Phase 1/2 Study of Subcutaneous Pegtibatinase (TVT‑058) for Safety, Tolerability, PK/PD and Clinical Outcomes in Patients with Classical Homocystinuria (COMPOSE)
- Trial ID
- 2023-509074-31-00
- Protocol
- CBS-HCY-CT-01
Trial statistics
Diseases & Conditions
Objectives
Primary objective: determine the dose‑related safety and tolerability of subcutaneous pegtibatinase in participants with classical homocystinuria; in the pediatric cohort, safety, tolerability, and immunogenicity are evaluated to support clinical risk assessment.
Secondary objectives:
- Define pharmacokinetic exposure parameters after single and repeat dosing in the double‑blind cohorts.
- Quantify pharmacodynamic changes in methionine‑cycle metabolites (plasma total homocysteine, methionine, cystathionine) following treatment.
- Examine effects on clinical outcomes, including ophthalmologic, skeletal, neurologic/psychiatric, and cognitive assessments.
- In the pediatric open‑label cohort, characterize pharmacokinetic profiles and pharmacodynamic effects on plasma total homocysteine and methionine.
Participants
The trial enrolled nine participants diagnosed with Classical Homocystinuria. Eligible individuals were aged between 5 and 65 years, encompassing both female and male subjects. Inclusion required confirmation of the disorder by CBS gene mutation analysis and a plasma total homocysteine concentration of at least 50 µM at screening, with historical values ≥ 80 µM for adult cohorts. Participants were required to be in generally stable health, able to comply with study procedures, and were classified as vulnerable under the protocol. The cohort composition included pediatric subjects (5–<12 years) and adult participants (≥12 years), reflecting the age spectrum defined in the study design.
Plans and Procedures
The study is a Phase 1/2, multicenter, randomized, double‑blind, placebo‑controlled trial evaluating subcutaneous Pegtibatinase in participants with classical homocystinuria. After an eligibility screening visit confirming genetic diagnosis and plasma total homocysteine ≥50 µM, participants are randomized to receive escalating doses of Pegtibatinase or matching placebo during a double‑blind treatment period (cohorts 1‑6) followed by an open‑label extension; a separate open‑label pediatric cohort (cohort 7) enrolls children 5–<12 years. Study visits occur at screening, baseline (first dose), regular follow‑up visits (e.g., weeks 2, 4, 8, 12 and monthly thereafter) to assess safety, tolerability, pharmacokinetics, pharmacodynamics and clinical outcomes, and a final end‑of‑study visit after the last dose. Participant involvement therefore extends from the screening visit through the end‑of‑study assessment, lasting approximately 12 months. Early termination may occur for predefined reasons such as serious adverse events, unacceptable toxicity, withdrawal of consent, or non‑compliance with protocol procedures.
Treatment
The investigational product, pegtibatinase, is supplied as a lyophilized powder for solution for injection and is administered by subcutaneous injection. The formulation is reconstituted according to the study protocol and delivered subcutaneously at a dose and frequency defined by the dose‑escalation schedule for each cohort. Pegtibatinase is designated as an orphan drug for the treatment of cystathionine betasynthase‑deficient homocystinuria.
Administration of pegtibatinase follows a predefined dosing regimen, with each injection performed under controlled conditions. Participants receive the study drug at intervals specified in the protocol, and compliance is monitored through injection logs, site‑recorded administration times, and periodic assessment of drug levels where applicable. All dosing and monitoring procedures are conducted in accordance with Good Clinical Practice guidelines.
Efficacy
Efficacy will be assessed through predefined secondary endpoints. Clinical efficacy endpoints comprise ophthalmologic examinations, bone densitometry, cognitive assessments, patient‑reported outcomes and quality‑of‑life questionnaires. Plasma biomarkers, including total homocysteine (tHcy), methionine, methionine‑cycle metabolites and phenylalanine, will be measured and changes from baseline will be calculated.
