What is Pompe disease?
Pompe disease is a rare disease characterized by the buildup of a molecule called glycogen within cells. Cells (primarily muscle and liver cells) use glycogen to store sugar for times when it 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 they cannot effectively turn it into sugar. Stored glycogen builds until it interferes with cell function, damaging, and even killing cells. This results in disease symptoms that affect smooth, skeletal, and heart muscles.
How does avalglucosidase alfa work?
Avalglucosidase alfa contains an artificial GAA enzyme to replace the enzyme that people with Pompe disease lack. It is a new and updated 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 cells, so it can enter cells. Compared to Lumizyme, avalglucosidase alfa is expected to have better receptor targeting and enzyme uptake.
Avalglucosidase alfa in clinical trials
A open-label Phase 1 clinical trial (NCT01898364), called NEO1, tested the safety and tolerability of avalglucosidase in 24 late-onset Pompe disease patients. A total of 14 people had previously used Lumizyme, and the remaining 10 were new to ERT treatment. All received the treatment for 24 weeks, via infusions every other week.
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. Researchers reported infusion reactions (an allergic reaction to the infusion, which can include fever, chills, rash, or more serious symptoms) in eight patients. 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. These results were published in the journal Neuromuscular Disorders.
Ongoing clinical trials
An open-label Phase 2 extension of the NEO1 study (NCT02032524), called NEO-EXT, is due to end in December 2021. Here, patients are being treated with avalglucosidase alfa every other week for 5.5 years.
Researchers presented interim trial data on 17 people at the WORLD Symposium 2020. These data indicated that safety, tolerability, and efficacy in NEO-EXT were consistent to date with those from the NEO1 study.
An ongoing Phase 2 pediatric trial (NCT03019406), called mini-COMET, is comparing the safety profile and preliminary effectiveness of avalglucosidase alfa with that of Lumizyme. A total of 22 children, ages 6 months to 17 years, with infantile-onset Pompe disease are taking part. 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 one group given either avalglucosidase alfa at 40 mg/kg every other week or Lumizyme weekly at their stable dose.
Six-month results of treatment in mini-COMET were also reported at the 2020 WORLD Symposium. Data indicated that patients tolerated avalglucosidase alfa well at both doses, with no serious adverse events. The most common side effects were mild to moderate, including vomiting, fever, upper respiratory tract infections and cough, and rash. Pompe disease markers like blood levels of creatine kinase and hexose (or glucose) tetrasaccharide were lower or stable in all three groups. This trial 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 benefit than Lumizyme. In the trial, 100 treatment-naïve children and adults with late-onset Pompe disease were randomized to either avalglucosidase alfa or Lumizyme at a dose of 20 mg/kg every two weeks for 49 weeks. After about one year of blinded treatment, the trial moved to an extended and open-label phase, where all are either starting or continuing treatment with avalglucosidase alfa for about 2.3 years (120 weeks). Its primary goal is changes in patients’ lung function at week 49, which researchers measure using percent predicted FVC in an upright position.
Top-line results showed meaningful and durable benefits with avalglucosidase alfa in respiratory function and mobility that were at least not inferior to Lumizyme’s. In fact, participants on avalglucosidase alfa were able to walk about 30 meters (nearly 98 feet) farther in six minutes compared to those given Lumizyme. Similar improvements were seen between the two therapy groups in health-related quality of life and lower extremity muscle strength. Avalglucosidase alfa and Lumizyme also had similar safety results.
Preliminary results from 20 patients who switched to avalglucosidase alfa from Lumizyme in the extension portion showed a 0.15-point improvement in FVC, and an ability to walk about 23 meters farther at week 97. COMET is due to conclude in September 2024.
Sanofi Genzyme announced plans to use findings from the COMET trial to support applications to regulatory authorities worldwide, requesting approval of avalglucosidase alfa to treat late-onset Pompe.
Last updated: July 6, 2020