Sanofi's Second-Generation Enzyme Replacement Therapy Avalglucosidase Alfa Demonstrates Clinically Meaningful Benefits in Phase III COMET Trial for Late-Onset Pompe Disease

June 18, 2020 /Bio ValleyBIOON/ -- Sanofi recently announced positive results from the head-to-head Phase III COMET study of its investigational enzyme replacement therapy (ERT), avalglucosidase alfa (neoGAA). The data demonstrated clinically meaningful improvements in key manifestations of late-onset Pompe disease (LOPD), namely respiratory impairment and declined mobility. The study also met its primary endpoint: in patients with LOPD, avalglucosidase alfa showed non-inferiority to the standard-of-care drug Lumizyme (alglucosidase alfa) in improving respiratory function.These data will form the basis for the global regulatory submissions expected to be filed in the second half of this year. Previously, the United StatesFDAAvalglucosidase alfa has been granted Breakthrough Therapy Designation (BTD) and Fast Track Designation (FTD) for the treatment of Pompe disease.

COMET was a randomized, double-blind, head-to-head Phase III study that enrolled 100 treatment-naïve pediatric and adult patients with late-onset Pompe disease (LOPD) across 56 centers in 20 countries. In the study, these patients were randomized into two groups to receive either intravenous infusions of avalglucosidase alfa at 20 mg/kg every two weeks or alglucosidase alfa (standard of care) at 20 mg/kg for 49 weeks. After 49 weeks, patients receiving standard of care switched to open-label treatment with avalglucosidase alfa at 20 mg/kg. The primary endpoint of the study was the change in respiratory muscle function, assessed by the percent predicted forced vital capacity (FVC) in the upright position.

Data show that, compared with standard-of-care therapy (95% CI, −0.13 to 4.99), patients treated with avalglucosidase alfa had a predicted 2.4-percentage-point increase in FVC percent predicted, with the numerical improvement in respiratory function exceeding the noninferiority margin prespecified in the study design (p=0.0074).

The primary endpoint also assessed superiority, showing that the advantage of avalglucosidase alfa was not statistically significant (p=0.0626). Therefore, according to the hierarchical testing procedure specified in the study protocol, no formal statistical testing was performed for any of the secondary endpoints.

A key secondary endpoint in this study was mobility, as measured by the 6-Minute Walk Test (6MWT). Patients treated with avalglucosidase alfa walked 30 meters farther than those receiving standard-of-care pharmacotherapy (95% CI: 1.33–58.69). Other secondary endpoints assessed respiratory muscle strength, motor function, and quality of life.

Furthermore, the prespecified preliminary analysis evaluated the predicted percent forced vital capacity (FVC%) and 6-minute walk test (6MWT) distance at Week 49 among patients who switched from standard-of-care therapy to avalglucosidase alfa during the open-label extension period of the study. Due to staggered enrollment, at the time of the preliminary analysis (Week 97), 20 of the 49 switch patients had available data for predicted FVC%, and 21 had available 6MWT data. Among these switch patients, avalglucosidase alfa demonstrated a 0.15-point improvement in FVC% (95% CI: -1.95, 2.25) and a 23.32-meter increase in 6MWT distance (95% CI: -3.87, 50.51).

The safety profile of avalglucosidase alfa was comparable to that of standard care. During the 49-week double-blind period, adverse events (AEs) occurred in 44 patients in the avalglucosidase alfa group and 45 patients in the standard care group. There were 6 serious adverse events in the avalglucosidase alfa group and 7 in the standard treatment group. Fewer patients experienced serious adverse events (SAEs) in the avalglucosidase alfa group (8 patients, including 1 potentially treatment-related SAE) than in the standard care group (12 patients, including 3 potentially treatment-related SAEs).

In the standard care group, 4 patients experienced adverse events leading to discontinuation of the study drug, and 1 patient died from acuteMyocardial Infarctionadverse events (unrelated to treatment). In the avalglucosidase alfa group, no patients discontinued treatment or died. The proportion of patients experiencing at least one protocol-defined infusion-associated reaction was lower in the avalglucosidase alfa group (25.5%) than in the standard-of-care group (32.7%). Immunogenicity data are currently under analysis and will be presented at future medicalMeetingpublished above.

Neuromuscular Diseases, Translational Medicine, and the John Walton Muscular Dystrophy Research Centre at Newcastle University, UKGeneticsProfessor Jordi Diaz-Manera stated, “Pompe disease progressively weakens muscles, leading to debilitation. It is significant that potential new treatment options can achieve clinically meaningful improvements in multiple measures of respiratory and motor function. The results from the Phase III COMET study are highly encouraging and add to the growing body of clinical evidence demonstrating the potential of avalglucosidase alfa to provide a new therapeutic option for addressing the characteristic symptoms of this disease.”

John Reed, M.D., Global Head of Research and Development at Sanofi, stated, “We are pleased that avalglucosidase alfa demonstrated clinically meaningful improvements in both respiratory function and mobility, as measured by recognized standard prognostic indicators for Pompe disease. These results underscore our ambition to establish avalglucosidase alfa as the new standard of care for Pompe disease.”

Pompe Disease Pathway (Image source: foodnhealth.org)

Pompe disease is caused byHeredityCaused by a deficiency or dysfunction of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to glycogen accumulation in muscles (including proximal muscles and the diaphragm), which ultimately results in progressive and irreversible muscle damage. This rare disease affects approximately 50,000 people worldwide and can manifest at any age, from infancy to late adulthood. Pompe disease is typically classified as either late-onset Pompe disease (LOPD) or infantile-onset Pompe disease (IOPD). Patients with LOPD usually present between the first year of life and late adulthood. Characteristic symptoms of LOPD include impaired respiratory function and skeletal muscle weakness, often leading to compromised mobility. Patients frequently require wheelchairs for assistance with movement and may also need mechanical ventilation to support breathing. Respiratory failure is the most common cause of death in patients with Pompe disease. When classified as IOPD, symptoms begin to appear before one year of age. In addition to skeletal muscle weakness, cardiac function is commonly affected.

The goal of enzyme replacement therapy (ERT) for Pompe disease is to deliver the enzyme (GAA) into lysosomes within muscle cells to replace missing or deficient GAA, an enzyme essential for preventing glycogen accumulation in muscles. Avaloglucosidase alfa is an investigational ERT for Pompe disease designed to improve enzyme delivery to muscle cells, particularly skeletal muscle. Compared with the standard-of-care drug alglucosidase alfa, avaloglucosidase alfa has approximately 15-fold higher mannose-6-phosphate (M6P) content, aiming to enhance cellular uptake of the enzyme and clearance of glycogen in target tissues. The clinical relevance of this difference has not yet been established.

Lumizyme (alglucosidase alfa) is the first-generation enzyme replacement therapy (ERT) developed by Sanofi and has been approved for the treatment of Pompe disease. Avaloglucosidase alfa is a second-generation alglucosidase alfa ERT, specifically designed to enhance receptor targeting and enzymatic uptake through greater affinity for the M6P receptor on muscle cells, thereby improving glycogen clearance and enhancing the clinical efficacy of alglucosidase alfa. In preclinical studies, avaloglucosidase alfa demonstrated approximately five-fold greater potency than alglucosidase alfa in reducing tissue glycogen. In mouse models of Pompe disease, avaloglucosidase alfa achieved similar levels of substrate reduction at one-fifth the dose of alglucosidase alfa.(Bioon.com)

Original Source: Sanofi’s Investigational Enzyme Replacement Therapy Shows Clinically Meaningful Improvement in Critical Manifestations of Late-Onset Pompe Disease