What is Pompe disease?
Pompe disease is a rare disorder in which a molecule called glycogen builds up within cells. Cells — primarily muscle and liver cells — use glycogen to store sugar for times when it is not available. During long periods of fasting or exercise, muscle and liver cells break down glycogen, releasing the sugar to produce energy.
The enzyme that breaks down glycogen is acid alpha-glucosidase (GAA). In Pompe, 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. Of note, smooth muscle, also called involuntary muscle, is often found in internal organs and the digestive system.
How does avalglucosidase alfa work?
Avalglucosidase alfa contains an artificial GAA enzyme to replace the one 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 that reside on the surface of cells and then enters the cell. Compared with Lumizyme, avalglucosidase alfa should have better receptor targeting and enzyme uptake.
Avalglucosidase alfa in clinical trials
An open-label Phase 1 clinical trial (NCT01898364), called NEO1, tested the safety and tolerability of avalglucosidase in 24 people with late-onset Pompe. Among them, 14 had previously used Lumizyme, and the remaining 10 were new to ERT. All received the treatment for 24 weeks (nearly six months), via infusions every other week.
The results showed that the treatment was safe and that both patient groups tolerated it well. Most adverse reactions, or side effects, were considered not serious and mild to moderate in intensity. The 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, the investigators assessed the participants’ 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 receiving avalglucosidase alfa treatment every other week for 5.5 years.
Interim trial data from 17 people were presented by researchers at the WORLD Symposium 2020. These data indicated that safety, tolerability, and efficacy in NEO-EXT were consistent with those from the NEO1 study.
An ongoing Phase 2 trial (NCT03019406) called mini-COMET is comparing the safety profile and preliminary effectiveness of avalglucosidase alfa with that of Lumizyme. Mini-COMET involves 22 children, ages 6 months to 17 years, with infantile-onset Pompe disease. These patients were randomly assigned to one of three treatment groups. One was given 20 mg/kg of avalglucosidase alfa by infusion every other week while another received 40 mg/kg on the same schedule. The other group received either avalglucosidase alfa at 40 mg/kg every other week or Lumizyme weekly at their stable dose.
The researchers also reported six-month results at the 2020 WORLD Symposium. These findings indicated that the 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 December 2024.
COMET, an ongoing Phase 3 clinical trial (NCT02782741), is evaluating whether avalglucosidase alfa leads to greater therapeutic benefit than Lumizyme. The trial involves 100 children and adults with late-onset Pompe who have not been previously treated. These patients were randomly selected to receive either avalglucosidase alfa or Lumizyme at a dose of 20 mg/kg every two weeks for 49 weeks (nearly one year).
After about one year of blinded treatment, the trial moves to an extended and open-label phase, in which all participants are either starting or continuing treatment with avalglucosidase alfa for 120 weeks (2 years and four months). Its primary goal is to observe the change in patients’ lung function at week 49 (just prior to one year) compared with baseline, meaning at the study’s start. The researchers are measuring lung function 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 with those who received Lumizyme. Similar improvements were found between the two therapy groups in health-related quality of life and lower extremity muscle strength, a measure of muscle strength in the legs. 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 (75.5 feet) farther at week 97 (just shy of two years). COMET is due to conclude in September 2024.
The European Medicines Agency accepted avalglucosidase alfa for review in October 2020 and a decision is expected in the second half of 2021. The U.S. Food and Drug Administration also received a new drug application for avalglucosidase alfa in November 2020. The treatment is now under priority review, with a decision expected by May 18, 2021.
Last updated: Feb. 1, 2021