Pegtibatinase as an Enzyme Therapy for Patients With Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency (COMPOSE)

A Double Blind, Randomized, Placebo-controlled, Phase 1/2 Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Effects on Clinical Outcomes of Pegtibatinase (TVT-058), Administered Subcutaneously in Patients With Cystathionine Beta-Synthase Deficient Homocystinuria (COMPOSE)

Homocystinuria caused by Cystathionine Beta-Synthase (CBS) Deficiency is a rare autosomal-recessive metabolic condition characterized by an excess of homocysteine (Hcy) in the plasma, tissues and urine. It is due to reduced or absent activity of the CBS enzyme, and is also known as classical homocystinuria. The symptoms associated with homocystinuria are variable in severity and time of onset across patients. Some affected individuals may have mild signs of the disorder; others may have multi-systemic involvement including potentially life-threatening complications. Homocystinuria can affect many different organ systems of the body; the four most commonly involved are the eyes, central nervous system, skeleton, and the vascular system.

The current approaches to treatment of homocystinuria patients include a highly restrictive diet and use of dietary supplements. Lifetime compliance with this diet is poor. Pegtibatinase (TVT-058) represents a novel therapeutic approach that incorporates the use of a modified version of the native, human CBS (hCBS) enzyme. The goal of treatment is to introduce the CBS enzyme into circulation, resulting in reduced Hcy levels, increased cystathionine (Cth) and cysteine (Cys) levels.

Study Overview

• Status: Active, not recruiting
• Conditions: Homocystinuria
• Intervention / Treatment: Drug: Pegtibatinase; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 32
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Culver City, California, United States, 90230
      • Travere Investigational Site - Virtual Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Travere Investigational Site
  • Florida
    • Miami, Florida, United States, 33136
      • Travere Investigational Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Travere Investigational Site
  • Maine
    • Portland, Maine, United States, 04102
      • Travere Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Travere Investigational Site
  • New York
    • New York, New York, United States, 10029
      • Travere Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Travere Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Confirmed diagnosis of homocystinuria based on genetic confirmation and plasma tHcy ≥50 micromoles and documentation of previous tHcy level ≥80 micromoles
• Willing and able to provide written, signed informed consent and to comply with all study related procedures.
• Subjects born biologically as female who are of child-bearing potential must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study. Subjects born biologically as male who identify as female and are not of childbearing potential are not required to undergo pregnancy tests
• Sexually active subjects who have childbearing potential or those who have partners of childbearing potential must be willing to use acceptable methods of contraception while on the study and for 4 weeks after the end of study
• Willing to maintain a stable diet with no significant modifications while on study and complete a daily diet diary.

Exclusion Criteria:

• Previous exposure to pegtibatinase and/or previous participation in a clinical trial that included administration of pegtibatinase
• Use of any investigational product or investigational medical device within 30 days prior to Screening, or while on study
• Use or planned use of any injectable drugs containing PEG (other than pegtibatinase or COVID-19 vaccines), including medroxyprogesterone (eg, Depo-Provera) injection, within 3 months prior to Screening and during study participation
• Known hypersensitivity to PEG-containing product or any components of pegtibatinase
• A positive test for HIV antibody, hepatitis B surface antigen, or hepatitis C antibody
• A history of organ transplantation, chronic immunosuppressive therapy, or substance abuse
• Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) or to breastfeed at any time during the study
• Concurrent disease or condition or planned major surgery that would interfere with study participation or safety in the opinion of the investigator.
• Any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study
• Major surgery planned during the study period

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Normal saline for subcutaneous injection
Active Comparator: Pegtibatinase	Drug: Pegtibatinase; Pegtibatinase sterile solution for subcutaneous injection; Other Names: TVT-058; OT-58; PEG modified CBS, PEG htCBS C15S, htCBS C15S ME-200GS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of AEs	Incidence of AEs (by type, severity and relationship to study drug)	Through double-blind study completion, approximately 10 months per patient
Anti-pegtibatinase antibodies	Presence and levels of anti-pegtibatinase antibodies in plasma as measured by antibody titers	Through double-blind study completion, approximately 10 months per patient
Anti-PEG antibodies	Presence and levels of anti-PEG antibodies in plasma as measured by antibody titers	Through double-blind study completion, approximately 10 months per patient

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in pegtibatinase levels	Changes in pegtibatinase levels following single and repeat administration at specified timepoints	Through double-blind study completion, approximately 10 months per patient
Changes in Met cycle metabolites levels - tHcy	Changes in total homocysteine levels in micromoles	Through double-blind study completion, approximately 10 months per patient
Changes in Met cycle metabolites levels - total Cys	Changes in total cysteine levels in micromoles	Through double-blind study completion, approximately 10 months per patient
Changes in Met cycle metabolites levels - Met	Changes in methionine levels in micromoles	Through double-blind study completion, approximately 10 months per patient
Changes in Met cycle metabolites levels - Cth	Changes in cystathionine levels in micromoles	Through double-blind study completion, approximately 10 months per patient
Changes in Met cycle metabolites levels - Phe	Changes in phenylalanine levels in micromoles	Through double-blind study completion, approximately 10 months per patient
Descriptive ophthalmology examination findings	Comprehensive ophthalmological examination (for each eye: visual acuity [myopia, hyperopia, exotropia], slit lamp examination [ectopic lentis, cataracts, corneal abrasion, and uveitis], retinal examination [retinal degeneration, retinal detachment, retinitis pigmentosa, uveitis)]). Assessment of presence and severity of findings.	Through double-blind study completion, approximately 10 months per patient
Bone densitometry using dual-energy X-ray absorptionmetry (DEXA) scans		Through double-blind study completion, approximately 10 months per patient
Cognitive assessments using the National Institutes of Health Toolbox Cognition Battery score		Through double-blind study completion, approximately 10 months per patient
Patient Reported Outcome (PRO): Quality of Life in Neurological Disorders [Neuro-QoL]	The Quality of Life in Neurological Disorders [Neuro-QoL] includes Anxiety Short Form, Depression Short Form, Satisfaction with Social Roles Short Form, Cognition Function Short Form for 18+ years of age; Anxiety Short Form, Depression Short Form, Social Relations - Interaction with Peers Short Form, and Cognitive Function Short Form for Ages 12 to 17 years old	Through double-blind study completion, approximately 10 months per patient
Patient Reported Outcome (PRO): Quality of Life by 36-Item Short Form Survey [SF-36]		Through double-blind study completion, approximately 10 months per patient
Patient Reported Outcome (PRO): Quality of Life by EuroQol 5-Dimentional Instrument [EQ 5D]		Through double-blind study completion, approximately 10 months per patient

Collaborators and Investigators

• Sponsor: Travere Therapeutics, Inc.
• Investigators: Study Director: Sagar A Vaidya, MD, PhD, Travere Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2019
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: December 5, 2017
• First Submitted That Met QC Criteria: January 15, 2018
• First Posted (Actual): January 23, 2018

Study Record Updates

• Last Update Posted (Actual): January 16, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

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: CBS-HCY-CT-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No