Clinical trial NCT02898753: VAL-1221 Delivered Intravenously in Ambulatory and Ventilator-free Participants With Late-Onset Pompe Disease
Official title: A Three-Month, Open-Label, Randomized, Dose-escalation Study of the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of VAL-1221 Versus Myozyme®/Lumizyme® in Patients With Late-Onset GSD-II (Pompe Disease) Followed by Open-Label Treatment With VAL-1221 in All Patients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Pompe Disease
Keywords: GSD-II
Pompe Disease
Glycogen Storage Diseases
GAA
Lead sponsor: Valerion Therapeutics, LLC
Sponsor class: INDUSTRY
First posted: 2016-09-13
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* Participant is able and willing to provide informed consent prior to any study procedures are performed
* 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
* Onset of Pompe disease-related symptoms after 1 year of age
* Previously treated with Myozyme or Lumizyme for at least 12 months and on a stable regimen for the past 6 months
* 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
* 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
* Able to comply with protocol requirements

Exclusion Criteria:

* 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

Primary outcomes:
measure: Number of Treatment-related Treatment-emergent Adverse Events (TEAEs)
timeFrame: Baseline of Study Part 1 though Month 24 of Study Part 2
measure: Number of Participants With Infusion-Associated Reactions to VAL-1221
timeFrame: Baseline of Study Part 1 though Month 24 of Study Part 2
measure: Percentage of Participants with Anti-VAL-1221 Antibodies
timeFrame: Baseline of Study Part 1 though Month 24 of Study Part 2
measure: Percentage of Participants with GAA Antibodies
timeFrame: Baseline of Study Part 1 though Month 24 of Study Part 2
Secondary outcomes:
measure: Pharmacokinetics of VAL-1221 in Plasma: Maximum Observed Concentration (Cmax)
timeFrame: 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
measure: Pharmacokinetics of VAL-1221 in Plasma: Time to Reach Maximum Concentration (Tmax)
timeFrame: 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
measure: Pharmacokinetics of VAL-1221 in Plasma: Area Under the Concentration Time Curve (AUC)
timeFrame: 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
measure: Pharmacokinetics of VAL-1221 in Plasma: Terminal Elimination Half-Life ( t1/2)
timeFrame: 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
measure: Pharmacokinetics of VAL-1221 in Plasma: Apparent Total Body Clearance (CL)
timeFrame: 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
measure: Pharmacokinetics of VAL-1221 in Plasma: Apparent Volume (V)
timeFrame: 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
measure: Change from Baseline in Urinary Hexose Tetrasaccharide (hex4) Excretion at Week 12, Months 6, 9, and 12
timeFrame: Baseline of Study Part 1, Week 12 of Study Part 1, Months 12, 24, and 36 of Study Part 2
measure: Change from Baseline in Serum Creatine Kinase (CK) at Week 12, Months 6, 9, and 12
timeFrame: Baseline of Study Part 1, Week 12 of Study Part 1, Months 12, 24, and 36 of Study Part 2
measure: Change from Baseline in the Amount of Acid Alpha Glucosidase (GAA) Activity Present in Muscle at Week 12
timeFrame: Baseline of Study Part 1, Week 12 of Study Part 1
measure: Change from Baseline in the Muscle Glycogen Content at Week 12
timeFrame: Baseline of Study Part 1, Week 12 Study Part 1
measure: Change from Baseline in Creatinine Excretion at Months 6, 9, and 12
timeFrame: Baseline of Study Part 1, Months 12, 24, 36 of Study Part 2
Other outcomes:
Locations:
city: Orange
country: United States
facility: University of California, Irvine
state: California
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: London
country: United Kingdom
facility: National Hospital for Neurology and Neurosurgery
Study officials:
affiliation: Valerion Therapeutics, LLC
name: Hal Landy, MD
role: STUDY_DIRECTOR
References: