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.

Study Overview

• Status: Terminated
• Conditions: Homocystinuria Due to Cystathionine Beta-Synthase Deficiency
• Intervention / Treatment: Drug: Pegtarviliase IV; Drug: Pegtarviliase SC

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 Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia
      • Westmead Hospital
  • Victoria
    • Parkville, Victoria, Australia
      • Royal Melbourne Hospital
    • Parkville, Victoria, Australia
      • Royal Children's Hospital
• United Kingdom
  • Birmingham, United Kingdom
    • University Hospitals Birmingham NHS
  • London, United Kingdom
    • University College London
  • London, United Kingdom
    • Great Ormond Street Hospital
  • London, United Kingdom
    • Guy's and St Thomas' Hospital NHS Foundation Trust
  • Salford, United Kingdom
    • Salford Royal NHS Foundation Trust
• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pegtarviliase Cohort 1; Planned for 4 subjects ≥18 years of age dosing at Dose A weekly for a total of 4 doses	Drug: Pegtarviliase IV; Administered IV; Other Names: ACN00177
Experimental: Pegtarviliase Cohort 2; Planned for 4 subjects ≥12 years of age dosing at Dose B weekly for a total of 4 doses	Drug: Pegtarviliase SC; Administered SC; Other Names: ACN00177
Experimental: Pegtarviliase Cohort 3; Planned for 4 subjects ≥12 years of age (≥18 in the US) dosing at Dose C weekly for a total of 4 doses	Drug: Pegtarviliase SC; Administered SC; Other Names: ACN00177
Experimental: Pegtarviliase Cohort 4; Planned for 4 subjects ≥12 years of age (≥18 in the US) dosing at Dose D weekly for a total of 4 doses	Drug: Pegtarviliase SC; Administered SC; Other Names: ACN00177
Experimental: Pegtarviliase Cohort 5; 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	Drug: Pegtarviliase SC; Administered SC; Other Names: ACN00177

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-emergent adverse events	Incidence of treatment-emergent adverse events	Reporting will be from signing consent through study completion, an average of 70 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in total plasma homocysteine after treatment with pegtarviliase	Changes in total plasma homocysteine after treatment with pegtarviliase	At Visit Day 29
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	Weekly, baseline through study completion, up to 12 weeks
Pharmacokinetic Profile of IV pegtarviliase Cmax	Cmax	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
Pharmacokinetic Profile of IV pegtarviliase AUC	AUC	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
Pharmacokinetic Profile of IV pegtarviliase Tmax	Tmax	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
Pharmacokinetic Profile of IV pegtarviliase T1/2	T1/2	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
Pharmacokinetic Profile of Subcutaneous pegtarviliase Cmax	Cmax	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
Pharmacokinetic Profile of Subcutaneous pegtarviliase AUC	AUC	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
Pharmacokinetic Profile of Subcutaneous pegtarviliase Tmax	Tmax	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours
Pharmacokinetic Profile of Subcutaneous pegtarviliase T 1/2	T1/2	At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours

Collaborators and Investigators

• Sponsor: Aeglea Biotherapeutics
• Investigators: Study Director: Cortney Caudill, Aeglea Biotherapeutics

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2021
• Primary Completion (Actual): April 21, 2023
• Study Completion (Actual): April 21, 2023

Study Registration Dates

• First Submitted: August 20, 2021
• First Submitted That Met QC Criteria: November 30, 2021
• First Posted (Actual): December 13, 2021

Study Record Updates

• Last Update Posted (Actual): July 27, 2023
• Last Update Submitted That Met QC Criteria: July 25, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Connective Tissue Diseases; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Hyperhomocysteinemia; Homocystinuria
• Other Study ID Numbers: CACN00177-100D; 2019-004791-19 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes