Initiation of pivotal phase III clinical trial of pegtibatinase for the treatment of classical homocystinuria (HCU)

Classical HCU is a rare genetic metabolic disorder caused by a deficiency in the enzyme cystathionine beta synthase (CBS). The study is designed to determine the safety and efficacy of pegtibatinase in reducing plasma total homocysteine (tHcy) levels, a key treatment goal in classical HCU, compared to placebo in participants who are receiving standard of care.

“Classical HCU is a devastating rare disease that often manifests in childhood and can lead to serious complications due to toxic levels of homocysteine. These complications include continuous risk of developing life-threatening thrombotic events, such as heart attack and stroke, skeletal abnormalities, cognitive developmental delays, and intellectual disabilities. Patients and caregivers have limited treatment options, including adherence to highly restrictive diets that often are very challenging to follow and inadequate for maintaining metabolic control of homocysteine levels,” said William Rote, Ph.D., senior vice president of research and development at Travere Therapeutics. “The initiation of the HARMONY Study is an exciting step forward in addressing this significant unmet need and advancing our goal to deliver pegtibatinase as the first disease-modifying treatment option for the classical HCU community.”

The HARMONY Study is a global, randomized, multi-center, double-blind, placebo-controlled Phase III clinical trial designed to evaluate the efficacy and safety of pegtibatinase as a novel treatment to reduce tHcy levels. The trial is expected to enroll approximately 70 patients (greater than 12 to less than 65 years of age at screening) with a diagnosis of classical HCU who continue to have tHcy levels greater than 50 uM while maintaining their standard-of-care treatment. Participants will be randomized 1:1 to receive 2.5 mg/kg of pegtibatinase or placebo, administered subcutaneously, for a 24-week blinded treatment duration. The primary endpoint is relative geometric mean change in plasma tHcy levels from baseline compared to weeks 6 through 12, and durability of treatment response through 24 weeks of treatment will be measured as a secondary endpoint.

The Company expects topline data from the HARMONY Study to become available in 2026. The Company will also be initiating the ENSEMBLE Study, a Phase IIIb, open-label, long-term extension, that will evaluate the ongoing efficacy and long-term safety of pegtibatinase in participants with HCU following their completion of the Phase 1/II COMPOSE Study or the Phase III HARMONY Study. The ENSEMBLE Study will include an optional protein tolerance modification sub-study that will evaluate if eligible patients can increase their natural dietary protein intake while maintaining an acceptable level of metabolic control while receiving pegtibatinase.

The initiation of the Phase III HARMONY Study is based on the positive safety and efficacy data from the Phase 1/II COMPOSE Study. In COMPOSE, pegtibatinase demonstrated dose-dependent reductions in tHcy during 12 weeks of treatment. At the 2.5 mg/kg dose, pegtibatinase provided rapid and sustained reductions in tHcy, with a 67.1% mean relative reduction in tHcy from baseline, as well as maintenance of mean tHcy below the clinically meaningful threshold of 100 uM, over weeks 6 to 12. To date in the COMPOSE Study, pegtibatinase has been generally well-tolerated.

Pegtibatinase has been granted Breakthrough Therapy, Rare Pediatric Disease and Fast Track designations by the FDA as well as Orphan Drug designation in the U.S. and Europe.