Homocystinuria Due to Cystathionine Beta-Synthase Deficiency
Conditions
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.
Interventions
DRUGPegtarviliase IV
Administered IV
DRUGPegtarviliase SC
Administered SC
Sponsors
Aeglea Biotherapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Profile of IV pegtarviliase Cmax | At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours | Cmax |
| 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 Tmax | At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours | Tmax |
| Pharmacokinetic Profile of Subcutaneous pegtarviliase AUC | At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours | AUC |
| Pharmacokinetic Profile of Subcutaneous pegtarviliase T 1/2 | At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours | T1/2 |
| Changes in total plasma homocysteine after treatment with pegtarviliase | At Visit Day 29 | Changes in total plasma homocysteine after treatment with pegtarviliase |
| 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 Subcutaneous pegtarviliase Cmax | At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours | Cmax |
Countries
Australia, United Kingdom, United States
Outcome results
None listed