Sanofi's Second Pompe Disease Therapy Avalglucosidase Alfa Approved in China for Long-Term Treatment

October 7,Sanofi Announces NMPA Approval of Next-Generation Enzyme Replacement Therapy (ERT) Avalglucosidase Alfa (Nexviazyme) for Long-Term Treatment of Pompe DiseaseThis marks the approval in China of Sanofi’s second enzyme replacement therapy for Pompe disease, following the global first-in-class treatment Myozyme (alglucosidase alfa for injection), with the aim of establishing a new standard of care for Pompe disease.

Pompe disease is an autosomal recessive genetic disorder and an ultra-rare disease with an extremely small patient population. Due to mutations in the gene encoding acid alpha-glucosidase (GAA), patients exhibit deficient or significantly reduced GAA enzyme activity within lysosomes. This impairment prevents glycogen degradation, leading to its accumulation in the lysosomes of cells such as skeletal muscle, cardiac muscle, and smooth muscle. The resulting lysosomal swelling, cellular damage, and organ dysfunction cause a series of clinical manifestations.

Based on the age of onset, organs involved, and rate of disease progression, Pompe disease is classified into infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). IOPD progresses rapidly; without effective treatment, patients often die from heart failure and respiratory failure at around one year of age. Untreated LOPD leads to irreversible, progressive damage to multiple organs and systems, resulting in long-term dependence on wheelchairs and ventilators, as well as premature death. In May 2018, the National Health Commission, jointly with five other departments, released the First Batch of Rare Diseases Catalogue, which included Pompe disease.

Enzyme Replacement Therapy (ERT) is currently the only proven effective disease-specific treatment for Pompe disease and is recommended as a long-term therapeutic regimen by multiple authoritative global guidelines and consensus statements.Avalglucosidase alfa can target the mannose-6-phosphate (M6P) receptor, thereby improving the delivery of GAA to muscle cells, enabling the breakdown of excess glycogen and reducing damage to patients' muscle cells.

In 2021, avalglucosidase alfa (avalglucosidase alfa for injection) received FDA approval for the treatment of late-onset Pompe disease in patients aged 1 year and older; this June, avalglucosidase alfa was approved by the European Commission for the long-term treatment of patients with Pompe disease, including both late-onset Pompe disease (LOPD) and infantile-onset Pompe disease (IOPD). Currently,Avalglucosidase alfa has been successively approved in Japan, Canada, Australia, Brazil, and other countries or regions, and has been granted “Breakthrough Therapy” designation by the FDA.。

In China, avalglucosidase alfa was first approved for clinical trials in September 2021, with its marketing application submitted in July 2022 and included in the priority review program in August of the same year.

The randomized, double-blind, multinational, multicenter, pivotal Phase III COMET study evaluated the efficacy and safety of avalglucosidase alfa in 100 patients with Pompe disease across 55 investigational centers in 20 countries. Results from the 97-week extension study showed that, compared with baseline:

1. Patients who received Neralzan treatment during both the initial analysis period (49 weeks) and the extension study period showed a 2.65 (1.05) percentage point increase in the percent predicted forced vital capacity (FVC);

2. Among patients who switched from first-generation enzyme replacement therapy to Nalzan during the extension study period, the percent predicted FVC increased by 0.36 (1.12) percentage points;

3. Patients who received Nairizan treatment during both the initial analysis period (49 weeks) and the extension study period showed an increase of 18.60 (12.01) meters in the 6-minute walk test (6MWT) distance;

4. Among patients who switched from first-generation enzyme replacement therapy to Nalzen during the extension study period, the 6-minute walk test (6MWT) distance increased by 4.56 (12.44) meters;

5. During the initial analysis period (49 weeks), Nairizan demonstrated a favorable safety profile, and no new safety events were observed during the extended study period (97 weeks).

According to the official website of the Center for Drug Evaluation (CDE), Sanofi is conducting an open-label, multicenter, Phase III clinical study in China to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of avalglucosidase alfa via intravenous infusion in pediatric subjects with untreated infantile-onset Pompe disease (IOPD) (Registration No.: CTR20220417). The clinical trial was first publicly registered in February 2022 and is currently ongoing.

