| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pompe Disease - acid maltase deficiency or glycogen storage disease type II. |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036143 |
| E.1.2 | Term | Pompe's disease |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the safety and tolerability of single-ascending doses of
intravenously (IV) infused ATB200.
To evaluate the safety and tolerability of single-ascending doses of IV infused ATB200 as a fixed dose, co-administered with ascending oral doses of AT2221.
To characterize the pharmacokinetics (PK) of single-ascending doses of IV infused ATB200.
To characterize the single- and multiple-dose PK of IV infused 20 mg/kg ATB200 when co-administered with oral 130 mg or 260 mg AT2221.
To characterize the PK of single- and multiple-oral doses of 130 mg or 260 mg AT2221 when co-administered with IV infused ATB200. |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate the long-term efficacy of 20mg/kg of IV infused ATB200 as a fixed dose co-administered with oral 260mg AT2221 in all subjects from Stage 3
Evaluate the long-term safety & tolerability of 20 mg/kg of IV infused ATB200 as a fixed dose co-administered with oral 260mg AT2221 in all subjects from Stage 3
Characterize single & multiple dose PK of plasma rhGAA activity & total rhGAA protein following IV infused 20mg/kg ATB200 as a fixed dose coadministered with oral 260mg AT2221 in ERT-naïve subjects
Characterize the single- & multiple-dose PK of plasma AT2221 following 20mg/kg of IV infused ATB200 co-administered with oral 260 mg AT2221 in ERT-naïve subjects
Exploratory
Anti-rhGAA antibody titersantibodies (total and neutralizing)
Cross-reactivity of anti-rhGAA antibodies to alglucosidase alfa
Pro-inflammatory cytokines and other biomarkers of immune system activation
PD markers
Impact of anti-rhGAA antibodies on plasma GAA total protein exposures |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Cohort 1:
1. Male and female subjects between 18 and 65 years of age, inclusive.
2. Subject must provide signed informed consent prior to any study-related procedures.
3. Subjects of childbearing potential must agree to use medically accepted methods of contraception during the study and for 90 days after last co-administration of ATB200 and AT2221.
4. Subject has a diagnosis of Pompe disease based on documented deficiency of GAA enzyme activity or by GAA genotyping.
5. Subject has received ERT with alglucosidase alfa (myozyme/lumizyme) for the previous 2 to 6 years inclusive.
6. Subject is currently receiving alglucosidase alfa (myozyme/lumizyme) at a frequency of once every other week.
7. Subject has received and completed the last two infusions without a drug-related adverse event resulting in dose interruption.
8. Subject must be able to walk 200 and 500 meters on the 6MWT.
9. Upright FVC must be 30% to 80% of predicted normal value.
Cohort 2:
10. Male and female subjects between 18 and 65 years of age, inclusive.
11. Subject must provide signed informed consent prior to any study-related procedures.
12. Subjects of childbearing potential must agree to use medically accepted methods of contraception during the study and for 90 days after last co-administration of ATB200 and AT2221.
13. Subject has a diagnosis of Pompe disease based on documented deficiency of GAA enzyme activity or by GAA genotyping.
14. Subject has received ERT with alglucosidase alfa (myozyme/lumizyme) for ≥2 years.
15. Subject is currently receiving alglucosidase alfa (myozyme/lumizyme) at a regular or set frequency.
16. Subject has received and completed the last two infusions without a drug-related adverse event resulting in dose interruption.
17. Subject must be completely wheelchair-bound and unable to walk unassisted.
Cohort 3:
18. Male and female subjects between 18 and 65 years of age, inclusive.
19. Subject must provide signed informed consent prior to any study related procedures.
20. Subjects of childbearing potential must agree to use medically accepted methods of contraception during the study and for 90 days after last coadministration of ATB200 and AT2221.
