Combined integrated protocol/basket trial design for a first-in-human trial.

Area of Science:

• Pharmacology
• Clinical Trial Design
• Immunology

Background:

• Innovative trial designs, including basket and integrated protocols, are crucial for rare disease drug development.
• These designs have primarily been used in oncology but are now being explored in other therapeutic areas.
• This study reports on a first-in-human integrated protocol design for rare complement-mediated disorders.

Purpose of the Study:

• To evaluate the safety and tolerability of TNT009, a novel monoclonal antibody targeting the C1s subunit of complement component C1.
• To demonstrate the feasibility of an integrated protocol design transitioning from healthy volunteers to patients with rare complement-mediated diseases.
• To explore pathway specificity as a paradigm for defining patient cohorts in basket trials.

Main Methods:

• A prospective, double-blind, randomized, placebo-controlled, first-in-human study.
• The trial included three parts: Phase Ia in healthy volunteers (parts one and two) and Phase Ib in patients (part three).
• Patients in part three had various complement-mediated diseases (bullous pemphigoid, antibody-mediated rejection, cold agglutinin disease, warm autoimmune hemolytic anemia) sharing a common pathophysiological mechanism.

Main Results:

• The study successfully evaluated the safety and tolerability of TNT009 in humans.
• The integrated protocol design facilitated the transition from healthy volunteers to patients with rare complement-mediated disorders.
• The trial involved a single cohort of patients with diverse complement-mediated diseases.

Conclusions:

• This trial presents a novel application of integrated protocol and basket trial designs outside of oncology.
• Pathway specificity, rather than single genetic aberrations, is a viable and potentially less restrictive paradigm for defining baskets in rare disease trials.
• This approach may serve as a model for future innovative drug development programs in rare diseases.