A Study to Investigate Efficacy and Safety of Pegtibatinase Compared With Placebo in Participants ≥12 to ≤65 Years of Age With Classical Homocystinuria (HCU) Due to Cystathionine Beta Synthase Deficiency Receiving Standard of Care Treatment

A Phase 3, Parallel-Group Treatment, Blinded, Randomized, Placebo-Controlled Study To Assess The Efficacy And Safety Of Pegtibatinase Administered Subcutaneously In Addition To Standard Of Care In Participants With Classical Homocystinuria Due To Cystathionine Beta Synthase Deficiency (HARMONY)

The purpose of this study is to measure efficacy and safety of pegtibatinase treatment compared with placebo in participants with classical HCU receiving standard of care. Study details include:

• Total Study duration: up to 38 weeks

• Screening:

  • Initial Screening duration: up to 4 weeks
  • Pre-treatment Diet Standardization Period duration: up to 6 weeks

• Blinded Treatment Duration: 24 weeks

  • 2-week blinded dose titration period
  • 22-week blinded assessment period

• Safety Follow-Up: 4 weeks after last dose (as applicable for those not enrolling in the long term extension study, ENSEMBLE)

Overall Design:

This global Phase 3 multi-center, multi-national, randomized, blinded, placebo-controlled study will be conducted in participants with classical CBS deficient HCU receiving standard of care who continue to have tHcy levels ≥50 μM. The total study duration will be up to 38 weeks. Approximately 70 participants (35 per arm) will be randomized to receive active drug or placebo (1:1 allocation).

Screening:

Participants will enter into a 2-phase Screening period of up to 10 weeks:

1. Initial Screening: up to 4-week period during which participants will be assessed for eligibility
2. Pre-treatment Diet Standardization Period (DSP): After meeting initial eligibility criteria, participants will begin a pre treatment DSP of up to 6 weeks. The DSP is intended to help minimize variability in protein intake and supplements throughout the randomized portion of the study.

The baseline diet and compliance with HCU-related treatments will be recorded by the dietitian using the HCU-specific diet monitoring tool, called SING (Simplified Ingested Nutrients Guide). The baseline diet and treatment compliance will be used as a reference for future evaluation of daily intact protein intake (DIPI) and HCU treatments.

Blinded Treatment Period:

During the 24-week blinded treatment period, study visits will occur at regular intervals including home visits for study drug administration. Some study visits may be conducted remotely. Dietary protein intake and compliance with HCU treatments will continue to be monitored and recorded to ensure a stable diet and HCU treatment compliance.

Inclusion Criteria:

• Must be ≥12 to ≤65 years of age, at the time of signing the informed consent
• Must have a diagnosis of classical HCU based on clinical, biochemical, and/or molecular genetic testing
• Plasma tHcy ≥80 µM at Screening visit, with allowance for up to 18 participants who may be enrolled with a Screening plasma tHcy ≥50 to <80 µM
• Participants who can become pregnant must have a negative pregnancy test before starting the study and must use a highly effective form of birth control (less than 1% risk of pregnancy per year) during the study and for at least 4 weeks after the last dose.
• Willing to maintain a generally stable diet for the duration of the study (unless changes are required based on medical/safety reasons)
• Willing to maintain generally stable intake and doses of betaine, pyridoxine, and medical food for the duration of the study (unless changes are required based on medical/safety reasons)

Exclusion Criteria:

• Diagnosis of Marfan syndrome, methylenetetrahydrofolate reductase (MTHFR) deficiency, or disorder of cobalamin metabolism
• Concurrent disease or condition (eg, history or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurological, oncologic, or psychiatric disease) that would interfere with study participation or safety (excluding complications of HCU).
• History of major thrombotic event (eg, cerebrovascular accident, myocardial infarction, pulmonary embolism) in the previous 6 months.
• Body weight ≥160 kg.
• Use or planned use of any injectable drugs containing PEG (excluding PEG-containing vaccines)
• Any previous exposure to pegtibatinase and/or previous participation in a clinical study that included administration of pegtibatinase or pegtarviliase
• Prior severe immune reaction to a PEG-containing product