A Multiple Ascending Dose Study of ACN00177 (Pegtarviliase) in Subjects With CBS Deficiency

A Phase 1/2 Multiple Ascending-Dose Study in Subjects With Homocystinuria Due to Cystathionine β-Synthase (CBS) Deficiency to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of ACN00177

The purpose of this study is to evaluate the safety and tolerability of pegtarviliase in approximately 36 subjects with homocystinuria due to CBS deficiency.

The purpose of this Phase 1/2 study is to evaluate the safety, pharmacokinetics and pharmacodynamics of multiple ascending doses of pegtarviliase in subjects with homocystinuria due to CBS deficiency. The study is composed of 2 parts: Part 1: a single IV (intravenous) cohort with 4 once-weekly (QW) doses of study drug and Part 2: three SC (subcutaneous) cohorts with 4 QW doses of study drug, with an optional fifth.

Planned for 4 subjects ≥12 years of age (≥18 in the US) dosing at Dose C weekly for a total of 4 doses

Planned for 4 subjects ≥12 years of age (≥18 in the US) dosing at Dose D weekly for a total of 4 doses

Optional cohort for up to 12 subjects ≥12 years of age (≥18 in the US) dosing at Dose E weekly for a total of 13 doses

Time course of tHcy change after pegtarviliase administration and reversibility upon follow up post dosing

Time course of tHcy change after pegtarviliase administration and reversibility upon follow up post dosing

Inclusion Criteria: Diagnosis of homocystinuria due to CBS deficiency Capable of providing signed informed consent/assent and to comply with all study related procedures Is ≥12 years of age (≥18 in the US) at the time of signing the informed consent/assent Plasma tHcy ≥50 µM (rounded to the nearest whole number) and documentation of previous tHcy ≥80 µM Female subjects of child-bearing potential must have a negative serum pregnancy test during the screening period and a negative urine pregnancy test prior to dosing on the first day of treatment If the subject (male or female) is engaging in sexual activity, he/she must be unable to become pregnant/cause pregnancy or must agree to use highly effective contraception Subjects receiving pyridoxine and/or betaine must be on the same dose of the medication(s) for at least 6 weeks prior to the first administration of study drug and be willing and able to remain on a stable dose for the duration of the study. Similarly, those on prescribed dietary therapy must be on a consistent dietary regimen for at least 6 weeks prior to study drug and should maintain this regimen for the duration of the study Exclusion Criteria: Other medical conditions or co-morbidity(ies) that, in the opinion of the investigator, would put the subject at increased medical risk or interfere with study compliance or data interpretation (eg, severe intellectual disability that precludes completion of the required study assessments) Currently participating in another therapeutic clinical study or has received any investigational agent within 30 days or 5 half-lives, whichever is longer, prior to the first dose of study drug in this study Surgery requiring general anesthesia within 8 weeks prior to the first dose of study drug or planned surgery druing the treatment period Active infection requiring anti-infective therapy <2 weeks prior to the first dose of study drug in this study; anti-infective therapy that completes ≥2 weeks prior to first dose of study drug is acceptable Pregnant or nursing Females of child-bearing potential who are using or plan to use estrogen-containing contraception during the study (unless the subject currently using estrogen-containing contraceptives is willing to switch to a non-estrogen-containing contraceptive at least 1 week before dosing and for the duration of the study) and for 30 days after the last dose History of hypersensitivity to polyethylene glycol (PEG) that, in the judgment of the investigator, puts the subject at unacceptable risk for adverse events (AEs) Serum creatinine level >1.5× the upper limit of normal (ULN) Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin level > 2× the ULN