Travere Therapeutics Announces Positive Topline Results From Ongoing Phase 1/2 COMPOSE Study of Pegtibatinase in Classical Homocystinuria

Travere Therapeutics, Inc. recently announced positive topline results from the ongoing Phase 1/2 COMPOSE Study of pegtibatinase, a novel investigational enzyme replacement therapy being evaluated for the treatment of classical homocystinuria (HCU). In the highest dose cohort to date evaluating 1.5mg/kg of pegtibatinase twice weekly (BIW), treatment with pegtibatinase resulted in rapid and sustained reductions in total homocysteine (tHcy) through 12 weeks of treatment, including a 55.1% mean relative reduction in tHcy from baseline as well as maintenance of tHcy below a clinically meaningful threshold of 100 μmol. To date in the study, pegtibatinase has been generally well-tolerated.

“These promising topline results from the ongoing COMPOSE Study show that pegtibatinase has the potential to improve overall metabolic function and provide clear proof of concept for pegtibatinase as a potential novel therapy for patients living with HCU,” said Bill Rote, PhD, Senior Vice President of Research and Development at Travere Therapeutics. “With the strength of these data, we are furthering efforts to refine our formulation and explore pegtibatinase dosing, while in parallel engaging with regulators to establish next steps for a pivotal development program designed to ultimately support potential approvals of pegtibatinase for the treatment of HCU.”

“Most patients with HCU are at high risk of developing long term and often devastating complications from HCU because they cannot sustain low levels of toxic homocysteine with currently available treatment options,” said Harvey Levy, MD, senior physician in medicine/genetics, Division of Genetics and Genomics, Boston Children’s Hospital, professor of pediatrics, Harvard Medical School. “The data from the ongoing COMPOSE Study are highly encouraging and provide promise for a potentially novel approach to targeting the underlying enzymatic defect in HCU.”

To date in the COMPOSE Study, a total of 19 patients with HCU have been randomized 3:1 to receive either pegtibatinase or placebo in independent ascending subcutaneous dose cohorts, ranging from 0.33mg/kg once weekly to 1.5mg/kg BIW. The study protocol provided for an unblinded assessment to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical effects after twelve weeks of treatment had been completed in the fifth cohort (1.5mg/kg BIW).

Key findings from the topline results:

• To date in the COMPOSE Study, pegtibatinase has been generally well-tolerated.

• There were no discontinuations due to treatment-related adverse events. There was one serious adverse event, moderate acute urticaria (hives), that was categorized by the treating physician to be likely related to pegtibatinase treatment but did not lead to treatment discontinuation and resolved following a single dose interruption.

• Pegtibatinase demonstrated dose-dependent reductions in tHcy during the 12 weeks of treatment.

• At the two highest doses, pegtibatinase appeared to reduce tHcy regardless of starting baseline tHcy levels or background therapy.

• In the highest dose cohort to date of 1.5mg/kg BIW, treatment with pegtibatinase resulted in rapid and sustained reductions in tHcy, resulting in a maintenance of tHcy below a clinically meaningful threshold of 100 μmol from week 2 through week 12 of treatment.

• In the 1.5mg/kg BIW dose cohort, treatment with pegtibatinase resulted in a mean relative reduction from baseline of 55.1% (n=3, mean baseline tHcy = 187.0 μmol), compared to a mean relative reduction from baseline of 4.8% for all patients receiving placebo in the study (n=5, mean baseline tHcy = 131.1 μmol).

• In a dose-dependent manner in the study to date, methionine levels were substantially reduced and cystathionine levels were substantially elevated following treatment with pegtibatinase, suggesting that pegtibatinase acts in a manner similar to the native CBS enzyme.

• The Company plans to present additional detailed study results at an upcoming medical meeting or in a peer-reviewed publication.

Based on these results, the company is preparing to engage with regulators to establish next steps for a pivotal development program to ultimately support potential approvals of pegtibatinase for the treatment of HCU. In parallel, the company has initiated one additional cohort in the COMPOSE Study to inform and refine formulation work for future development and commercial purposes and to further evaluate the dose response curve for pegtibatinase. Patients enrolled in the COMPOSE Study are eligible to enter into an open-label extension and receive the 1.5mg/kg dose of pegtibatinase.

Classical homocystinuria (HCU) is a rare genetic metabolic disorder caused by a deficiency in the enzyme cystathionine beta synthase (CBS). CBS is a pivotal enzyme that is essential for the management of methionine and cysteine in the body. Classical HCU leads to toxic levels of homocysteine that can result in life-threatening thrombotic events such as stroke and heart attacks, ophthalmologic and skeletal complications, as well as developmental delay. Current treatment options are limited to protein-restricted diet and supplemental use of vitamin B6 and betaine.

The ongoing Phase 1/2 COMPOSE Study is a randomized, multicenter, placebo controlled, double-blind dose escalation trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical effects of pegtibatinase in up to 40 patients with classical homocystinuria. Patients in COMPOSE are randomized 3:1 to receive subcutaneous doses of either pegtibatinase or placebo, and patients are eligible to continue in an open-label extension after the initial blinded twelve-week treatment period.

Pegtibatinase is an investigational PEGylated, recombinant enzyme replacement therapy designed to address the underlying cause of classical homocystinuria (HCU). In preclinical studies, pegtibatinase has demonstrated an ability to reduce total homocysteine levels and improve clinical parameters. Pegtibatinase is currently advancing in the Phase 1/2 COMPOSE Study to assess its safety, tolerability, pharmacokinetics, pharmacodynamics and clinical effects in patients with classical HCU. Pegtibatinase has been granted Rare Pediatric Disease and Fast Track designations by the US Food and Drug Administration (FDA), as well as Orphan Drug designation in the US and Europe.

At Travere Therapeutics, we are in rare for life. We are a biopharmaceutical company that comes together every day to help patients, families and caregivers of all backgrounds as they navigate life with a rare disease. On this path, we know the need for treatment options is urgent – that is why our global team works with the rare disease community to identify, develop and deliver life-changing therapies. In pursuit of this mission, we continuously seek to understand the diverse perspectives of rare patients and to courageously forge new paths to make a difference in their lives and provide hope – today and tomorrow. For more information, visit travere.com.