Safety and Efficacy of Avalglucosidase Alfa in Patients With Non-classic Pompe Disease Aged ≥ 5 Years

An Open Label, Single Center, Exploratory Study of the Safety and Efficacy of Avalglucosidase Alfa Patients With Non-classic Pompe Disease Aged ≥ 5 Years

The goal of this clinical trial is to study the efficacy and safety of treatment with avalglucosidase alfa in patients with late onset Pompe disease that previously deteriorated on alglucosidase alfa.

The main question it aims to answer is:

• Is switching to avalglucosidase alfa in late-onset Pompe patients deteriorating on alglucosidase alfa safe?
• Is switching to avalglucosidase alfa in late-onset Pompe patients deteriorating on alglucosidase alfa potentially more effective?

Participants will switch to biweekly avalglucosidase alfa infusions (instead of alglucosidase alfa infusions) and perform assessment for:

• Efficacy: muscle strength and function, pulmonary function, patient-reported outcomes.
• Safety: Adverse events assessment, physical examination, clinical laboratory evaluations, vital signs, ECGs and immunogenicity assessments.
• Pharmacokinetic assessments during 2 avalglucosidase alfa infusions.

Rationale: Not all patients with non-classic Pompe disease have a good response to current treatment with alglucosidase alfa. Therefore innovative enzyme replacement therapies are developed. The study drug avalglucosidase alfa has been tested in multiple clinical studies and will now be studied in a small population of patients that are unresponsive to alglucosidase alfa.

Objective: To explore safety, tolerability and efficacy of avalglucosidase alfa in patients with non-classic Pompe disease aged ≥ 5 years of whom clinical condition deteriorates while on standard treatment with alglucosidase alfa.

Study design: Single-center, open-label, repeated bi-weekly intravenous infusion study of avalglucosidase alfa in patients with non-classic Pompe disease patients aged ≥ 5 years, previously treated with alglucosidase alfa.

Study population: Non-classic Pompe disease patients aged ≥ 5 years and ≤ 55 years previously treated ≥ 2 years with alglucosidase alfa, who deteriorate despite treatment with alglucosidase alfa at a dose of 20 or 40 mg/kg bi-weekly.

Total number of patients = 6.

Intervention: Avalglucosidase alfa. Sterile lyophilized powder administered by intravenous infusion following reconstitution and dilution. 20 mg/kg bi-weekly

Main study parameters:

• Safety

  • Assessment of adverse events / treatment-emergent adverse events, including infusion associated reactions (IARs)
  • Clinical laboratory evaluations including hematology, biochemistry, urinalysis
  • Immunogenicity assessments

• Pharmacokinetics

  • Single and multiple dose estimates for Cmax, AUC, CL,.

• Efficacy

  • Muscle strength: manual muscle testing (MMT), hand- held dynamometry (HHD).
  • Muscle function: Quick Motor Function test (QMFT), six Minute Walk Test (6MWT), timed tests.
  • Pulmonary function: (forced) vital capacity ((F)VC) in sitting and supine positions, Maximum Inspiratory Pressure (MIP), Maximum Expiratory Pressure (MEP).
  • 'PRO-measures': Rasch-build Pompe Activity scale (R- Pact), Quality of Life (QoL), modified Borg scale,

Nature and extent of burden and risks associated with participation, benefit and group relatedness: Blood samples will be collected at 14 time points, the amount of blood will not exceed the maximum amount of 5 ML/kg over a period of 8 weeks. Patients will visit the hospital every other week to receive treatment. This treatment will last 4-6 hours. During every visit the vital signs of the patients will be checked and a physical examination is performed.

Inclusion Criteria:

• Age> 5 years and < 55 years
• Childhood or juvenile/adult onset
• Residing in the Netherlands
• Current ERT with alglucosidase alfa> 2 years (dose regimen 20 or 40 mg/kg bi-weekly).
• Confirmed diagnosis: enzyme deficiency in any tissue source and/or 2 confirmed disease-causing variants in the GAA gene.
• Willing and able to adhere to study procedures
• Deterioration in pulmonary function and/or 6MWT and/or muscle strength despite current treatment regimen with alglucosidase alfa.
• Disease status: measurable pulmonary (dys)function: (F)VC ≤ 80% predicted (mechanic ventilation during the day or night allowed); Measurable muscle weakness in proximal and/or distal muscle groups (non- ambulant/wheelchair bound patients allowed); measurable functional ability

Exclusion Criteria:

• Age>55 years
• Invasive mechanical ventilation
• No remaining useful functional ability, as decided by the treating physician
• Unmanageable, sever IAR's on alglucosidase alfa
• Deterioration due to high levels of anti-alglucosidase alfa antibodies interfering with treatment efficacy
• Female patient of childbearing potential not protected by highly effective contraceptive method of birth control and/or who is unwilling or unable to be tested for pregnancy