An Open-label Study to Evaluate the Safety, Efficacy, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Cipaglucosidase Alfa/Miglustat in Both ERT-experienced and ERT-naïve Pediatric Subjects with Infantile-onset Pompe Disease Aged 0 to <18 Years
- Trial ID
- 2022-501095-25-01
- Protocol
- ATB200-08
- Sponsor
- Amicus Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of the co-administration of cipaglucosidase alfa/miglustat in enzyme replacement therapy (ERT)-experienced subjects with infantile-onset Pompe disease (IOPD) aged 6 months to less than 18 years, and in ERT-naïve subjects with IOPD aged 0 to less than 6 months. This is clinically relevant as it aims to ensure that the treatment regimen is safe for pediatric patients, which is crucial for the management of IOPD, a severe and progressive condition.
Secondary objectives include:
- Evaluating the efficacy of the co-administration of cipaglucosidase alfa/miglustat in ERT-experienced subjects with IOPD aged 6 months to less than 18 years and in ERT-naïve subjects with IOPD aged 0 to less than 6 months.
Participants
The clinical trial involves a total of **21 participants** diagnosed with **infantile-onset Pompe disease**. The study population includes both male and female subjects, with an age range from **0 to < 18 years**. Participants are divided into two cohorts: Cohort 1 consists of subjects aged **6 months to < 18 years** who have prior experience with enzyme replacement therapy (ERT), while Cohort 2 includes ERT-naïve subjects aged **0 to < 6 months**. The selection of participants was based on specific genetic documentation and clinical criteria, including the presence of hypertrophic cardiomyopathy at diagnosis. The trial population is considered vulnerable due to the pediatric nature of the participants. Lifestyle considerations such as diet and physical activity are not specified in the available data. The study aims to evaluate the safety and tolerability of co-administration of cipaglucosidase alfa/miglustat in these subjects.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and tolerability of co-administration of **cipaglucosidase alfa** and **miglustat** in pediatric subjects with infantile-onset Pompe disease. This study is an open-label, Phase III trial involving both enzyme replacement therapy (ERT)-experienced subjects aged 6 months to less than 18 years and ERT-naïve subjects aged 0 to less than 6 months. The trial will assess the primary endpoint of the proportion of subjects experiencing infusion-associated reactions, with secondary endpoints including the incidence of treatment-emergent adverse events, changes in clinical laboratory test results, vital signs, 12-lead ECG results, and echocardiogram parameters.
The trial is expected to last for a total of 104 weeks, with participant involvement beginning from the screening visit and continuing through the end-of-study visit. The sequence of study visits includes an initial screening visit to confirm eligibility based on inclusion criteria such as age, genetic documentation, and previous ERT experience. Following the screening, participants will undergo regular follow-up visits to monitor safety and efficacy outcomes. The end-of-study visit will conclude the participant's involvement, assessing the overall impact of the treatment regimen.
Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include significant safety concerns or adverse reactions that warrant discontinuation of the study drug. The trial is structured to ensure rigorous monitoring and data collection throughout the study period, with the aim of providing comprehensive insights into the treatment's impact on the target population.
Treatment
The clinical trial involves the administration of **cipaglucosidase alfa**, marketed under the name ATB200, which is provided as a **lyophilized powder for preparation for injection**. This experimental medication is administered via **intravenous infusion**. The dosing regimen for cipaglucosidase alfa is set at a maximum daily dose of 30 mg/kg, with a total treatment period extending up to 104 weeks. The formulation is not specifically designed for pediatric use, although it is being tested in a pediatric population. The active substance, cipaglucosidase alfa, is a protein of non-standard origin, developed by Amicus Therapeutics, and holds an orphan drug designation under the number EU/3/18/2000.