Ophthalmologic evaluation will use standardized retinal imaging and visual acuity testing. Bone densitometry will be performed with dual‑energy X‑ray absorptiometry (DXA). Cognitive function will be assessed using validated neuropsychological test batteries. Patient‑reported outcomes and quality‑of‑life will be captured with validated questionnaires administered at baseline, during the double‑blind period (e.g., week 4, week 12) and at the end of treatment. Blood samples for biomarker analysis will be collected at baseline, after single administration, and at scheduled intervals throughout repeat dosing; concentrations will be quantified using validated laboratory assays.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Double-blind Treatment Period (Cohorts 1-6): 1. A diagnosis of HCU with the following: 1.1. Confirmation of genetic HCU by mutation analysis of CBS gene AND 1.2. Plasma tHcy ≥50 µM at Screening, confirmed by retest as appropriate AND documentation of previous plasma tHcy level ≥80 µM; 2. At the screening visit, ≥12 and ≤65 years of age (participants must be ≥18 years old to be eligible for Cohort 1); 3. Willing and able to comply, as assessed by the Investigator, with all study related procedures.
- OLE Period (Cohorts 1-6): A participant must have participated in 1 of the double-blind treatment cohorts (1 through 6) and continue to meet the above main study criteria.
- Pediatric Open-label Treatment Period (Cohort 7): 1. Participants must be ≥5 and <12 years of age, at the time of signing the informed consent/assent; 2. Participants must have a diagnosis of HCU based on clinical, biochemical, and/or molecular genetic testing; 3. Plasma tHcy ≥50 µM at Screening; 4. Willing and able to comply, as assessed by the Investigator, with all study-related procedures.
Exclusion Criteria
- Double-blind Treatment Period (Cohorts 1-6): 1. Previous exposure to pegtibatinase and/or previous participation in a clinical trial that included administration of pegtibatinase; 2. Use or planned use of any injectable drugs containing PEG (other than pegtibatinase or coronavirus disease 2019 [COVID-19] vaccines), including medroxyprogesterone (eg, Depo-Provera) injection, within 3 months prior to Screening and during study participation; 3. A prior reaction that included systemic symptoms (eg, abnormal respiratory or gastrointestinal signs or symptoms, fever, hypotension, angioedema, or anaphylaxis) to a PEG-containing product; 4. Known hypersensitivity to any components of pegtibatinase; 5. A history of organ transplantation or of chronic immunosuppressive therapy; 6. Concurrent disease or condition (eg, history or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurological, oncologic, or psychiatric disease) that would interfere with study participation or safety (excluding complications of HCU).
- OLE Period (Cohorts 1-6): 1. The participant developed an intolerance to the study drug.
- Pediatric Open -label Treatment Period (Cohort 7): 1. Diagnosis of Marfan syndrome, methylenetetrahydrofolate reductase (MTHFR) deficiency, or disorder of cobalamin metabolism, based on clinical, biochemical, and/or molecular genetic testing. 2. Concurrent disease or condition (eg, history or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurological, oncologic, or psychiatric disease) that would interfere with study participation or safety (excluding complications of HCU); 3. Body weight <15 kg; 4. Use or planned use of any injectable drugs containing PEG (other than pegtibatinase and PEG-containing vaccines), including medroxyprogesterone (eg, Depo-Provera) injection, within 3 months prior to Screening and during study participation; 5. Previous exposure to pegtibatinase and/or previous participation in a clinical trial that included administration of pegtibatinase or pegtarviliase. Participants may be consented to the ENSEMBLE study prior to COMPOSE study completion to ensure continuity of study drug between the 2 studies; 6. A prior severe immune reaction that included systemic symptoms (eg, abnormal respiratory or gastrointestinal signs or symptoms, fever, hypotension, angioedema, or anaphylaxis) to a PEG-containing product; 7. Known hypersensitivity to any components of pegtibatinase; 8. A history of organ transplantation or severe chronic immunosuppressive therapy during the last 6 months prior to Screening.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 01 Sept 2026 | 6 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Pegtibatinase | Test | LYOPHILIZED POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | — | — | PRD11410845 |