Sanofi Pompe Disease Second-generation Enzyme Replacement Therapy Avalglucosidase Alfa Head-to-head Phase III Clinical Success!

- Jun 29, 2020-

Sanofi recently announced the positive results of the head-to-head Phase III COMET study of the enzyme replacement therapy (ERT) avalglucosidase alfa (neoGAA). The data showed that the drug showed clinically significant improvements in the key manifestations of late-onset Pompe disease (LOPD) (disordered breathing and decreased mobility). The study also reached the primary endpoint: in LOPD patients, avalglucosidase alfa showed non-inferiority in improving respiratory function compared to the standard-of-care drug Lumizyme (alglucosidase alfa, aglucosidase alpha). These data will form the basis for the expected global regulatory filing in the second half of this year. Previously, the US FDA has granted avalglucosidase alfa for the breakthrough drug qualification (BTD) and fast-track qualification (FTD) for the treatment of Pompe disease.

COMET is a randomized, double-blind, head-to-head phase III study that enrolled 100 children and adults with LOPD who had not previously received treatment in 56 centers in 20 countries. In the study, these patients were randomly divided into two groups and received intravenous infusion of 20 mg/kg avalglucosidase alfa or 20 mg/kg aglucosidase alpha (standard care) every 2 weeks for 49 weeks. After 49 weeks, patients receiving standard care switched to open-label treatment with avalglucosidase alfa at 20 mg/kg. The main endpoint of the study was: the percentage of forced vital capacity (FVC) predicted in an upright position to assess changes in respiratory muscle function.

The data shows that compared with standard care medicines (95%CI, -0.13/4.99), the percentage of FVC predicted by patients receiving avalglucosidase alfa increased by 2.4 percentage points, and the numerical improvement in respiratory function exceeded the non-inferiority of the study design. Index (p=0.0074).

The primary endpoint also measured superiority, showing that the advantage of avalglucosidase alfa was not statistically significant (p=0.0626). Therefore, according to the hierarchical system of the research program, there is no formal statistical test for all secondary endpoints.

A key secondary endpoint in this study was the 6-minute walk test (6MWT) to measure mobility. Patients treated with avalglucosidase alfa had a distance of 30 meters more than patients who received standard care medication (95% CI: 1.33-58.69). Other secondary endpoints assessed respiratory muscle strength, motor function, and quality of life.

In addition, a pre-specified preliminary analysis evaluated the predicted FVC percentage and 6MWT among patients who switched from standard care medication to avalglucosidase alfa treatment at week 49 during the open label expansion period of the study. Due to sequential enrollment, at the initial analysis time point: 97 weeks, 20 of 49 converted patients had predicted FVC percentage data and 21 patients had 6MWT data. Among these converted patients, avalglucosidase alfa showed an improvement of FVC (95%CI: -1.95/2.25) by 0.15 points and 6MWT (95%CI: -3.87/50.51) by 23.32 meters.

The safety of avalglucosidase alfa is comparable to standard care medicines. During the 49-week double-blind period, 44 patients in the avalglucosidase alfa group and 45 patients in the standard care group experienced adverse events (AE). There were 6 serious adverse events in the avalglucosidase alfa group and 7 in the standard treatment group. There were fewer patients with severe adverse events (SAE) in the avalidase alfa group (8 patients, including 1 potential treatment-related SAE) than in the standard care group (12 patients, including 3 potential treatment-related SAEs).

In the standard care group, 4 patients had adverse events that led to discontinuation of the study, and 1 patient died from an adverse event of acute myocardial infarction (not related to treatment). In the avalglucosidase alfa group, no patients discontinued or died. The avalglucosidase alfa group (25.5%) had at least one infusion-related reaction defined by the protocol than the standard care group (32.7%). The immunogenicity data is currently being analyzed and will be announced at a future medical conference.

avalglucosidase alfa

Dr. Jordi Diaz-Manera, Professor of Neuromuscular Diseases, Translational Medicine and Genetics, John Walton Muscular Dystrophy Research Center, University of Newcastle, UK, said: "Pompeii disease will gradually deteriorate muscles and make people weak. Importantly, the potential The new treatment regimen will allow patients to achieve clinically meaningful improvements in multiple measurements of respiratory and motor function. The results of the phase III COMET study are very encouraging, and more and more clinical evidence has been added to prove that avalglucosidase alfa is The potential to provide new treatment options in addressing the characteristic symptoms of this disease."

John Reed, MD, Sanofi’s global head of research and development, said: “We are pleased that avalglucosidase alfa has shown clinically significant improvements in respiratory function and activity, as measured by the accepted standard prognostic indicators of Pompe disease. These results underscore our ambition to use avalglucosidase alfa as a new standard of care for Pompe disease."

Pompeii Pathway

Pompeii Pathway (Image source:

Pompe disease is caused by genetic defects or dysfunction of the lysosomal enzyme acid alpha-glucosidase (GAA), resulting in the accumulation of glycogen in muscles (including proximal muscles and diaphragm), which ultimately leads to progressive and irreversible Muscle damage. This rare disease affects approximately 50,000 people worldwide, and can manifest at any age from infants to late adulthood. Pompeii disease is usually classified as late-onset Pompe disease (LOPD) or infantile Pompe disease (IOPD). Patients with LOPD usually appear from the first year of life to late adulthood. The characteristic symptoms of LOPD are impaired respiratory function and skeletal muscle weakness, often resulting in impaired exercise capacity. Patients usually need a wheelchair to help move, or they may need mechanical ventilation to help breathe. Respiratory failure is the most common cause of death in patients with Pompe disease. When Pompe disease is classified as IOPD, symptoms begin to appear before the age of one. In addition to skeletal muscle weakness, heart function is also generally affected.

The purpose of Pompeii's enzyme replacement therapy (ERT) is to introduce enzymes (GAA) into lysosomes in muscle cells to replace the missing or lacking GAA. GAA is an enzyme necessary to prevent the accumulation of glycogen in muscle. Avaloglucosidase alfa is a Pompe disease ERT under development, which aims to improve the delivery of enzymes to muscle cells, especially to skeletal muscle. Compared with the standard care medicine alglucosidase alfa (Aglucosidase alpha), the mannose-6-phosphate (M6P) content of avaloglucosidase alfa is increased by about 15 times, the purpose is to help increase the absorption of cellular enzymes and the glycogen in target tissues Clear. The clinical relevance of this difference has not been confirmed.

Lumizyme (glucosidase alpha) is the first-generation ERT developed by Sanofi and has been approved for the treatment of Pompe disease. avaloglucosidase alfa is a second-generation glucosidase alpha (alglucosidase alfa) ERT, specifically designed to enhance receptor targeting and enzyme absorption to enhance glycogen clearance by greater affinity for M6P receptors on muscle cells And improve the clinical efficacy of glucosidase α. In preclinical studies, avaloglucosidase alfa showed about 5 times the efficacy of aglucosidase α in reducing tissue glycogen. In a mouse model of Pompe disease, avaloglucosidase alfa showed a similar level of substrate reduction at a fifth dose of aglucosidase alpha.