VAL-1221 Delivered Intravenously in Ambulatory and Ventilator-free Participants With Late-Onset Pompe Disease
- Registration Number
- NCT02898753
- Lead Sponsor
- Valerion Therapeutics, LLC
- Brief Summary
This Phase I/II open-label, randomized, dose-escalation study will assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of VAL-1221 versus Myozyme®/Lumizyme® in participants with late-onset glycogen storage disease-II (GSD-II) (Pompe disease)
- Detailed Description
Part 1 comprises 3 sequential cohorts of 4 patients each randomized to treatment with either VAL-1221 (at 3, 10, or 30 mg/kg) or positive control (rhGAA). Patients randomized to VAL-1221 will receive 7 intravenous (IV) infusions of VAL-1221 (one infusion every other week) over 12 weeks. Control patients will continue receiving their accustomed dose and regimen of Myozyme®. Part 2 is an uncontrolled extension to evaluate long-term effects of VAL-1221 given by IV infusion once every other week at doses up to 40 mg/kg.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 12
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Participant is able and willing to provide informed consent prior to any study procedures are performed
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Diagnosis of GSDII based on one of the following:
- Endogenous cultured skin fibroblast GAA activity less than (<) 40 percent (%) of adult normal level
- Endogenous whole blood or dried blood spot GAA activity in deficiency range
- Genetic analysis showing pathogenic variants in both alleles
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Onset of Pompe disease-related symptoms after 1 year of age
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Previously treated with Myozyme or Lumizyme for at least 12 months and on a stable regimen for the past 6 months
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Sexually active participants who are willing to use an acceptable method of contraception (abstinence, oral contraceptives, barrier method with spermicide, surgical sterilization, implanted or injectable contraceptives with a stable dose for at least 1 month prior to Baseline, hormonal intra-uterine device [IUD] inserted at least 1 month prior to Baseline) during the study and for 30 days after completion of treatment
- If participant is female and not considered to be of childbearing potential, she is at least 2 years post-menopause, has undergone a tubal ligation, a total hysterectomy or bilateral oophorectomy
- If participant is female and of childbearing potential, she has a negative serum pregnancy test during screening and Baseline and must be willing to undergo pregnancy testing at specific intervals during the study
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Participant meets at least one of the following criteria: greater than (>) 30% and <80% predicted upright forced volume capacity (FVC) or participant is able to walk >20% but <80% predicted normal on 6-minute walk test with or without use of assistive devices
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Able to comply with protocol requirements
- Cardiac involvement in first year of life
- Anti-GAA antibody titers >1:51,200 at two time points
- Prior use of chaperone therapy for GSD-II within the last 12 months
- Use of immunosuppressive medication other than glucocorticoids within 6 months prior to study enrollment
- Use of invasive ventilatory assistance other than Bilevel Positive Airway Pressure (BiPAP) at night or during periods of rest
- Has received any investigational medication or has enrolled in any study involving investigational drugs or therapies within 30 days prior to first dose of study drug
- Start of or change in usual regimen of albuterol or respiratory muscle training within 30 days prior to first dose of study drug
- History of sensitivity to any of the constituents of the study drug
- Participant is breastfeeding or planning to become pregnant or to breastfeed during the study or is currently breastfeeding
- Participant has a medical condition or circumstance that, in the opinion of the investigator, might compromise the participant's ability to comply with the protocol or the participant's well-being or safety
- Participant has any condition that, in the view of the investigator, places the participant at high risk of poor treatment compliance or of not completing the study
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description rhGAA VAL-1221 Part 1: Participants will be maintained on their current dose and regimen of Myozyme or Lumizyme. Part 2: Participants from Part 1 of the study who were randomized to rhGAA can enter Part 2 of the study and receive VAL-1221 either 3 mg/kg, 10 mg/kg, or 30 mg/kg (based on the dose of VAL-1221 in respective cohorts to which they were randomized in Part 1) IV infusion every other week. VAL-1221 30 mg/kg VAL-1221 Part 1: Participants will receive VAL-1221 30 mg/kg IV every other week for 12 weeks, inclusive, for a total of 7 infusions. Part 2: Participants from Part 1 of the study who were randomized to VAL-1221 30 mg/kg can enter Part 2 of the study and receive VAL-1221 at a dose of 30 mg/kg IV inufsion every other week. VAL-1221 3 mg/kg VAL-1221 Part 1: Participants will receive VAL-1221 3 mg/kg IV infusion every other week for 12 weeks, inclusive, for a total of 7 infusions. Part 2: Participants from Part 1 of the study who were randomized to VAL-1221 3 mg/kg can enter Part 2 of the study and receive VAL-1221 at a dose of 3 mg/kg IV infusion every other week. The dose can be increased by the Investigator to 10 mg/kg and further to 30 mg/kg (after at least 12 weeks of dosing at 10 mg/kg), depending upon the pharmacodynamics, efficacy, and safety data. VAL-1221 10 mg/kg VAL-1221 Part 1: Participants will receive VAL-1221 10 mg/kg IV infusion every other week for 12 weeks, inclusive, for a total of 7 infusions. Part 2: Participants from Part 1 of the study who were randomized to VAL-1221 10 mg/kg can enter Part 2 of the study and receive VAL-1221 at a dose of 10 mg/kg IV infusion every other week. The dose can be increased by the Investigator to 30 mg/kg IV infusion, depending upon the pharmacodynamics, efficacy, and safety data. rhGAA RhGAA Part 1: Participants will be maintained on their current dose and regimen of Myozyme or Lumizyme. Part 2: Participants from Part 1 of the study who were randomized to rhGAA can enter Part 2 of the study and receive VAL-1221 either 3 mg/kg, 10 mg/kg, or 30 mg/kg (based on the dose of VAL-1221 in respective cohorts to which they were randomized in Part 1) IV infusion every other week.
