Efficacy and Safety of Pegtibatinase Added to Standard of Care in Participants with Classical Homocystinuria Due to Cystathionine Beta Synthase Deficiency

The primary objective is to evaluate the efficacy of subcutaneous pegtibatinase in reducing plasma total homocysteine (tHcy) and methionine (Met) levels in participants with classical homocystinuria due to cystathionine beta synthase deficiency compared to a placebo. Additionally, the study aims to assess the safety and tolerability of the investigational product (5, 4). Secondary objectives include:

• Characterization of the pharmacokinetics (6) of pegtibatinase.
• Evaluation of the immunogenicity (7) of the treatment.
• Assessment of the impact on the quality of life regarding daily activities for individuals living with the disease.

This clinical trial involves a total of 48 participants diagnosed with classical homocystinuria. The study population includes both male and female patients within an age range of 12 to 65 years. Inclusion requires a diagnosis confirmed via clinical, biochemical, or molecular genetic testing. A specific distribution is planned where approximately 25% of subjects present with plasma tHcy levels between 50 and 80 µM, while the remaining 75% present with levels ≥80 µM. Participants must be able to maintain a stable diet with consistent dietary protein intake and adhere to standard HCU-related therapies, such as betaine, pyridoxine, or medical food, during the pre-study period. The primary objectives are:

• To evaluate the efficacy of pegtibatinase administered subcutaneously on plasma tHcy and methionine compared to a placebo.
• To assess the safety and tolerability of the subcutaneous administration of pegtibatinase.

This Phase 3, parallel-group, blinded, randomized, placebo-controlled study is designed to evaluate the efficacy and safety of pegtibatinase administered via subcutaneous injection in addition to the standard of care for individuals with classical homocystinuria. The study will compare the effects of pegtibatinase against a placebo consisting of 0.9% sodium chloride. The primary efficacy objective is to measure the change from baseline in plasma tHcy levels. Secondary objectives include assessing changes in plasma methionine levels and the proportion of participants achieving specific biochemical thresholds. The study involves a screening period to confirm diagnosis and baseline biochemical parameters, followed by treatment and follow-up assessments. Participant involvement includes monitoring plasma levels through various intervals, including weeks 6 through 12 and post-week 12 assessments up to week 24. The overall duration of the study is estimated to conclude by August 31, 2027.

Pegtibatinase is an orphan drug administered as a solution for injection. The experimental treatment is provided via subcutaneous injection at a dosage of 2.5 mg/kg. This medication is investigated in participants with classical homocystinuria due to cystathionine beta synthase deficiency.

A placebo consisting of 0.9% sodium chloride is utilized for comparison. This saline solution is administered alongside standard of care therapy to evaluate the efficacy and safety of the test substance on plasma total homocysteine and methionine levels.

The efficacy assessment in this study focuses on the evaluation of pegtibatinase in participants with classical homocystinuria. The primary endpoint is the change from baseline in plasma total homocysteine levels, averaged over Weeks 6 through 12, relative to the baseline measurements collected during Week -3, Week -1, and Day 1 pre-dose.

Secondary efficacy parameters include:

• The change from baseline in plasma total homocysteine levels averaged during the period post Week 12, specifically at Weeks 16, 20, and 24.
• The change from baseline in plasma methionine levels averaged over Weeks 6 through 12 and post Week 12.
• The proportion of participants achieving total homocysteine levels below 100 µM or below 50 µM during the Weeks 6 through 12 period and the post Week 12 period, among those with levels above 100 µM at baseline.
• The proportion of participants with total homocysteine levels below 15 µM averaged over Weeks 6 through 12 and post Week 12.
• The proportion of participants achieving a total homocysteine reduction of 35% or greater from baseline, both individually and in combination with total homocysteine levels below 100 µM, during the Weeks 6 through 12 period and the post Week 12 period.