。淀粉样变性论坛包括ATTR淀粉样变性患者群体、治疗他们的医生以及共同准备支持进一步研究以开发新型有效疗法的申办方和监管机构。
