Drug-drug Interaction Study

An Open-Label, Multi-Center, International Study to Investigate Drug-Drug Interactions Between AT2220 and Alglucosidase Alfa in Patients With Pompe Disease

This study evaluates drug-drug interactions between AT2220 (duvoglustat) and recombinant human alpha-glucosidase (rhGAA, also known as alglucosidase alfa) in participants with Pompe Disease.

Study Overview

• Status: Completed
• Conditions: Pompe Disease
• Intervention / Treatment: Drug: duvoglustat; Drug: rhGAA

Detailed Description

This was a multi-center, international, open-label, two-period, fixed-sequence crossover study to evaluate the safety and pharmacokinetic effect of single ascending doses of duvoglustat on rhGAA administered 1 hour before initiation of a single rhGAA infusion. During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
• France
  • Paris, France, 75013
• United Kingdom
  • Salford, United Kingdom, M68 HD
  • Queen Square
    • London, Queen Square, United Kingdom, WC1N 3BG
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85018
    • Scottsdale, Arizona, United States, 85258
  • California
    • Orange, California, United States, 92868
  • Florida
    • Gainesville, Florida, United States, 32610
  • Georgia
    • Decatur, Georgia, United States, 30033
  • Kansas
    • Kansas City, Kansas, United States, 66160
  • Montana
    • Great Falls, Montana, United States, 59405
  • North Carolina
    • Durham, North Carolina, United States, 27710
  • Ohio
    • Cincinnati, Ohio, United States, 45299
  • Oregon
    • Portland, Oregon, United States, 97239
  • Virginia
    • Springfield, Virginia, United States, 22152

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female, diagnosed with Pompe disease and between 18 and 65 years of age, inclusive
• Participant has been on a stable regimen and dose of rhGAA for at least 3 months before screening (stable regimen defined as currently receiving rhGAA every 2 weeks and stable dose defined as not varying by more than ± 10%)
• Participant has an estimated glomerular filtration rate (eGFR) ≥ 50 mL/min at Screening; eGFR to be estimated using the 4-parameter Modification of Diet in Renal Disease (MDRD) equation:

eGFR (mL/min/1.73 m^2) = 175 x (Scr)^(-1.154) x (Age)^(-0.203) x (0.742 if female) x (1.212 if African-American)

• Male and female participants of childbearing potential agree to use medically accepted methods of contraception during the study and for 30 days after study completion
• Participant is willing and able to provide written informed consent and is able to comply with all study procedures

Exclusion Criteria:

