Sanofi's Next-Generation Enzyme Replacement Therapy Nexviazyme Demonstrates Sustained Improvements in Respiratory Function and Mobility in Late-Onset Pompe Disease Patients

News on February 12, 2022 /BioValleyBIOON/ -- Sanofi recently announced the open-label long-term extension analysis of the pivotal Phase 3 COMET trial (NCT02782741) for Nexviazyme (avalglucosidase alfa, neoGAA) in the treatment of late-onset Pompe disease (LOPD). The data showed,After nearly 2 years of treatment with Nexviazyme, patients' respiratory function and mobility continued to improve.

Nexviazyme is an enzyme replacement therapy (ERT) specifically targeting the mannose-6-phosphate (M6P) receptor, a key pathway for cellular uptake in enzyme replacement therapy for Pompe disease. Nexviazyme effectively clears accumulated glycogen in muscle cells.Clinical TrialHas been proven in China to improve patients' respiratory function and walking distance.

This analysis evaluated the long-term efficacy and safety of patients receiving continuous treatment with Nexviazyme. Additionally, patients who had switched from previous treatment with Lumizyme/Myozyme (alglucosidase alfa, recombinant alpha-glucosidase) to Nexviazyme for at least 48 weeks were included in this analysis. Over a period of 97 weeks, among patients who switched from Lumizyme/Myozyme to Nexviazyme,Respiratory Function(Measured by the predicted percentage of Forced Vital Capacity [FVC]) andWalking Distance(As measured by the 6-minute walk test [6MWT]),Nexviazyme treatment continues to be effective, with stable therapeutic outcomes.

Lumizyme/Myozyme is the first-generation enzyme replacement therapy (ERT) for the treatment of Pompe disease, and was previously the only available treatment option and standard of care for Pompe disease. The drug, developed by Genzyme, Sanofi’s rare disease unit, is a recombinant acid alpha-glucosidase (GAA), an enzyme that is deficient in patients with Pompe disease. GAA is crucial in preventing the accumulation of glycogen in muscle cells to toxic levels. Lumizyme/Myozyme aims to replace defective GAA and reduce glycogen accumulation in cardiac and skeletal muscles.

Nexviazyme, developed by Sanofi Genzyme as the second-generation ERT, will provide a new standard of care for the treatment of Pompe disease.. This medication is a long-acting ERT designed to improve the delivery of GAA to muscle cells, transporting more GAA to the lysosomes of muscle cells. Nexviazyme will provide a new standard of care for patients with Pompe disease. InClinical TrialIn China, Nexviazyme treatment showed clinically meaningful improvements in respiratory function and mobility among patients with Pompe disease.

In August 2021, the U.S. FDA approved Nexviazyme for the treatment of patients aged one year and older with late-onset Pompe disease (LOPD). This is a progressive, debilitating muscle disorder that impairs patients' mobility and respiratory function. Nexviazyme provides an important new treatment option for the LOPD patient population. Previously, in the U.S.,FDANexviazyme has been granted Breakthrough Therapy Designation (BTD) and Fast Track Designation (FTD) for the treatment of Pompe disease.

First-Generation ERT (alglucosidase alfa) vs. Second-Generation ERT (avalglucosidase alfa): Structural Differences (Click image to enlarge)

COMET is a randomized, double-blind, head-to-head Phase 3 study that enrolled 100 previously untreated patients with late-onset Pompe disease (LOPD) across 55 clinical centers in 20 countries. The primary endpoint assessed the relative change from baseline in predicted forced vital capacity (FVC) percentage in an upright position, and the key secondary endpoint was mobility measured by the 6-minute walk test (6MWT). During the 49-week double-blind treatment period of the study, patients were randomly assigned to receive either Nexviadyme or the standard-of-care drug Lumizyme, both at a dose of 20mg/kg administered intravenously every two weeks. After completing the double-blind treatment period, patients entered an extension phase where those initially treated with Nexviazyme continued on Nexviazyme, while those previously on Lumizyme switched to Nexviazyme 20mg/kg. Of the 95 patients entering the extension phase, 86 (91%) remained on treatment until the last follow-up.

Previously published results from the double-blind treatment phase showed that during the nearly one-year (49-week) treatment period,Nexviadyme Shows Clinically Meaningful Improvements in Key LOPD Disease Manifestations (Respiratory Impairment and Reduced Mobility), and the safety has been confirmed.

The long-term extension analysis data published this time show that, nearly 2 years later, the change from baseline at Week 97 (LS Mean SE): (1)Patients who received Nexviazyme treatment during both the double-blind period and the extension period (nearly 2 years) showed a 2.65-point improvement (SE=1.05) in predicted FVC percentage compared to baseline.; Patients who received Nexviazyme treatment only during the extension period showed an improvement of 0.36 points (SE=1.12) compared to baseline. (2)Patients who received Nexviazyme treatment during both the double-blind period and the extension period (nearly 2 years) showed an average increase of 18.6 meters (SE=12.01) in walking distance as measured by the 6-minute walk test (6MWT) compared to baseline.; Patients who received Nexviazyme treatment only during the extension period showed an average increase of 4.56 meters (SE=12.44) compared to baseline.

During the treatment with Nexviazome, the safety profiles of the two treatment groups (the group of patients who continued Nexviazome throughout the study and the group switched to Nexviazome) were comparable. During the extension period, no new safety signals were observed in patients switching from Lumizyme to Nexviazyme. In the two groups, five patients experienced adverse events (AEs) during the extension period (ocular congestion, erythema, urticaria, respiratory distress, acute...Myocardial Infarction, pancreatic cancer) and discontinued treatment. Six patients experienced serious treatment-related adverse events during the treatment period.Adverse Reactions。

Pompe Disease Pathway (Source: foodnhealth.org)

Pompe disease is caused byGeneticsCaused by defects or dysfunction of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to glycogen accumulation in muscles (including proximal muscles and the diaphragm), ultimately resulting in progressive and irreversible muscle damage. This rare disease affects approximately 50,000 people worldwide, manifesting at any age from infancy to late adulthood. Pompe disease is typically categorized as either Late-Onset Pompe Disease (LOPD) or Infantile-Onset Pompe Disease (IOPD). LOPD patients usually present symptoms from the first year of life to late adulthood. Characteristic symptoms of LOPD include impaired respiratory function and skeletal muscle weakness, often leading to reduced mobility. Patients generally require wheelchairs for mobility assistance and may also need mechanical ventilation to aid breathing. Respiratory failure is the most common cause of death among Pompe disease patients. When classified as IOPD, symptoms begin before the age of one. In addition to skeletal muscle weakness, cardiac function is also commonly affected.

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

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

Source of the original text:Nexviazyme? (avalglucosidase alfa) shows sustained improvements in respiratory function and mobility in patients with Pompe disease