- Primary Outcome Measures
Name Time Method Number of Treatment-related Treatment-emergent Adverse Events (TEAEs) Baseline of Study Part 1 though Month 24 of Study Part 2 Number of Participants With Infusion-Associated Reactions to VAL-1221 Baseline of Study Part 1 though Month 24 of Study Part 2 Percentage of Participants with Anti-VAL-1221 Antibodies Baseline of Study Part 1 though Month 24 of Study Part 2 Percentage of Participants with GAA Antibodies Baseline of Study Part 1 though Month 24 of Study Part 2
- Secondary Outcome Measures
Name Time Method Change from Baseline in Urinary Hexose Tetrasaccharide (hex4) Excretion at Week 12, Months 6, 9, and 12 Baseline of Study Part 1, Week 12 of Study Part 1, Months 12, 24, and 36 of Study Part 2 Pharmacokinetics of VAL-1221 in Plasma: Apparent Total Body Clearance (CL) Part 1: Pre-infusion, end of infusion (EOI) (infusion duration 1 mg/kg/hour), at 0.25, 0.5, 1, 2, 4, 12, 24, 48 and 336 hours after EOI on Days 1, 2, 3 and Week 12; Part 2: Pre-infusion on Weeks 12, 14, 16, 18, 20, 22, Months 12, 24, 36 Pharmacokinetics of VAL-1221 in Plasma: Apparent Volume (V) Part 1: Pre-infusion, end of infusion (EOI) (infusion duration 1 mg/kg/hour), at 0.25, 0.5, 1, 2, 4, 12, 24, 48 and 336 hours after EOI on Days 1, 2, 3 and Week 12; Part 2: Pre-infusion on Weeks 12, 14, 16, 18, 20, 22, Months 12, 24, 36 Pharmacokinetics of VAL-1221 in Plasma: Maximum Observed Concentration (Cmax) Part 1: Pre-infusion, end of infusion (EOI) (infusion duration 1 mg/kg/hour), at 0.25, 0.5, 1, 2, 4, 12, 24, 48 and 336 hours after EOI on Days 1, 2, 3 and Week 12; Part 2: Pre-infusion on Weeks 12, 14, 16, 18, 20, 22, Months 12, 24, 36 Pharmacokinetics of VAL-1221 in Plasma: Area Under the Concentration Time Curve (AUC) Part 1: Pre-infusion, end of infusion (EOI) (infusion duration 1 mg/kg/hour), at 0.25, 0.5, 1, 2, 4, 12, 24, 48 and 336 hours after EOI on Days 1, 2, 3 and Week 12; Part 2: Pre-infusion on Weeks 12, 14, 16, 18, 20, 22, Months 12, 24, 36 Pharmacokinetics of VAL-1221 in Plasma: Terminal Elimination Half-Life ( t1/2) Part 1: Pre-infusion, end of infusion (EOI) (infusion duration 1 mg/kg/hour), at 0.25, 0.5, 1, 2, 4, 12, 24, 48 and 336 hours after EOI on Days 1, 2, 3 and Week 12; Part 2: Pre-infusion on Weeks 12, 14, 16, 18, 20, 22, Months 12, 24, 36 Pharmacokinetics of VAL-1221 in Plasma: Time to Reach Maximum Concentration (Tmax) Part 1: Pre-infusion, end of infusion (EOI) (infusion duration 1 mg/kg/hour), at 0.25, 0.5, 1, 2, 4, 12, 24, 48 and 336 hours after EOI on Days 1, 2, 3 and Week 12; Part 2: Pre-infusion on Weeks 12, 14, 16, 18, 20, 22, Months 12, 24, 36 Change from Baseline in Serum Creatine Kinase (CK) at Week 12, Months 6, 9, and 12 Baseline of Study Part 1, Week 12 of Study Part 1, Months 12, 24, and 36 of Study Part 2 Change from Baseline in the Amount of Acid Alpha Glucosidase (GAA) Activity Present in Muscle at Week 12 Baseline of Study Part 1, Week 12 of Study Part 1 Change from Baseline in the Muscle Glycogen Content at Week 12 Baseline of Study Part 1, Week 12 Study Part 1 Change from Baseline in Creatinine Excretion at Months 6, 9, and 12 Baseline of Study Part 1, Months 12, 24, 36 of Study Part 2
Trial Locations
- Locations (3)
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
National Hospital for Neurology and Neurosurgery
🇬🇧London, United Kingdom
University of California, Irvine
🇺🇸Orange, California, United States