In conjunction with cipaglucosidase alfa, the trial also includes the administration of **miglustat**, known as AT2221, which is provided in the form of **hard gelatin capsules**. Miglustat is administered orally, with a maximum daily dose of 260 mg, and the treatment duration is also set for up to 104 weeks. This compound is of chemical origin and is also developed by Amicus Therapeutics. Miglustat holds an orphan drug designation under the number EU/3/18/2129. The trial aims to evaluate the safety and efficacy of the co-administration of these two substances in subjects with infantile-onset Pompe disease, both those who have previously received enzyme replacement therapy (ERT) and those who are ERT-naïve.
Efficacy
The efficacy of the clinical trial evaluating the co-administration of **cipaglucosidase alfa** and miglustat in pediatric subjects with infantile-onset Pompe disease will be assessed through several endpoints. The primary endpoint focuses on the proportion of subjects experiencing infusion-associated reactions (IARs). Secondary endpoints include the incidence of treatment-emergent adverse events (TEAEs), such as treatment-emergent serious adverse events (TESAEs), hypersensitivity or anaphylactic reactions, and TEAEs leading to discontinuation of the study drug. Additionally, changes in clinical laboratory test results, vital signs, 12-lead ECG results, and echocardiogram parameters (excluding left ventricle mass index) will be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Cohort 1: 1. Male or female subjects who are aged 6 months to < 18 years on Day 1.
- Cohort 1: 2. Subject's parent or legally authorized representative is willing and able to provide written informed consent and authorization for study participation and use and disclosure of personal health information or research-related health information.
- Cohort 1: 3. Subject must have documentation of bi-allelic gene encoding human acid α-glucosidase (GAA) variants prior to initiation of study drug.
- Cohort 1: 4. Subject must have had hypertrophic cardiomyopathy at the time of diagnosis defined as: • > 1 standard deviation above the mean age-specific left ventricle mass index (LVMI) for subjects diagnosed by newborn screening or sibling screening • > 2 standard deviations above the mean age-specific LVMI for subjects diagnosed by clinical evaluation
- Cohort 1: 5. Subject must have received ERT for at least 6 months immediately before enrollment. For subjects whose ERT dosage has been modified, the subject must have been on the modified dosage and regimen for at least 3 months before enrollment.
- Cohort 1: 6. Subject must have experienced a clinical decline based on the protocol-specified criteria on their current rhGAA dose and frequency.
- Cohort 1: 7. If of reproductive potential and sexually active, female and male subjects must agree to use a highly effective method of contraception throughout the duration of the study and for at least 90 days after their last dose of cipaglucosidase alfa/miglustat.
- Cohort 1: 8. For subjects aged ≥ 12 to < 18 years, subject must perform one 6-minute walk test (6MWT) (≥ 75 meters) at screening that is valid, as determined by the clinical evaluator; for subjects aged ≥ 5 to < 12 years, subject must perform one 6MWT (≥ 40 meters) at screening that is valid, as determined by the clinical evaluator. Subjects aged 18 months to < 5 years must be ambulatory and in the opinion of the investigator assessed to be likely to be able to perform 6MWT (≥ 40 meters) when they turn 5 years old.
- Cohort 2: 1. Male or female subjects who are aged 0 to < 6 months at on Day 1.
- Cohort 2: 2. Subject’s parent or legally authorized representative is willing and able to provide written informed consent and authorization for study participation and use and disclosure of personal health information or research-related health information.
- Cohort 2: 3. Subject must have documentation of bi-allelic gene encoding human acid α-glucosidase (GAA) variants prior to initiation of study drug.
- Cohort 2: 4. Subject must have had hypertrophic cardiomyopathy at the time of diagnosis defined as: • > 1 standard deviation above the mean age-specific LVMI for subjects diagnosed by newborn screening or sibling screening • > 2 standard deviations above the mean age-specific LVMI for subjects diagnosed by clinical evaluation
- Cohort 2: 5. Subject is ERT-naïve (having had no prior ERT-treatment).
- Long-term Extension (Cohort 1 or Cohort 2) Inclusion Criteria: 1. Subject must have, in the opinion of the investigator, benefitted from therapy with cipaglucosidase alfa/miglustat during the 104-week primary treatment period (Stage 1) with no significant safety concerns.