21. Subject has a diagnosis of Pompe disease based on documented deficiency of GAA enzyme activity or by GAA genotyping.
22. Subject must be able to walk between 200 to 500 meters on the 6MWT.
23. Upright FVC must be 30% to 80% of predicted normal value.
Cohort 4:
24. Male and female subjects between 18 and 75 years of age, inclusive
25. Subject must provide signed informed consent prior to any study related procedures
26. Subject has documented 6MWT on three separate occasions, each at least six months apart with at least two values in the past three years
27. Subjects of childbearing potential must agree to use medically accepted methods of contraception during the study and for 90 days after last co-administration of ATB200 and AT2221
28. Subject has a diagnosis of Pompe disease based on documented deficiency of GAA enzyme activity or by GAA genotyping
29. Subject has received ERT for the previous ≥ 7 years
30. Subject is currently receiving alglucosidase alfa (Myozyme/Lumizyme) at a frequency of once every other week
31. Subject has received and completed the last 2 infusions without a drug-related AE resulting in dose interruption
32. Subject must be able to walk between 75 and 600 meters on the 6MWT
33. Upright FVC must be 30% to 85% of predicted normal value |
|
| E.4 | Principal exclusion criteria |
Cohort 1, 2, 3, 4:
- Subject has received treatment with prohibited medications within 30 days or 5 half lifes of the therapy treatment, whichever is longer prior to the Baseline Visit.
- Subject, if female, is pregnant or breastfeeding at screening.
- Subject, whether male or female, is planning to conceive a child during the study.
- Subject has a medical or any other extenuating condition or circumstance that may, in the opinion of the investigator or the medical monitor, pose an undue safety risk to the subject or compromise his/her ability to comply with
protocol requirements.
- Subject has a history of allergy or sensitivity to miglustat or other iminosugars.
- Subject with active bronchial asthma. All subjects with autoimmune disease must be discussed with the Amicus Medical Monitor.
- Subject with active systemic autoimmune disease such as lupus, scleroderma, or rheumatoid arthritis. All subjects with autoimmune disease must be discussed with the Amicus Medical Monitor.
Cohort 1:
- Subject requires invasive ventilatory support.
- Subject uses noninvasive ventilatory support ≥6 hours a day while awake.
- Subject has a history of anaphylaxis to alglucosidase alfa.
- Subject has a history of high sustained anti-rhGAA antibodies.
-Subject has received any investigational therapy including adjunctive therapy for Pompe disease, other than alglucosidase alfa within 30 days prior to the Baseline Visit, or anticipates doing so during the study.
Cohort 2:
- Subject has a history of anaphylaxis to alglucosidase alfa.
- Subject has a history of high sustained anti-rhGAA antibodies.
-Subject has received any investigational therapy including adjunctive therapy for Pompe disease, other than alglucosidase alfa within 30 days prior to the Baseline Visit, or anticipates doing so during the study.
Cohort 3
- Subject has received any enzyme replacement therapy, including alglucosidase alfa at any time, or any investigational therapy for Pompe disease within 30 days prior to the Baseline Visit, or anticipates doing so
during the study.
- Subject requires invasive ventilatory support.
- Subject uses noninvasive ventilatory support ≥6 hours a day while awake.
Cohort 4
- Subject requires invasive ventilatory support.
- Subject uses noninvasive ventilatory support ≥ 6 hours a day while awake.
- Subject has a history of anaphylaxis to alglucosidase alfa.
- Subject has a history of high sustained anti-rhGAA antibodies.