• Participant has had a documented transient ischemic attack, ischemic stroke, unstable angina, or myocardial infarction within the 3 months before Screening
• Participant has clinically significant unstable cardiac disease (for example, cardiac disease requiring active management, such as symptomatic arrhythmia, unstable angina, or New York Heart Association class III or IV congestive heart failure)
• Participant requiring mechanical ventilation or is confined to a wheelchair
• Participant has a history of allergy or sensitivity to study drug (including excipients) or other iminosugars (for example, miglustat, miglitol)
• Participant is pregnant or breastfeeding
• Participant tests positive for hepatitis B surface antigen or hepatitis C antibody
• Participant has received any investigational/experimental drug or device within 30 days of Screening
• Participant has any intercurrent illness or condition that may preclude the participant from fulfilling the protocol requirements or suggests to the investigator that the potential participant may have an unacceptable risk by participating in this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1, Duvoglustat 50 mg + rhGAA; During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 50 milligram (mg) oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion. Participants were on a stable regimen and dose of rhGAA for at least 3 months before screening.	Drug: duvoglustat; Single oral dose; Other Names: AT2220; duvoglustat hydrochloride; Drug: rhGAA; Single intravenous infusion; Other Names: alglucosidase alfa; Myozyme; Lumizyme; recombinant human alpha-glucosidase
Experimental: Cohort 2, Duvoglustat 100 mg + rhGAA; During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 100 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion. Participants were on a stable regimen and dose of rhGAA for at least 3 months before screening.	Drug: duvoglustat; Single oral dose; Other Names: AT2220; duvoglustat hydrochloride; Drug: rhGAA; Single intravenous infusion; Other Names: alglucosidase alfa; Myozyme; Lumizyme; recombinant human alpha-glucosidase
Experimental: Cohort 3, Duvoglustat 250 mg + rhGAA; During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 250 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion. Participants were on a stable regimen and dose of rhGAA for at least 3 months before screening.	Drug: duvoglustat; Single oral dose; Other Names: AT2220; duvoglustat hydrochloride; Drug: rhGAA; Single intravenous infusion; Other Names: alglucosidase alfa; Myozyme; Lumizyme; recombinant human alpha-glucosidase
Experimental: Cohort 4, Duvoglustat 600 mg + rhGAA; During Period 1, participants received a single intravenous infusion of rhGAA. During Period 2, each participant received a single 600 mg oral dose of duvoglustat 1 hour prior to initiation of a single rhGAA infusion. Participants were on a stable regimen and dose of rhGAA for at least 3 months before screening.	Drug: duvoglustat; Single oral dose; Other Names: AT2220; duvoglustat hydrochloride; Drug: rhGAA; Single intravenous infusion; Other Names: alglucosidase alfa; Myozyme; Lumizyme; recombinant human alpha-glucosidase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number Of Participants Who Experienced Severe Treatment-Emergent Adverse Events (TEAEs)	A TEAE was defined as an adverse event (AE) with an onset date on or after the first dose of investigational medicinal product (IMP), or an AE with an onset date before the first dose date that worsened in severity after the first dose date. A severe AE was defined as an AE that was incapacitating and required medical intervention. The number of participants who experienced 1 or more severe TEAEs after dosing on Day 1 up to Day 60 (includes end of study follow-up period) is reported. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.	Day 1 after dosing up to Day 60
Pharmacokinetics (PK): Maximum Measured Plasma Concentration (Cmax) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease	The Cmax of total GAA and rhGAA protein in plasma was measured after a single rhGAA intravenous infusion and after pre-administration of single ascending oral doses of duvoglustat. During Treatment Period 1, participants received a single intravenous infusion of rhGAA. During Treatment Period 2, participants received a single oral dose of duvoglustat 1 hour before initiation of a single rhGAA intravenous infusion. PK samples were taken at time points Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2.	Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2
PK: Time To The Maximum Plasma Concentration (Tmax) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease	The Tmax of total GAA and rhGAA protein in plasma was measured after a single rhGAA intravenous infusion and after pre-administration of single ascending oral doses of duvoglustat. During Treatment Period 1, participants received a single intravenous infusion of rhGAA. During Treatment Period 2, participants received a single oral dose of duvoglustat 1 hour before initiation of a single rhGAA intravenous infusion. PK samples were taken at time points Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2.	Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2
PK: Elimination Half-life (T1/2) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease	The T1/2 of total GAA and rhGAA protein in plasma was measured after a single rhGAA intravenous infusion and after pre-administration of single ascending oral doses of duvoglustat. During Treatment Period 1, participants received a single intravenous infusion of rhGAA. During Treatment Period 2, participants received a single oral dose of duvoglustat 1 hour before initiation of a single rhGAA intravenous infusion. PK samples were taken at time points Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2. Values presented are arithmetic mean (percent coefficient of variation, [CV%]). The number of participants analyzed for some cohorts are reduced because the terminal phase of the concentration profile for these participants was not estimable.	Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2
PK: Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Time Of The Last Measurable Concentration (AUC0-t) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease	The AUC0-t of total GAA and rhGAA protein in plasma was measured after a single rhGAA intravenous infusion and after pre-administration of single ascending oral doses of duvoglustat. During Treatment Period 1, participants received a single intravenous infusion of rhGAA. During Treatment Period 2, participants received a single oral dose of duvoglustat 1 hour before initiation of a single rhGAA intravenous infusion. PK samples were taken at time points Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2.	Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2
PK: AUC From Time 0 Extrapolated To Infinity (AUCinf) Of Total GAA And rhGAA Protein In Plasma In Participants With Pompe Disease	The AUCinf of total GAA and rhGAA protein in plasma was measured after a single rhGAA intravenous infusion and after pre-administration of single ascending oral doses of duvoglustat. During Treatment Period 1, participants received a single intravenous infusion of rhGAA. During Treatment Period 2, participants received a single oral dose of duvoglustat 1 hour before initiation of a single rhGAA intravenous infusion. PK samples were taken at time points Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2. The number of participants analyzed for some cohorts are reduced because the terminal phase of the concentration profile for these participants was not estimable.	Predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours, and 3 or 7 days postdose during Periods 1 and 2, and 24 to 30 days postdose during Period 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total GAA Activity In Skeletal Muscle	The total GAA activity in skeletal muscle was measured after a single intravenous administration of rhGAA alone and after pre-administration of single ascending oral doses of duvoglustat. Participants were assessed using skeletal muscle biopsies at either Day 3 or Day 7 during Treatment Periods 1 and 2.	Day 3 or Day 7
Duvoglustat Concentration In Skeletal Muscle	The concentration of duvoglustat in skeletal muscle tissue homogenate was measured after pre-administration of single ascending oral doses of duvoglustat during Treatment Period 2. Participants had skeletal muscle biopsies at either Day 3 or Day 7 during Treatment Period 2. Three participants were excluded from this analysis due to the following reasons: treatment sequence was inadvertently switched due to study site error, follow-up biopsy sample could not be conclusively identified, or muscle biopsies were mislabeled at the clinical site. Values presented are arithmetic mean (percent coefficient of variation, [CV%]) because of the prevalence of participants with values below the limit of quantification. Concentrations below the limit of quantification were treated as zero.	Day 3 or Day 7

Collaborators and Investigators

• Sponsor: Amicus Therapeutics
• Investigators: Study Director: Medical Monitor, Study Sponsor (Amicus Therapeutics, Inc)

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2011
• Primary Completion (Actual): January 4, 2013
• Study Completion (Actual): January 4, 2013

Study Registration Dates

• First Submitted: June 23, 2011
• First Submitted That Met QC Criteria: June 23, 2011
• First Posted (Estimate): June 27, 2011

Study Record Updates

• Last Update Posted (Actual): October 2, 2018
• Last Update Submitted That Met QC Criteria: September 4, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: Amicus Therapeutics; alglucosidase alfa; AT2220; duvoglustat; alpha-glucosidase
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Lysosomal Storage Diseases, Nervous System; Glycogen Storage Disease; Glycogen Storage Disease Type II; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; 1-Deoxynojirimycin
• Other Study ID Numbers: AT2220-010