Amondys 45, previously casimersen, is a treatment by Sarepta Therapeutics for Duchenne muscular dystrophy (DMD) patients with mutations amenable to exon 45 skipping.

It is the third Sarepta exon-skipping therapy that the U.S. Food and Drug Administration (FDA) approved for DMD patients. The other two are Exondys 51 (eteplirsen) for patients amenable to exon 51 skipping and Vyondys 53 (golodirsen) for those with mutations amenable to exon 53 skipping.

How does Amondys 45 work?

DMD is a rare genetic disease in which muscles lose strength and degenerate over time. It is caused by mutations in the DMD gene. The largest in the human genome, the DMD gene consists of 79 exons (portions of a gene that code for protein). As a result of the mutations, the protein that the gene encodes is either shorter-than-normal or made with errors. This is because the exons after the mutation do not align in a proper sequence. Dystrophin, the protein that the DMD gene encodes plays an essential role in maintaining muscle health. So its absence causes the muscle cells to weaken and degenerate over time. 

Amondys 45 uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology. It directs the muscle cells to skip exon 45 when processing the messenger molecule that cells use to make dystrophin protein. When exon 45 is skipped, the remaining exons can “fit together” in the right sequence. This allows the production of a shorter but still functional dystrophin protein. The treatment could potentially slow the decline in muscle strength. 

Amondys 45 in clinical trials

A randomized, placebo-controlled dose-adjustment Phase 1 study (NCT02530905) evaluated the safety, tolerability, and pharmacokinetics (movement in the body) of Amondys 45 in 12 patients with advanced-stage DMD with mutations amenable to exon 45 skipping. The study is complete but researchers have not published the results yet.

Ongoing clinical trials

A Phase 3, double-blind, placebo-controlled clinical trial called ESSENCE (NCT02500381) is underway to evaluate the efficacy and safety of Amondys 45 and Vyondys 53. Preliminary data from this global study supported conditional FDA approval of both Amondys 45 and Vyondys 53. Conditional approval requires longer-term and supporting trial data to merit full approval.

The trial in 222 boys, ages 7 to 13, with DMD amenable to exon 45 or exon 53 skipping is taking place at clinical sites in the U.S., Europe, Canada, and Israel. Participants randomly receive either active treatment or a placebo as a once-weekly infusion into the bloodstream for up to 96 weeks. This randomized phase is followed by an open-label extension phase. Here, all patients will receive active treatment for up to 48 weeks.

Its main goal is changes in muscle strength from study start (baseline), as measured by changes in the six-minute walk test. Secondary outcomes include changes in dystrophin protein production and respiratory strength (measured by forced vital capacity, or the amount of air that can be expelled in one forced breath). Researchers expect to complete the trial in May 2023.

Sarepta Therapeutics announced positive results from an interim analysis after 48 weeks. The key findings were:

  • Mean dystrophin protein levels in the Amondys 45 treatment group increased by a statistically significant 1.736% compared with 0.925% in the placebo group. 
  • When researchers tested a sample of 22 DMD patients who received Amondys 45, all showed an increase in the levels of mRNA in which exon 45 was skipped compared with their baseline levels. This represented a 100% response rate. Moreover, there was a statistically significant positive correlation between exon 45 skipping and dystrophin protein production.

A Phase 3, open-label, extension study (NCT03532542) is enrolling 260 DMD male participants, ages 7 to 23, by invitation. Its aim is to evaluate the long-term effects of Amondys 45 and Vyondys 53. Researchers expect to complete it in August 2026.

Other information

The FDA gave accelerated, or conditional, approval to Amondys 45 on Feb. 25, 2021. This made it the first treatment available for the estimated 8% of DMD patients with mutations amenable to exon 45 skipping.

In the ESSENCE trial, the most common side effects (reported in at least 20% of treated patients) were upper respiratory tract infections, cough, fever, headache, joint pain, and pain in the mouth and throat.

Amondys 45 is a once-weekly intravenous infusion at a dose of 30 mg/kg of body weight.

 

Last updated: Feb. 25, 2021

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Muscular Dystrophy News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.
Total Posts: 31
Özge has a MSc. in Molecular Genetics from the University of Leicester and a PhD in Developmental Biology from Queen Mary University of London. She worked as a Post-doctoral Research Associate at the University of Leicester for six years in the field of Behavioural Neurology before moving into science communication. She worked as the Research Communication Officer at a London based charity for almost two years.
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Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.
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