Safety and efficacy of pegtibatinase enzyme replacement therapy in adults with classical homocystinuria in the COMPOSE® phase 1/2 randomized trial

Authors

Can Ficicioglu, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: ficicioglu@chop.edu.
Janet A. Thomas, University of Colorado School of Medicine, Aurora, CO, USA.
Jaya Ganesh, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
David Kudrow, Science 37, Culver City, CA, USA.
Melissa Lah, Indiana University School of Medicine, Indianapolis, IN, USA.
Wendy E. Smith, MaineHealth Maine Medical Center, Portland, ME, USA.
Jalé Güner, Travere Therapeutics, Inc., San Diego, CA, USA.
Sharon McDermott, Former employee, Travere Therapeutics, Inc., San Diego, CA, USA.
Sagar A. Vaidya, Former employee, Travere Therapeutics, Inc., San Diego, CA, USA.
Liz Wilkening, Travere Therapeutics, Inc., San Diego, CA, USA.
Harvey L. Levy, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Document Type

Article

Publication Date

5-14-2025

Institution/Department

Pediatrics

Journal Title

Genetics in medicine : official journal of the American College of Medical Genetics

Abstract

PURPOSE: As classical homocystinuria (HCU) standard-of-care treatment often cannot achieve adequate metabolic control, the phase 1/2 COMPOSE® trial (NCT03406611) evaluated pegtibatinase enzyme replacement therapy. METHODS: Participants with HCU aged 12-65 years with elevated total plasma homocysteine (tHcy) receiving standard-of-care treatment were randomized 3:1 into six increasing dose cohorts (each n≈4) of subcutaneous pegtibatinase (≤2.5 mg/kg twice weekly [BIW]) or placebo. Primary end points included adverse event incidence and immunogenicity. Secondary end points included tHcy change from baseline to post-treatment (geometric mean of weeks 6-12). RESULTS: Overall, 24 participants were enrolled. Pegtibatinase was generally well tolerated at all doses with no anaphylaxis or severe immune reactions; 15 participants (62.5%) experienced ≥1 treatment-related treatment-emergent adverse event (most commonly injection-site reactions; one serious [acute urticaria]). At the two highest doses, substantial tHcy reductions were observed post-treatment (relative reduction: 57% for 1.5 mg/kg BIW; 67% for 2.5 mg/kg BIW) and all participants maintained tHcy < 100 μM. One participant receiving 2.5 mg/kg BIW achieved tHcy < 15 μM (normal) and methionine < 14 μM (below normal), enabling increased dietary intact protein intake. Changes in other metabolites aligned with tHcy. CONCLUSION: Pegtibatinase was generally well tolerated and substantially reduced tHcy levels, demonstrating potential as a treatment for HCU.

First Page

101456

Recommended Citation

Ficicioglu C, Thomas JA, Ganesh J, et al. Safety and efficacy of pegtibatinase enzyme replacement therapy in adults with classical homocystinuria in the COMPOSE® phase 1/2 randomized trial. Genet Med. Published online May 14, 2025. doi:10.1016/j.gim.2025.101456