Astria Therapeutics, Inc. (NASDAQ:ATXS) has announced the design of its ALPHA-ORBIT Phase 3 clinical trial, evaluating navenibart for the treatment of hereditary angioedema (HAE). The global, randomized, double-blind, placebo-controlled trial is set to begin in Q1 2025, with top-line results expected in early 2027. The study aims to assess the efficacy and safety of navenibart over a 6-month treatment period, incorporating both every 3-month (Q3M) and every 6-month (Q6M) administration schedules.
Trial Design and Objectives
The ALPHA-ORBIT trial will enroll up to 145 patients with Type 1 or Type 2 HAE. Participants will be randomized to receive one of three navenibart dose arms or a placebo: 1) an initial 600 mg dose followed by 300 mg Q3M, 2) 600 mg Q6M, and 3) 600 mg Q3M. The primary endpoint is the time-normalized monthly HAE attack rate at 6 months. A key secondary endpoint is the proportion of participants who are attack-free at 6 months. Following the initial 6-month period, patients may be eligible to enter a long-term extension trial where all participants will receive open-label navenibart, including a patient-centric flexible dosing period.
Rationale Behind Navenibart
Hereditary angioedema is characterized by recurrent episodes of severe swelling, often affecting the limbs, face, airway, and gastrointestinal tract. These attacks are driven by an overproduction of bradykinin, mediated by plasma kallikrein. Navenibart is a monoclonal antibody designed to inhibit plasma kallikrein, thereby reducing bradykinin production and preventing HAE attacks. The goal is to provide rapid and sustained attack prevention with a validated mechanism and a convenient administration schedule.
Prior Clinical Data
The planned doses for the Phase 3 ALPHA-ORBIT program were selected based on positive top-line results from the Phase 1b/2 ALPHA-STAR trial. The ALPHA-STAR trial demonstrated rapid onset of robust and durable efficacy, favorable safety and tolerability, and pharmacokinetics and pharmacodynamics consistent with sustained plasma kallikrein inhibition for both Q3M and Q6M administration. Final results included a reduction in mean monthly attack rate of 90-95% and up to a 67% attack-free rate over 6 months.
Management Commentary
"We are thrilled to announce our planned Phase 3 design, which reflects feedback from regulators and is intended to support global registration for both Q3M and Q6M administration," said Jill C. Milne, Ph.D., Chief Executive Officer at Astria. "With navenibart, we are pioneering patient-centric dosing flexibility in HAE with the goal of maximizing attack rate reduction with a compellingly low burden of treatment. Assuming approval, we believe navenibart will become the market-leading, first-choice therapy for HAE."
Christopher Morabito, M.D., Chief Medical Officer at Astria, added, "Our Phase 3 program was designed in collaboration with the patient community and physicians, is based on input from global regulatory authorities, and addresses the importance of providing options to patients for a disease that’s highly variable."