Subject has received any investigational therapy including adjunctive therapy for Pompe disease, other than alglucosidase alfa within 30 days prior to the Baseline Visit, or anticipates doing so during the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety:
Identification and counts of treatment-emergent SAEs, including IARs
Changes from baseline in 12-lead ECG
Changes from baseline in clinical safety laboratory evaluations: serum chemistry, hematology, and urinalysis
Changes from baseline in PEs
Changes from baseline in vital signs
Changes from baseline in serum CK
PK for subjects from Cohort 1:
Plasma GAA activity levels and total GAA protein concentration PK parameters: Cmax, tmax, AUC0-t, AUC0-∞, t½, Vss and CLT for each dose level
Stage 1: Ratios of plasma GAA activity levels and total GAA protein concentration Cmax,
AUC0-t, and AUC0-∞ for 20 mg/kg versus 5 mg/kg, 20 mg/kg versus 10 mg/kg, and 10 mg/kg versus 5 mg/kg
Stage 2: Ratios of plasma GAA activity levels and total GAA protein concentration Cmax,
AUC0-t, and AUC0-∞ for 20 mg/kg ATB200 (from Stage 1) versus single-dose 20 mg/kg ATB200 + 130 mg AT2221, and versus single-dose 20 mg/kg ATB200 + 260 mg AT2221
Stage 2: Ratios of plasma GAA activity levels and total GAA protein concentration, Cmax,
AUC0-t, and AUC0-∞ for 20 mg/kg ATB200 + 130 mg AT2221 single-dose versus multiple-dose, and 20 mg/kg ATB200 + 260 mg AT2221
single-dose versus multiple-dose
Plasma AT2221 PK parameters: Cmax, tmax, AUC0-t, AUC0-∞, t½,
CLT/F, and Vz/F for each dose level
Ratios of plasma AT2221 Cmax, AUC0-t, and AUC0-∞ for 260 mg single-dose versus 130 mg single-dose, and for 260 mg multiple-dose versus 130 mg multiple-dose |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Exploratory Endpoints:
- Anti-rhGAA antibody titers (total and neutralizing).
- Cross-reactivity of anti-rhGAA antibodies to alglucosidase alfa.
- Pro-inflammatory cytokines and other biomarkers of immune system activation.
- PD biomarkers: urinary Hex4 and serum CPK levels.
- Evaluation of anti-rhGAA antibody impact on AUC and CLT after at least 18 months of ATB200/AT2221 treatment as compared to AUC and CLT after the first and third doses of 20 mg/kg ATB200 + 260 mg AT2221. |
|
| E.5.2 | Secondary end point(s) |
Functional:
• For ambulatory subjects: change and percent change from Baseline in Gower's Maneuver, 4-stair-climb, 6MWT, 10MWT, GSGC score, TUG, muscle strength tests (MRC and hand-held dynamometer [for both upper and lower limbs]), and pulmonary function tests (FVC, MIP, MEP, and SNIP [for subjects without invasive ventilatory support]).
• For nonambulatory subjects: change and percent change from Baseline in muscle strength tests (MRC and hand-held dynamometer [upper limbs only]) and pulmonary function tests (FVC,
MIP, MEP, and SNIP [for subjects without invasive ventilatory support])
Patient-Reported Outcomes:
• Change and percent change from Baseline to 6 months in FSS, RHS, and R-PAct Scale.
Impression of Change:
• PGIC and SGIC
PK parameters for subjects from Cohort 1 and 3:
• Plasma GAA activity levels and total GAA protein concentration PK parameters: Cmax, tmax, AUC0-t, AUC0-∞, t½, and Vss.
• Plasma GAA activity levels and total GAA protein concentration ratios for Cmax, AUC0-t, and AUC0-∞ for single-dose versus multiple-dose
• Plasma AT2221 PK parameters: Cmax, tmax, AUC0-t, AUC0-∞, t½, CLT/F, and Vz/F.
• Plasma AT2221 Cmax, AUC0-t, and AUC0-∞ ratios for single-dose versus multiple-dose.
• Single-dose plasma GAA activity levels, total protein concentration and AT2221 Cmax, AUC0-t, and AUC0-∞ ratios for subjects from Cohort 3 versus subjects from Cohort 1 following 20 mg/kg ATB200 alone, 20 mg/kg ATB200 + 130 mg AT2221 single-dose, and 20 mg/kg ATB200 + 260 mg AT2221 single-dose.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| New Zealand |
| Australia |
| United Kingdom |
| United States |
| Germany |
| Netherlands |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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