Clinical trial NCT05154890: A Multiple Ascending Dose Study of ACN00177 (Pegtarviliase) in Subjects With CBS Deficiency
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Homocystinuria Due to Cystathionine Beta-Synthase Deficiency
Lead sponsor: Aeglea Biotherapeutics
Sponsor class: INDUSTRY
First posted: 2021-12-13
Enrollment: 13
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of treatment-emergent adverse events
timeFrame: Reporting will be from signing consent through study completion, an average of 70 days
Secondary outcomes:
measure: Pharmacokinetic Profile of IV pegtarviliase Cmax
timeFrame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
measure: Pharmacokinetic Profile of IV pegtarviliase AUC
timeFrame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
measure: Pharmacokinetic Profile of IV pegtarviliase Tmax
timeFrame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
measure: Pharmacokinetic Profile of IV pegtarviliase T1/2
timeFrame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
measure: Pharmacokinetic Profile of Subcutaneous pegtarviliase Cmax
timeFrame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
measure: Pharmacokinetic Profile of Subcutaneous pegtarviliase AUC
timeFrame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
measure: Pharmacokinetic Profile of Subcutaneous pegtarviliase Tmax
timeFrame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
measure: Pharmacokinetic Profile of Subcutaneous pegtarviliase T 1/2
timeFrame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
measure: Changes in total plasma homocysteine after treatment with pegtarviliase
timeFrame: At Visit Day 29
measure: Time course of tHcy change after pegtarviliase administration and reversibility upon follow up post dosing
timeFrame: Weekly, baseline through study completion, up to 12 weeks
Other outcomes:
Locations:
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: London
country: United Kingdom
facility: Guy's and St Thomas' Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: University College London
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
Study officials:
affiliation: Aeglea Biotherapeutics
name: Cortney Caudill
role: STUDY_DIRECTOR
References: