Study to Evaluate the Safety of AT2220 (Duvoglustat) in Pompe Disease

Phase 2

Terminated

Brief Summary: The main purpose of this study was to determine the safety and tolerability of 3 different doses of duvoglustat (AT2220) in participants affected by Pompe disease. The study also evaluated the effects of duvoglustat on functional parameters in Pompe disease.

Detailed Description: This was a Phase 2, open-label study in participants with Pompe disease, a lysosomal storage disorder. Duvoglustat is designed to act as a pharmacological chaperone of alpha-glucosidase, in order to restore enzyme activity. This study consisted of a 28-day screening period, an 11-week treatment period, and a 1-week follow-up period. Three dosing regimens of oral duvoglustat were to be evaluated (Cohort 1: 2.5 g daily for 3 days, followed by no study drug for 4 days; Cohort 2: 5 g daily for 3 days, followed by no study drug for 4 days; Cohort 3: 5 g daily for 7 days, followed by no study drug for 7 days).

Participants meeting all eligibility criteria underwent physical examination, electrocardiogram, spirometry, muscular strength test, functional muscle test, 6-minute walk test (when appropriate), laboratory tests, magnetic resonance imaging, and muscle (needle) biopsy. Quality of life was assessed via the 36-Item Short Form Health Survey questionnaire. Functional ability and level of handicap was assessed by Rotterdam handicap scale.

Recruitment & Eligibility

Inclusion Criteria

Male or female, 18 to 74 years of age inclusive
Diagnosis of Pompe disease based on clinical assessment, enzyme assay, and/or genotyping. Confirmatory genotyping will be performed on all participants who are screened for the study
Naïve to enzyme replacement therapy (ERT) or has not received ERT in the 3 months prior to screening
Willing not to initiate ERT or other prohibited treatment during study participation
Functional grade for arms and/or legs ≥2 OR sitting forced vital capacity ≥30% and <80% of predicted value, reproducible between screening and baseline (±15%)
Participants of reproductive potential agree to use reliable methods of contraception during the study
Participant or legal representative is willing and able to provide written informed consent

Exclusion Criteria

Any intercurrent condition that may preclude accurate interpretation of study data
Obstructive pulmonary disease
Invasive ventilatory support
Use of noninvasive ventilatory support >8 hours/day while awake
History of QTc prolongation >450 milliseconds (msec) for males and >470 msec for females
History of allergy or sensitivity to the study drug, including any prior serious adverse reaction to iminosugars (such as miglustat or miglitol)
Pregnancy or breast-feeding
Current or recent drug or alcohol abuse
Treatment with another investigational drug within 30 days of study start
Use of prohibited medications ≤3 months prior to screening
Otherwise unsuitable for the study in the opinion of the Investigator

Arm && Interventions

Group	Intervention	Description
Cohort 1	Duvoglustat	Regimen 1: Low-dose duvoglustat (2.5 grams \[g\]) once a day (QD) for 3 days, followed by no drug for 4 days, for 11 weeks.
Cohort 3	Duvoglustat	Regimen 2: High-dose duvoglustat (5.0 g) QD for 7 days, followed by no drug for 7 days, for 11 weeks.
Cohort 2	Duvoglustat	Regimen 1: High-dose duvoglustat (5.0 g) QD for 3 days, followed by no drug for 4 days, for 11 weeks.

Primary Outcome Measures

Name	Time	Method
Proportion Of Participants Experiencing Severe Treatment-emergent Adverse Events (TEAEs)	Baseline, Week 11	The number of participants experiencing severe TEAEs is presented for participants who received duvoglustat treatment in this open-label study. The duration of duvoglustat exposure for Cohort 1 ranged from 2 to 24 days, and their exposure ranged from a total of 7,500 to 32,500 milligrams of duvoglustat. An adverse event (AE) refers to any unfavorable and unintended sign, symptom, syndrome, or illness that develops or worsens during the period of observation in the clinical study. The following guideline was used to grade the intensity of an AE: mild, the AE is easily tolerated and does not interfere with daily activity; moderate, the AE interferes with the daily activity but the participant is still able to function; severe, the AE is incapacitating and requires medical intervention. A summary of serious and all other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

Secondary Outcome Measures

Name	Time	Method
Change In 6-minute Walk Test (6MWT) From Baseline To End Of Study	Baseline, Week 11	The 6MWT (American Thoracic Society standards) was evaluated in ambulatory participants at screening, baseline, and to the end of the study. It was a standardized test that measured the distance in meters (m) covered over a 6-minute walk. Reference equations used (for 6MWT distance in healthy adults) included: (height in centimeters \[cm\], weight in kilograms \[kg\]) 6MWT distance for men = \[7.57 × height (cm)\] - \[5.02 × age\] - \[1.76 × weight (kg)\] - 309 m; 6MWT distance for women = \[2.11 × height (cm)\] - \[5.78 × age\] - \[2.29 × weight (kg)\] + 667 m