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

• ClinicalTrials.gov Identifier: NCT05154890
• Recruitment Status: Recruiting
• First Posted: December 13, 2021
• Last Update Posted: January 17, 2023
• Sponsor: Aeglea Biotherapeutics
• Information provided by (Responsible Party): Aeglea Biotherapeutics

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Homocystinuria Due to Cystathionine Beta-Synthase Deficiency	Drug: Pegtarviliase	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 36 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 13, 2021
• Estimated Primary Completion Date: December 2023
• Estimated Study Completion Date: December 2023

Arms and Interventions

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; Administered IV; Other Name: 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; Administered SC; Other Name: 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; Administered SC; Other Name: 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; Administered SC; Other Name: 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; Administered SC; Other Name: ACN00177

Outcome Measures

Primary Outcome Measures :

1. Incidence of treatment-emergent adverse events [ Time Frame: Reporting will be from signing consent through study completion, an average of 70 days ]
   Incidence of treatment-emergent adverse events

Secondary Outcome Measures :

1. Pharmacokinetic Profile of IV pegtarviliase [ Time Frame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours ]
   Cmax
2. Pharmacokinetic Profile of IV pegtarviliase [ Time Frame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours ]
   AUC
3. Pharmacokinetic Profile of IV pegtarviliase [ Time Frame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours ]
   Tmax
4. Pharmacokinetic Profile of IV pegtarviliase [ Time Frame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours ]
   T1/2
5. Pharmacokinetic Profile of Subcutaneous pegtarviliase [ Time Frame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours ]
   Cmax
6. Pharmacokinetic Profile of Subcutaneous pegtarviliase [ Time Frame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours ]
   AUC
7. Pharmacokinetic Profile of Subcutaneous pegtarviliase [ Time Frame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours ]
   Tmax
8. Pharmacokinetic Profile of Subcutaneous pegtarviliase [ Time Frame: At pre-dose, 1hour, 6hours, 24hours, 48hours, 72hours, 96hours and 120hours ]
   T1/2
9. Changes in total plasma homocysteine after treatment with pegtarviliase [ Time Frame: At Visit Day 29 ]
   Changes in total plasma homocysteine after treatment with pegtarviliase
10. Time course of tHcy change after pegtarviliase administration and reversibility upon follow up post dosing [ Time Frame: Weekly, baseline through study completion, up to 12 weeks ]
    Time course of tHcy change after pegtarviliase administration and reversibility upon follow up post dosing

Eligibility Criteria

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

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

Contacts and Locations

Contacts

Contact: Aeglea Clinical Department; 1.855.509.9921; clinicaltrials@aegleabio.com

Contact: Josie Gayton

Locations

United States, Texas

UT Southwestern Medical Center; Recruiting

Dallas, Texas, United States, 75390

Contact: Markey McNutt, II, MD

Principal Investigator: Markey McNutt, II, MD

Australia, New South Wales

Westmead Hospital; Recruiting

Westmead, New South Wales, Australia

Contact: Michel Tchan, FRACP

Principal Investigator: Michel Tchan, FRACP

Australia, Victoria

Royal Children's Hospital; Recruiting

Parkville, Victoria, Australia

Contact: Heidi Peters

Principal Investigator: Heidi Peters

Royal Melbourne Hospital; Recruiting

Parkville, Victoria, Australia

Contact: Timothy Fazio, MBBS

Principal Investigator: Timothy Fazio, MBBS

United Kingdom

University Hospitals Birmingham NHS; Recruiting

Birmingham, United Kingdom

Contact: Charlotte Dawson

Principal Investigator: Charlotte Dawson

Great Ormond Street Hospital; Recruiting

London, United Kingdom

Contact: Mildrid Yeo

Principal Investigator: Mildrid Yeo

Guy's and St Thomas' Hospital NHS Foundation Trust; Recruiting

London, United Kingdom

Contact: Radha Ramachandran

Principal Investigator: Radha Ramachandran

University College London; Recruiting

London, United Kingdom

Contact: Elaine Murphy, MB

Principal Investigator: Elaine Murphy, MB

Salford Royal NHS Foundation Trust; Recruiting

Salford, United Kingdom

Contact: Reena Sharma

Principal Investigator: Reena Sharma

Sponsors and Collaborators

Aeglea Biotherapeutics

Investigators

• Principal Investigator: Reena Sharma, MD; Northern Care Alliance NHS Foundation Trust

More Information

• Responsible Party: Aeglea Biotherapeutics
• ClinicalTrials.gov Identifier: NCT05154890
• Other Study ID Numbers: CACN00177-100D; 2019-004791-19 ( EudraCT Number )
• First Posted: December 13, 2021
• Last Update Posted: January 17, 2023
• Last Verified: January 2023

• 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

Additional relevant MeSH terms:

Homocystinuria; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hyperhomocysteinemia; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Connective Tissue Diseases; Metabolic Diseases