Amondys 45: New targeted drug for Duchenne Muscular Dystrophy (DMD)

Amondys 45: New targeted drug for Duchenne Muscular Dystrophy (DMD).   Duchenne muscular dystrophy is a relatively rare genetic disease that mainly affects boys.

Rare diseases refer to diseases with a prevalence rate of less than one in ten thousand. At present, more than 6000 rare diseases have been discovered internationally. About 50% of rare diseases come onset at birth or childhood, with high rates of death and disability, causing great suffering to families. What we are concerned about today is such a rare disease-Duchenne muscular dystrophy (DMD).

The US FDA has accelerated the approval of the antisense oligonucleotide therapy Ammondys 45 (Casimersen) for the treatment of patients with Duchenne muscular dystrophy with a jumping mutation in the exon 45 gene.

This is the third targeted therapy approved by the FDA for exon skipping mutations and the fifth approved drug for Duchenne muscular dystrophy.

In the past five years, the FDA has approved three drugs that target exon gene jumping to treat DMD: Exondys 51, Vyondys 53, and Viltepso.

Exondys 51 is the first DMD targeted therapy approved for the treatment of jumping mutations in the exon 51 gene. Vyondys 53 and Viltepso were approved for the treatment of DMD patients with jumping mutations in the exon 53 gene in December 2019 and August 2020, respectively.

Up to now, three antisense oligonucleotide therapies targeting skip mutations in exons 51, 53, and 45 have been approved, covering about 30% of DMD patients, which is a major advancement in clinical treatment.

▌Rare genetic disease: DMD

Duchenne muscular dystrophy (DMD) is a rare X-chromosome recessive genetic disease characterized by progressive muscle degeneration and weakness. It is the most common type of muscular dystrophy and mainly occurs in boys.

DMD patients generally suffer from muscle weakness or atrophy due to the continuous degeneration of skeletal muscles when they are 3 to 5 years old, resulting in difficulty in sitting and standing, inconvenience in walking, and difficulty in climbing stairs. Afterwards, the sexual aggravation gradually increases. Around the age of 7 to 12, they will completely lose the ability to walk and need the help of a wheelchair; and most of them will die of heart and lung failure if they live less than 20 years old.

According to statistics, one out of every 3,600 newborn boys in the world suffers from this terrible disease. Currently, like most rare genetic diseases, DMD cannot be cured. Most patients mainly focus on symptomatic treatment and supportive treatment, including nutrition, physical therapy and orthopedics, and prevention of spinal deformation and joint contractures.

▌Exon skipping therapy

Duchenne muscular dystrophy is caused by a mutation in the dystrophin (DMD) gene on the X chromosome, which causes the loss of dystrophin (dystrophin), a protein that helps keep muscle cells intact. Can cause progressive muscle degeneration and atrophy. Therefore, increasing dystrophin as early as possible is the key goal for the treatment of DMD.

The exon skipping therapy is in the process of protein manufacturing, part of the gene code is “skipped” (spliced ​​or omitted), allowing cells to produce short but preserved part of the function of dystrophin, that is, the muscle protein missing in DMD.

In this way, although the newly produced dystrophin protein is smaller than the normal protein, it retains part of the normal function of the protein and helps reduce severe muscle weakness and atrophy.

▌Antisense oligonucleotide therapy: Amondys 45

Amondys 45 is an antisense oligonucleotide drug that uses Sarepta’s proprietary phosphodiamide morpholino oligomer (PMO) chemistry and exon “jumping” technology to skip exon 45 of the DMD gene Mutations to avoid genetic mutations and produce more dystrophin.

It is estimated that 8% of DMD patients are suitable for Amondys 45 treatment.

Although Amondys 45 cannot cure DMD, it can slow the progression of the disease, which in turn may prolong the time for DMD patients to walk independently, eat alone, and breathe independently.

▌Achieving the target ahead of schedule, the new drug has amazing effects!

This accelerated approval is based on the positive results of a global, randomized, double-blind, placebo-controlled Phase 3 clinical trial (ESSENCE). The trial aims to evaluate the efficacy and safety of Amondys 45 in DMD patients with skip mutations in exon 45.

The ESSENCE trial is underway and is expected to end in 2024. The FDA’s current approval is based on the fact that Ammondys 45 has reached all statutory standards regarding safety and effectiveness, and has proven that the production of dystrophin in the skeletal muscle of DMD patients has increased.

Amondys 45 is expected to become a therapy for the treatment of DMD’s fourth exon gene jumping. It is believed that in the future, with the continuous acceleration of drug development, all neuromuscular rare diseases can have a broad therapeutic prospect.
Compared with other diseases with higher morbidity rates, patients with rare diseases face greater dilemmas: difficult diagnosis, high misdiagnosis rate, inability to afford special medicines, and lack of R&D motivation for patients due to the small market size and the lack of available medicines for patients Wait.

In the past decade, 14 therapies for the treatment of neuromuscular diseases have been approved globally, of which 12 have been approved by the FDA, which can be described as “high-yielding.” 

(source:internet, reference only)

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