Study to evaluate the safety and efficacy of Cipaglucosidase Alfa and Miglustat in pediatric subjects with late-onset Pompe disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Amicus Therapeutics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

21 Mar 2024 → ongoing

Decision date (initial)

2023-10-24

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Amicus Therapeutics, Inc.

External identifiers

EU CT number

2022-502547-36-00

ClinicalTrials.gov

NCT03911505

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Pharmacodynamic, Efficacy

To evaluate the safety and tolerability of cipaglucosidase alfa/miglustat co-administration

Secondary objectives 6

1. To characterize the pharmacokinetics (PK) of cipaglucosidase alfa/miglustat for Cohort 1 and Cohort 2
2. To compare plasma cipaglucosidase alfa (total human acid α-glucosidase [GAA] protein by signature peptide T09)/plasma miglustat exposure in each pediatric age group to adult exposure and confirm or adjust the starting dose regimens that were originally simulated from adult exposures
3. To evaluate the effect of cipaglucosidase alfa/miglustat on efficacy
4. To evaluate the effect of cipaglucosidase alfa/miglustat on PD
5. To evaluate the effect of cipaglucosidase alfa exposure on efficacy and PD endpoints (exposure-response relationships)
6. To evaluate the effect of anti-rhGAA antibodies and immunogenicity on cipaglucosidase alfa exposure

Conditions and MedDRA coding

Late-onset Pompe disease

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002447-PIP01-18

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. (Cohort 1) Male or female subjects (ERT-naïve [have never received a dose of rhGAA] or ERT-experienced [have received rhGAA for at least 6 months immediately before enrollment, and if ERT dosage has been modified, must have been on the modified dosage for at least 3 months before enrollment]) diagnosed with LOPD who are aged 12 to < 18 years at screening.
2. 2. (Cohort 1) Subject weighs ≤ 115 kg.
3. 3. (Cohort 1) Subject has a sitting forced vital capacity (FVC) ≥ 30% of the predicted value for healthy adolescents (Global Lung Function Initiative) at screening
4. 4. (Cohort 1) Subject performs one 6-Minute Walk Test (6MWT) (≥ 75 meters) at screening that is valid, as determined by the clinical evaluator
5. 5. (Cohort 2) Male or female subjects (ERT-naïve [have never received a dose of rhGAA] or ERT-experienced [have received rhGAA for at least 6 months immediately before enrollment, and if ERT dosage has been modified, must have been on the modified dosage for at least 3 months before enrollment]) diagnosed with LOPD who are aged 0 months to < 12 years at screening
6. 6. (Cohort 2) Subjects aged ≥ 5 to < 12 years who perform one 6MWT (≥ 40 meters) at screening that is valid, as determined by the clinical evaluator
7. 7. (Cohort 1 & 2) Subject’s parent or legally authorized representative is willing and able to provide written informed consent and authorization for use and disclosure of personal health information or research-related health information, and subject provides assent, if applicable, based on site and local regulations.
8. 8. (Cohort 1 & 2) Subject must have a diagnosis of LOPD based on documentation of at least one of the following: a. deficiency of GAA enzyme b. gene encoding human acid α-glucosidase (GAA) genotyping
9. 9. (Cohort 1 & 2) If of reproductive potential and if sexually active, female and male subjects agree to use a highly effective method of contraception throughout the duration of the study and for up to 90 days after their last dose of cipaglucosidase alfa/miglustat

Exclusion criteria 13

1. 1. (Cohort 1 & 2) Subject has received any investigational/experimental drug, oral anabolic steroid or derivative, biologic, or device within 30 days or 5 half-lives of the therapy or treatment, whichever is longer, before screening
2. 8. (Cohort 1) Subject has moderate to severe hypertrophic cardiomyopathy aligning with classic IOPD
3. 9. (Cohort 1 & 2) In the opinion of the investigator, the parent or legally authorized representative is unlikely or unable to comply with the study requirements
4. 12. (Cohort 1 & 2) Subject has been placed in an institution by court or official order.
5. 10. (Cohort 1 & 2) Subject has any prior history of illness or condition known to affect motor function, such as, but not limited to, eg. Guillain-Barre syndrome, cerebral palsy
6. 11. (Cohort 2) Subject is asymptomatic (ie, showing no signs and symptoms of Pompe disease)
7. 2. (Cohort 1 & 2) Subject has received treatment with prohibited medications within 30 days of screening
8. 3. (Cohort 1 & 2) Subject has received any gene therapy at any time
9. 4. (Cohort 1 & 2) 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
10. 5. (Cohort 1 & 2) Subject has 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.
11. 6. (Cohort 1 & 2) Female subject is pregnant or breast-feeding at screening
12. 7. (Cohort 1 & 2) Subject requires the use of ventilation support for > 6 hours per day while awake
13. 12. (Cohort 2) Subject has clinical presentation of classic IOPD (ie, GAA enzyme activity less than 1% of normal).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. 1. Incidence of treatment-emergent AEs, SAEs, IARs, and AEs leading to discontinuation of study drug
2. 2. Change in anti-rhGAA antibody titers (total and neutralizing) from baseline over time
3. 3. Change in clinical laboratory test results from baseline over time
4. 4. Change in vital signs from baseline over time
5. 5. Change in 12-lead ECG values from baseline over time

