About Pompe disease
Pompe, a rare disease, is caused by the buildup of a molecule called glycogen within cells. Cells (primarily muscle and liver cells) use glycogen to store sugar molecules for times when sugar is not available. During long fasts or prolonged exercise, muscle and liver cells break down glycogen, releasing the sugar for cells to use to produce energy.
The enzyme that cells use for this is called acid alpha-glucosidase (GAA). In Pompe disease, mutations in the GAA gene that encodes for this enzyme lead to a reduction in its activity. Cells are still able to store sugar as glycogen, but cannot access the sugar efficiently once it is stored. The stored glycogen builds up until it interferes with cell function, damaging and even killing cells. This results in disease symptoms that include in smooth, skeletal and heart muscles.
How does avalglucosidase alfa work?
Avalglucosidase alfa contains an artificial GAA enzyme that replaces the enzyme Pompe disease patients lack. It is a new derivative of Sanofi’s approved ERT medication, Lumizyme (alglucosidase alfa).
Once infused into the bloodstream, the replacement enzyme binds to mannose-6-phosphate (M6P) receptors found on the surface of the cells, and enters the cells. Compared to Lumizyme, avalglucosidase alfa is designed to have better receptor targeting and enzyme uptake.
Avalglucosidase alfa in clinical trials
A Phase 1 clinical trial (NCT01898364), called NEO1 tested the safety and tolerability of avalglucosidase in 24 late-onset Pompe disease patients. Fourteen had previously used Lumizyme, and the other 10 were new to ERT treatment.
Study results were published in the journal Neuromuscular Disorders. Patients were treated with avalglucosidase alfa for 24 weeks, via infusions every other week. The treatment was found to be safe and well-tolerated in both patient groups, with most adverse reactions considered not serious and mild to moderate in intensity. Infusion reactions (an allergic reaction to the infusion, which can include fever, chills, rash, or more serious symptoms) were reported in eight people.
One patient withdrew from the study due to treatment-related respiratory distress and chest discomfort.
While efficacy was not a primary trial goal, researchers assessed lung function using forced vital capacity (FVC), in which patients exhale strongly into a device that measures the force and volume of the exhalation. FVC remained stable or improved with treatment.
Ongoing clinical trials
An open-label, Phase 2 extension of the NEO1 study (NCT02032524), called NEO-EXT, is due to end in December 2021. In this trial, patients are being given avalglucosidase alfa every other week for 5.5 years. Researchers presented trial data on 17 people at the WORLD Symposium 2020, also detailed in a company press release. These data indicated that safety, tolerability, and efficacy in this study were consistent with those from the NEO1 study.
An ongoing Phase 2 clinical trial (NCT03019406), called mini-COMET, is comparing the safety profile and preliminary effectiveness of avalglucosidase alfa with that of Lumizyme (alglucosidase alfa). A total of 22 children (18 or younger) with infantile-onset Pompe disease are taking part in the study. Researchers randomly assign patients to one of three treatment groups: one at 20 mg/kg and another at 40 mg/kg of avalglucosidase alfa by infusion every other week, and a third group given either 40 mg/kg of avalglucosidase alfa every other week or alglucosidase alfa weekly at their stable dose.
Researchers also presented six-month results of this study at the 2020 WORLD Symposium. Data indicated that patients tolerated avalglucosidase alfa well at both doses given, with no serious adverse events reported. The most common side effects were mild to moderate, including vomiting (six patients), fever (six patients), upper respiratory tract infections (five patients), and cough and rash (four patients).
Pompe disease markers like blood levels of creatine kinase and hexose (or glucose) tetrasaccharide were lower or stable in all three groups at six months of treatment. This study is expected to conclude in April 2022.
An ongoing Phase 3 clinical trial (NCT02782741), called COMET, is evaluating whether avalglucosidase alfa leads to greater therapeutic effects than Lumizyme (each given at a 20 mg/kg dose every two weeks for 49 weeks) in 102 treatment-naïve children and adults with late-onset Pompe disease.
After about one year of blinded treatment, all will either be moved to or continue treatment with avalglucosidase alfa for about 4.6 years (240 weeks). The trial’s primary outcome measure is changes in patients’ lung function at week 49, which researchers will measure using FVC in an upright position. Data on this main trial goal is expected soon; COMET continues as an open-label safety and efficacy study and is due to conclude in September 2024.
Last updated: March 11, 2020