Exclusion Criteria
- Cohort 1: 1. Subject requires invasive ventilation (eg, tracheostomy).
- Cohort 1: 2. Subject requires respiratory assistance for ≥ 16 hours per day (including noninvasive ventilator support) continuously for ≥ 14 days in the absence of an acute reversible illness, excluding perioperative ventilation.
- Cohort 1: 3. Subject received any investigational drug or any investigational biologic for Pompe disease within 30 days or 5 half-lives of the therapy or treatment, whichever is longer, before screening.
- Cohort 1: 4. Subject is CRIM-negative and has not received prophylactic immunomodulation.
- cohort 1: 5. Subject has received any gene therapy within the past 3 years.
- Cohort 1: 6. Subject has any intercurrent illness or condition at screening or baseline that may preclude the subject from fulfilling the protocol requirements or suggests to the investigator and/or the medical monitor that the potential subject may have an unacceptable risk by participating in this study.
- Cohort 1: 7. Subject has any prior history of illness or condition known to affect motor function, such as, but not limited to, Guillain Barre syndrome, cerebral palsy, etc.
- Cohort 1: 8. Subject has a history of life-threatening infusion-associated reactions (IARs)/hypersensitivity (eg, anaphylaxis and severe cutaneous reactions) to ERT (eg, alglucosidase alfa, cipaglucosidase alfa), miglustat, or other iminosugars, or to any of the excipients, where rechallenge was unsuccessful.
- Cohort 1: 9. Female subject is pregnant (or intends to get pregnant) or breastfeeding at screening.
- Cohort 1: 10. In the opinion of the investigator, the parent or legally authorized representative is unlikely or unable to comply with the study requirements.
- Cohort 2: 1. Subject requires invasive ventilation (eg, tracheostomy).
- Cohort 2: 2. Subject requires respiratory assistance for ≥ 16 hours per day (including noninvasive ventilator support) continuously for ≥ 14 days in the absence of an acute reversible illness, excluding perioperative ventilation.
- Cohort 2: 3. Subject received any investigational drug or any investigational biologic for Pompe disease within 30 days or 5 half-lives of the therapy or treatment, whichever is longer, before screening.
- Cohort 2: 4. Subject is CRIM-negative and will not be receiving prophylactic immunomodulation.
- Cohort 2: 5. Subject has received any gene therapy at any time.
- Cohort 2: 6. Subject has any intercurrent illness or condition at screening or baseline that may preclude the subject from fulfilling the protocol requirements or suggests to the investigator and/or the medical monitor that the potential subject may have an unacceptable risk by participating in this study.
- Cohort 2: 7. Subject has any prior history of illness or condition known to affect motor function, such as, but not limited to, Guillain Barre syndrome, cerebral palsy, etc.
- Cohort 2: 8. Subject has a history of life-threatening IARs/hypersensitivity (eg, anaphylaxis and severe cutaneous reactions) to ERT (eg, alglucosidase alfa, cipaglucosidase alfa), miglustat, or other iminosugars, or to any of the excipients, where rechallenge was unsuccessful.
- Cohort 2: 9. In the opinion of the investigator, the parent or legally authorized representative is unlikely or unable to comply with the study requirements.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Recruiting | 01 Aug 2024 | 1 |
 France | Not Recruiting | 01 Aug 2024 | 3 |
 Germany | Recruiting | 01 Aug 2024 | 6 |
 Italy | Recruiting | 01 Aug 2024 | 3 |
 The Netherlands | Recruiting | 01 Aug 2024 | — |
| Netherlands | — | — | 3 |
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 |
|---|---|---|---|---|---|---|
Miglustat Oral Solution 40 mg/mL | Test | ORAL SOLUTION | ORAL | 260 | 208 | PRD12764428 |
AT2221 | Test | HARD GELATIN CAPSULE | ORAL USE | 260 | 104 | PRD3970603 |
ATB200 | Test | LYOPHILIZED POWDER FOR PREPARATION FOR INJECTION (8) | INTRAVENOUS INFUSION | 30 | 104 | PRD3833422 |