34: Pegtibatinase in Classical Homocystinuria (COMPOSE)

Ficicioglu C et al., Genetics in Medicine (2025) 27, 101456 - Phase 1/2 COMPOSE trial tested subcutaneous pegtibatinase in 24 participants with classical homocystinuria; treatment was generally well tolerated and produced rapid, dose-dependent reductions in total plasma homocysteine (tHcy). Key terms: classical homocystinuria, pegtibatinase, enzyme replacement therapy, total plasma homocysteine, clinical trial. Study Highlights:COMPOSE randomized 24 participants across six ascending dose cohorts of pegtibatinase versus placebo to evaluate safety and effects on tHcy. Pegtibatinase was generally well tolerated with mostly mild injection-site reactions and no anaphylaxis or severe immune reactions. At 1.5 mg/kg BIW and 2.5 mg/kg BIW, geometric mean tHcy fell by 57% and 67% respectively, with all participants at these doses achieving tHcy <100 μM and one achieving normal tHcy. Anti-drug and anti-PEG antibodies were frequently detected but were typically low or transient and did not affect tHcy pharmacokinetics. Conclusion:Pegtibatinase was generally well tolerated and produced substantial, sustained reductions in tHcy at the two highest doses, supporting further evaluation as a potential enzyme replacement therapy for classical homocystinuria. Music:Enjoy the music based on this article at the end of the episode. Article title:Safety and efficacy of pegtibatinase enzyme replacement therapy in adults with classical homocystinuria in the COMPOSE phase 1/2 randomized trial First author:Ficicioglu C Journal:Genetics in Medicine (2025) 27, 101456 DOI:10.1016/j.gim.2025.101456 Reference:Ficicioglu C, Thomas JA, Ganesh J, Kudrow D, Lah M, Smith WE, Guner J, McDermott S, Vaidya SA, Wilkening L, Levy HL. Safety and efficacy of pegtibatinase enzyme replacement therapy in adults with classical homocystinuria in the COMPOSE phase 1/2 randomized trial. Genetics in Medicine. 2025;27:101456. doi:10.1016/j.gim.2025.101456 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/ep34-pegtibatinase-compose-hcu QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-06. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantive audit of the scientific content in the transcript, including mechanism (metabolic sink), study design, efficacy (tHcy and methionine), safety/immunogenicity, and limitations as reported in the original article.- transcript topics: Mechanism of action: metabolic sink in plasma to reduce tissue tHcy; COMPOSE study design: phase 1/2, 6 dose cohorts, 3:1 randomization; Efficacy outcomes: tHcy reductions at high doses, threshold of 100 μM; Individual patient outcomes: one case with <15 μM tHcy and low methionine enabling dietary protein increase; Methionine-cycle metabolite changes indicating pathway restoration; Safety and immunogenicity: TEAEs, injection-site reactions, urticaria, antibody data QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 8- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Aud...