First DMD Gene Therapy Approved—How Many More Are on the Horizon?

March 15, 2024

eMedClub News

Last year, Elevidys (delandistrogene moxeparvovec), a gene therapy developed by Roche in collaboration with Sarepta Therapeutics, received accelerated approval from the U.S. FDA for marketing. It became the first one-time gene therapy for treating Duchenne muscular dystrophy (DMD) in patients aged 4-5.

Muscular Dystrophy (MD) is a group of genetic disorders,Affecting the generation and maintenance of muscles,Can lead to progressive muscle weakness and muscle loss in patients. There are over 30 known types of MD, each with different causes and symptoms.In MD,Duchenne Muscular Dystrophy (DMD) is consideredThe Majority of the Rare, with an incidence rate of 1/3300 in infants and young children, and a probability of causing disability.AlsoExtremely high. The muscles of DMD patients gradually atrophy and lose strength, leading to difficulties in walking during childhood. As the disease progresses, they may completely lose their ability to walk and become dependent on wheelchairs.The extremely urgent clinical treatment needs make this diseaseHas garnered significant attention from numerous enterprises.ElevidysProduct Approved for Marketing，Other gene therapy pipelines have also made significant progress.

The 4th International Conference on Gene Editing and Gene Therapy TechnologySeminar

 

• Next-Generation AAV Gene Therapy Development Strategies

• Innovative Trends and Commercial Translation in Gene Therapy

• Clinical Progress of China's First Phase 3 AAV Gene Therapy for Hemophilia B

• Innovative Design and Clinical Progress of the New Generation SMA Gene Therapy

• AAV-Mediated Delivery of Neurotranscription Factors for In Situ Neural Regeneration in ALS Treatment

• Gene Editing Treatment Strategies for Different DMD Targets

• Gene Therapy for Chronic Diseases: Epigenetic Precision Regulation

• Development Strategies for Gene Therapy Drugs Targeting Telomere Mechanisms in Aging Diseases

• mRNA/LNP-Mediated In Vivo Gene Editing Delivery Strategies

• Non-Viral Vector Gene Therapy Ushers in Gene Therapy 2.0

• In Vivo Gene Therapy for Neurofibromatosis Mediated by Fifth-Generation Lentiviral Vectors

• Opportunities and Challenges of In Vivo Gene Editing Therapy

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Elevidys is the world's first gene therapy for DMD to receive FDA approval.Developed by Sarepta/Roche, it combines the MHCK7 promoter with the AAVrh74 vector to specifically deliver a gene encoding a micro-dystrophin protein to muscle tissue. Through a single intravenous injection, it enables the patient's muscles to produce a recombinant protein with partial dystrophin functionality, which can be effective for patients carrying pathogenic DMD gene mutations.

In the fourth quarter of 2023,Elevidys Generates Net Product Revenue of $131.2 Million, increasing by approximately 90% compared to its net product revenue of nearly $70 million in the early stages of its market launch. Despite being priced at $3.2 million, Elevidys continues to gain market traction due to strong demand and has already become the core driver of Sarepta Therapeutics, Inc.'s performance growth.

PF-06939926 is Pfizer's DMD gene therapy acquired from Bamboo Therapeutics for $150 million. The core technology lies in the utilization ofRecombinant Adeno-Associated Virus Serotype 9 (rAAV9), which is aEfficient Carrier System with Targeted Muscle Tissue CapabilityThis therapy is specifically designed with a mini-dystrophin gene sequence driven by a human muscle-specific promoter, aiming to restore the expression of the missing or defective protein in patients, thereby improving or reversing the disease progression.

It is driven by a human muscle-specific promoter and utilizes rAAV9 as the vector. PF-06939926 is currently in Phase 3 clinical trials, with 14 clinical trial sites established across 8 countries globally. Previously, the drug received Orphan Drug Designation and Rare Pediatric Disease Designation from the FDA.