Secondary endpoints 24

1. 1. AUC: area under the plasma drug concentration-time curve
2. 2. Cmax: maximum observed concentration obtained directly from the concentration profile
3. 3. (Cohort 1) Change from baseline to Week 52 in the following variables related to ambulatory function: − 6MWD (distance walked, in meters, in the 6MWT) − 6MWD (% predicted)
4. 4. (Cohort 1) Change from baseline to Week 52 in the following variables related to motor function: − total score of the Gait, Stairs, Gowers’ maneuver, and Chair (GSGC) test − time to complete the 10-meter walk (ie, assessment of gait) of the GSGC test − time to complete the 4-stair climb of the GSGC test − time to complete the Gowers’ maneuver of the GSGC test − time to arise from a chair as part of the GSGC test − time to complete the TUG test − total and subdomain scores for the GMFM-88
5. 5. (Cohort 1) Time to initiation of use of assistive device
6. 6. (Cohort 1) Change from baseline to Week 52 in the following variables related to muscle strength: − MMT score for the lower and upper extremities − MMT total score
7. 7. (Cohort 1) Change from baseline to Week 52 in the following measures of pulmonary function: − FVC sitting (% predicted) − SVC sitting (% predicted) − maximal inspiratory pressure (MIP) (cmH2O) − MIP (% predicted) − maximal expiratory pressure (MEP) (cmH2O) − MEP (% predicted) − ventilator use (hours per day)
8. 8. (Cohort 1) Ventilator independence (for non ventilator-dependent subjects only)
9. 9. (Cohort 1) CPAP/BiPAP use
10. 10. (Cohort 1) Change from baseline to Week 52 in the following variables from PRO measures: − score for NeuroQOL Pediatric Lower Extremity Function (Mobility)
11. 11. (Cohort 1) Actual value of the subject’s functional status (improving, stable, or declining) pertaining to the effects of study drug in the following areas of life, as measured by the SGIC as reported by the subject or subject’s caregiver: − overall physical well-being − effort of breathing − muscle strength − muscle function − ability to move around − activities of daily living − energy level − level of muscular pain
12. 12. (Cohort 1) Actual value of the subject’s functional status (improving, stable, or declining), as measured by the PGIC
13. 13. (Cohort 2) Change from baseline to Week 52 in the following variables related to ambulatory function (for subjects ≥ 5 years of age) − 6MWD (distance walked, in meters, in the 6MWT) − 6MWD (% predicted)
14. 14. (Cohort 2) Change from baseline to Week 52 in the following variables related to motor function: − total score for the AIMS (for subjects ≤ 18 months of age) − total and subdomain scores for the GMFM-88 (for subjects ≥ 5 months of age)
15. 15. (Cohort 2) Time to initiation of use of assistive device
16. 16. (Cohort 2) Change from baseline to Week 52 in the following variables related to muscle strength (for subjects ≥ 4 years of age) − MMT score for the lower and upper extremities and neck − MMT total score
17. 17. (Cohort 2) Change from baseline to Week 52 in the following measures of pulmonary function (for subjects ≥ 5 years of age): − FVC sitting (% predicted) − SVC sitting (% predicted) − MIP (cmH2O) − MIP (% predicted) − MEP (cmH2O) − MEP (% predicted) − ventilator use (hours per day)
18. 18. (Cohort 2) Ventilator independence (for non-ventilator dependent subjects only)
19. 19. (Cohort 2) CPAP/BiPAP use
20. 20. (Cohort 2) Change from baseline to Week 52 in the following variables from patient-reported outcomes (PRO) measures: − score for NeuroQOL Pediatric Lower Extremity Function (Mobility)
21. 21. (Cohort 2) Actual value of the subject’s functional status (improving, stable, or declining) pertaining to the effects of study drug in the following areas of life, as measured by the SGIC as reported by the subject or subject’s caregiver: − overall physical well-being − effort of breathing − muscle strength − muscle function − ability to move around − activities of daily living − energy level − level of muscular pain
22. 22. (Cohort 2) Actual value of the subject’s functional status (improving, stable, or declining), as measured by the PGIC
23. 23. Change from baseline to Week 52 in the following PD variables: − serum CK level − urinary Hex4 level
24. 24. Immunogenicity endpoints are as follows for both cohorts: Total and neutralizing anti-rhGAA antibodies

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Amicus Therapeutics Inc.

Sponsor organisation

Amicus Therapeutics Inc.

Address

47 Hulfish Street

City

Princeton

Postcode

08542-3713

Country

United States

Scientific contact point

Organisation

Amicus Therapeutics Inc.

Contact name

Amicus Patient Advocacy

Public contact point

Organisation

Amicus Therapeutics Inc.

Contact name

Amicus Patient Advocacy

Third parties 10

Locations

2 EU/EEA countries · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 78 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications