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

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.