Derhaschnig Ulla, Gilbert Jim, Jäger Ulrich, Böhmig Georg, Stingl Georg, Jilma Bernd
Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria.
Orphanet J Rare Dis. 2016 Oct 4;11(1):134. doi: 10.1186/s13023-016-0494-z.
Innovative trial designs are sought to streamline drug development in rare diseases. Basket- and integrated protocol designs are two of these new strategies and have been applied in a handful oncologic trials. We have taken the concept outside the realm of oncology and report about a first-in-human integrated protocol design that facilitates the transition from phase Ia in healthy volunteers to phase Ib in patients with rare complement-mediated disorders driven by the classical pathway.
We have been conducting a prospective, double-blind, randomized, placebo-controlled first-in-human study with TNT009, which is a humanized monoclonal antibody directed against the C1s subunit of human complement component C1. The trial consisted of three subparts, including normal healthy volunteers (part one and two) and a single cohort of patients in part three. Patients suffered from various complement-mediated diseases sharing the same pathophysiological mechanism, i.e. bullous pemphigoid, antibody-mediated rejection of organ transplants, cold agglutinin disease and warm autoimmune hemolytic anemia. Primary objective of the trial has been to evaluate the safety and tolerability of TNT009 in humans.
This trial provides probably the first example that basket trials may not be limited to single genetic aberrations, which is overly restrictive, but our trial design demonstrates that pathway specificity is a viable paradigm for defining baskets. This will hopefully serve as a role model that could benefit other innovative drug development programs targeting rare diseases.
人们一直在寻求创新的试验设计，以简化罕见病药物的研发。篮子试验设计和整合方案设计是其中两种新策略，已应用于少数肿瘤学试验中。我们将这一概念拓展到肿瘤学领域之外，并报告了首个在人体中开展的整合方案设计，该设计有助于从健康志愿者的Ia期过渡到由经典途径驱动的罕见补体介导疾病患者的Ib期。
我们一直在进行一项针对TNT009的前瞻性、双盲、随机、安慰剂对照的人体首次研究，TNT009是一种针对人补体成分C1的C1s亚基的人源化单克隆抗体。该试验包括三个子部分，包括正常健康志愿者（第一部分和第二部分）以及第三部分中的一组患者。患者患有各种具有相同病理生理机制的补体介导疾病，即大疱性类天疱疮、抗体介导的器官移植排斥反应、冷凝集素病和温抗体型自身免疫性溶血性贫血。该试验的主要目的是评估TNT009在人体中的安全性和耐受性。
该试验可能提供了首个例子，表明篮子试验可能不限于单一基因异常（这过于严格），但我们的试验设计表明，途径特异性是定义篮子的可行范例。这有望成为一个范例，造福于其他针对罕见病的创新药物研发项目。
