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

Phase 1

Terminated

• Conditions: Homocystinuria Due to Cystathionine Beta-Synthase Deficiency
• Interventions: Drug: Pegtarviliase IV; Drug: Pegtarviliase SC

• Registration Number: NCT05154890
• Lead Sponsor: Aeglea Biotherapeutics

Brief Summary

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

Detailed Description

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.

Study Timeline

• Study Start: 2021-05-13
• Study First Submitted: 2021-08-20
• Study First Submitted QC: 2021-11-30
• Study First Posted: 2021-12-13
• Primary Completion: 2023-04-21
• Study Completion: 2023-04-21
• Status Verified: 2023-07
• Last Update Submitted: 2023-07-25
• Last Update Posted: 2023-07-27

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 13

Inclusion Criteria

1. Diagnosis of homocystinuria due to CBS deficiency
2. Capable of providing signed informed consent/assent and to comply with all study related procedures
3. Is ≥12 years of age (≥18 in the US) at the time of signing the informed consent/assent
4. Plasma tHcy ≥50 µM (rounded to the nearest whole number) and documentation of previous tHcy ≥80 µM
5. 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
6. 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
7. 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

1. 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)
2. 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
3. Surgery requiring general anesthesia within 8 weeks prior to the first dose of study drug or planned surgery druing the treatment period
4. 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
5. Pregnant or nursing
6. 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
7. History of hypersensitivity to polyethylene glycol (PEG) that, in the judgment of the investigator, puts the subject at unacceptable risk for adverse events (AEs)
8. Serum creatinine level >1.5× the upper limit of normal (ULN)
9. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin level > 2× the ULN

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Pegtarviliase Cohort 1	Pegtarviliase IV	Planned for 4 subjects ≥18 years of age dosing at Dose A weekly for a total of 4 doses
Pegtarviliase Cohort 2	Pegtarviliase SC	Planned for 4 subjects ≥12 years of age dosing at Dose B weekly for a total of 4 doses
Pegtarviliase Cohort 3	Pegtarviliase SC	Planned for 4 subjects ≥12 years of age (≥18 in the US) dosing at Dose C weekly for a total of 4 doses
Pegtarviliase Cohort 4	Pegtarviliase SC	Planned for 4 subjects ≥12 years of age (≥18 in the US) dosing at Dose D weekly for a total of 4 doses
Pegtarviliase Cohort 5	Pegtarviliase SC	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

Primary Outcome Measures

Name	Time	Method
Incidence of treatment-emergent adverse events	Reporting will be from signing consent through study completion, an average of 70 days	Incidence of treatment-emergent adverse events

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic Profile of IV pegtarviliase Cmax	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours	Cmax
Pharmacokinetic Profile of Subcutaneous pegtarviliase Tmax	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours	Tmax
Pharmacokinetic Profile of Subcutaneous pegtarviliase T 1/2	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours	T1/2
Time course of tHcy change after pegtarviliase administration and reversibility upon follow up post dosing	Weekly, baseline through study completion, up to 12 weeks	Time course of tHcy change after pegtarviliase administration and reversibility upon follow up post dosing
Pharmacokinetic Profile of IV pegtarviliase AUC	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours	AUC
Pharmacokinetic Profile of IV pegtarviliase Tmax	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours	Tmax
Pharmacokinetic Profile of IV pegtarviliase T1/2	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours	T1/2
Pharmacokinetic Profile of Subcutaneous pegtarviliase Cmax	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours	Cmax
Pharmacokinetic Profile of Subcutaneous pegtarviliase AUC	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours	AUC
Changes in total plasma homocysteine after treatment with pegtarviliase	At Visit Day 29	Changes in total plasma homocysteine after treatment with pegtarviliase

Trial Locations

Locations (9)

Royal Melbourne Hospital; 🇦🇺 Parkville, Victoria, Australia

Westmead Hospital; 🇦🇺 Westmead, New South Wales, Australia

UT Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

University College London; 🇬🇧 London, United Kingdom

Salford Royal NHS Foundation Trust; 🇬🇧 Salford, United Kingdom

Great Ormond Street Hospital; 🇬🇧 London, United Kingdom

Guy's and St Thomas' Hospital NHS Foundation Trust; 🇬🇧 London, United Kingdom

University Hospitals Birmingham NHS; 🇬🇧 Birmingham, United Kingdom

Royal Children's Hospital; 🇦🇺 Parkville, Victoria, Australia