Prior to avaloglucosidase alfa, alglucosidase alfa (Myozyme) was the only enzyme replacement therapy (ERT) approved for the treatment of Pompe disease. Alglucosidase alfa, also developed by Sanofi, received FDA approval in April 2006.

In China, alglucosidase alfa was first approved in 2015. The marketing application was submitted in June of the same year, and the product entered the Chinese market four months later through the CFDA’s process waiving Phase III clinical trials.

According to CDE data queries, alglucosidase alfa is currently undergoing Phase IV clinical trials for late-onset Pompe disease (LOPD). For infantile-onset Pompe disease (IOPD), Sanofi disclosed Phase IV clinical trial data last August. This marked the first clinical study of enzyme replacement therapy (ERT) for Pompe disease conducted in mainland China, aiming to evaluate the efficacy and safety of ERT in Chinese children with IOPD. The results demonstrated that alglucosidase alfa for injection significantly improved survival rates, reduced cardiomyopathy, and enhanced growth and development in Chinese pediatric patients with IOPD, while delaying disease progression and exhibiting a favorable safety profile.

Compared with alglucosidase alfa, avaloglucosidase alfa is specifically designed to enhance receptor targeting and enzyme uptake through greater affinity for the M6P receptors on muscle cells, thereby improving glycogen clearance and boosting the clinical efficacy of alglucosidase alfa. Sanofi stated that, as a next-generation ERT drug for Pompe disease, Nexviazyme (avaloglucosidase alfa) has mannose-6-phosphate (M6P) levels 15 times higher than those of first-generation enzyme replacement therapies. Higher M6P levels can improve enzyme delivery to muscle cells, increase cellular enzyme uptake, and thereby facilitate the breakdown of excess glycogen, reducing damage to patients’ muscle cells.

As a multinational pharmaceutical company, Sanofi has established research portfolios in cardiovascular diseases, vaccines, diabetes, immunology, rare diseases, and oncology.According to the official website, as of now, there are at least 78 clinical-stage projects.This includes expanding indications for already marketed drugs, such as the Phase 3 clinical trials of dupilumab for the treatment of chronic pruritus of unknown origin, bullous pemphigoid, and COPD.

In the field of rare diseases, in addition to Pompe disease, Sanofi is developing seven new drugs targeting conditions such as Fabry disease, Gaucher disease, and Mucopolysaccharidosis Type I. Furthermore, Sanofi has established a comprehensive presence in the field of rare hematological disorders, forming a product portfolio for the treatment of various rare blood diseases, including Hemophilia A and B, Immune Thrombocytopenia (ITP), and Cold Agglutinin Disease (CAD). This portfolio includes five investigational new drugs such as Efanesoctocog alfa, Fitusiran, and Rilzabrutinib.

Sanofi’s portfolio of rare disease medications has filled critical gaps in the treatment of rare diseases in China. In July 2018, teriflunomide was approved for marketing in China, indicated for the treatment of patients with relapsing forms of multiple sclerosis, becoming the first oral disease-modifying therapy (DMT) approved in the country for multiple sclerosis. In December 2019, agalsidase beta, developed by Sanofi, received approval in China for the treatment of Fabry disease; it was the first drug approved in China for this indication, suitable for children and adolescents aged 8 years and older, as well as adults.

Since entering China, Sanofi has introduced multiple ultra-rare disease medications, including Cerezyme, Myozyme, Fabrazyme, and Aldurazyme, for the treatment of lysosomal storage disorders such as Gaucher disease, Pompe disease, Fabry disease, and Mucopolysaccharidosis Type I. Currently, the number of diagnosed patients for these conditions in China is only in the hundreds, representing less than one in a million of the total population, which typifies them as “ultra-rare diseases.”

Currently, Sanofi has obtained approval for the market launch of 10 new rare disease drugs in China.

According to the National Healthcare Security Administration, 26 rare disease drugs have been included in the National Reimbursement Drug List through price negotiation for catalog access, with an average price reduction of over 50%. Combined with other drug access pathways, more than 50 of the 75 rare disease drugs currently approved for marketing in China have been included in the National Reimbursement Drug List.