Travere Therapeutics, Inc. announced the Company has opened enrollment in the HARMONY Study, a global, randomized pivotal Phase 3 clinical trial of pegtibatinase, a novel investigational enzyme replacement therapy being evaluated 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.

The HARMONY Study is a global, randomized, multi-center, double-blind, placebo-controlled Phase 3 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 (=12 to =65 years of age at screening) with a diagnosis of classical HCU who continue to have tHcy levels =50 µM 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 3b, 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 1/2 COMPOSE Study or the Phase 3 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 3 HARMONY Study is based on the positive safety and efficacy data from the Phase 1/2 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 µM, 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 U.S. Food and Drug Administration (FDA), as well as Orphan Drug designation in the U.S. and Europe.