SGT-001 is a gene therapy developed by Solid Biosciences, driven by the CK8 promoter and delivered via an AAV9 vector. It can deliver copies of the gene encoding micronutrient protein to muscle cells, replacing the defective anti-muscular dystrophy protein gene, thereby producing the relevant protein. It was once hailed as the "star player" in the field of DMD gene therapy, forming the "three main forces" in this field together with Sarepta Therapeutics and Pfizer. However, due to issues related to its safety and efficacy, the pipeline had to be shut down in 2022.

Solid Biosciences' research team has launched a new generation of DMD gene therapy candidate drug – SGT-003, based on previous research experience and lessons. Compared with the previous generation product, SGT-001,SGT-003 utilizes a novel AAV-SLB101 vector system, designed to deliver the micro-dystrophin gene containing R16 and R17 nNOS binding domains more safely and efficiently into patients.. This innovative design is expected to overcome the challenges faced by previous generations of products and further enhance the expression of functional proteins in muscle tissue. According to reports, SGT-003 demonstrated higher micro-dystrophin expression than SGT-001 in preclinical studies, indicating that SGT-003 can be administered at a lower therapeutic dose, thereby improving treatment safety.

This drug not only received approval from the U.S. FDA for a new drug clinical trial application (IND) on November 14, 2023, but also obtained FDA Fast Track designation in December of the same year, undoubtedly providing strong support for accelerating the clinical trial process of SGT-003.

RGX-202 is a product developed by Regen BioPharma.AAV gene therapy combining the muscle-specific promoter Spc5-12 with the NAV AAV8 vector enables precise targeted delivery., ensuring that the therapeutic gene can be expressed precisely and efficiently in skeletal muscle and cardiac muscle, the two main affected tissue sites. In addition, it carries a carefully designed "Mini-Dystrophin" transgene, whichThe micro-dystrophin contains key functional elements of the naturally occurring dystrophin C-terminal (CT) domain.The CT domain can help recruit key proteins to the muscle cell membrane under physiological conditions, thereby enhancing the muscle's resistance to injury, especiallyPrevent damage caused by repeated contractionIn preclinical studies, this was confirmed in a malnourished mouse model, where the transgenic expression successfully improved muscle health in the experimental animals. Additionally, the design of RGX-202 also includesStrategies such as codon optimization and reduction of CpG content can enhance gene expression efficiency and translation rate while minimizing potential risks of triggering immune responses.. It is currently in the phase 1/2 clinical trial stage.

CRD-TMH-001 is an in vivo CRISPR therapy developed by Cure Rare Disease, Inc. that delivers the Cas9 enzyme via high-dose AAV9 to reactivate the backup dystrophin gene in patients.

CRD-TMH-001 Therapy Was"First" CRISPR Gene-Editing Therapy Approved for Clinical Trials to Treat Duchenne Muscular Dystrophy。However, the progress of clinical trials has not been smooth. In October 2022, a 27-year-old patient unfortunately passed away after receiving treatment. In May 2023, researchers determined that the patient's death was not due to CRISPR gene editing but possibly caused by a strong immune response triggered by a high dose of the AAV vector. Therefore, selecting the appropriate dosage will remain a significant challenge in customizing adeno-associated virus (AAV) gene therapies.

Suzhou GenAssist Therapeutics Co., Ltd. is the first company in China to utilize base editing technology for the development of gene therapy drugs. Its first product, GEN6050, aims to restore the expression of dystrophin by achieving exon 50 skipping in the DMD gene through base editing.

On September 29, 2023, Suzhou GenAssist Therapeutics Co., Ltd. successfully completed an online consultation meeting with the TREAT-NMD Advisory Committee for Therapeutics (TACT). The meeting focused on the development plan for GEN6050, GenAssist's lead product, which is about to enter global multicenter clinical trials. On April 24, 2023, GenAssist had submitted a pre-IND application for GEN6050 to the FDA, which was accepted. As one of the early companies to engage in the development of in vivo base editing therapeutics, the company has established a comprehensive evaluation system for base editing drugs both in vitro and in vivo and is developing a series of products targeting DMD.

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