Last updated Feb. 21, 2022, by Teresa Carvalho, MS
Fact-checked by José Lopes, PhD
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.
The FDA gave accelerated, or conditional, approval to Amondys last year. Conditional approval requires longer-term and supporting trial data to merit full approval. But the FDA’s decision made this therapy the first available in the U.S. for the estimated 8% of DMD patients with mutations amenable to exon 45 skipping.
How Amondys works
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, which are portions of a gene that code for protein. As a result of such mutations, the protein that the gene encodes is either shorter than normal or made with errors. This is because the mutation makes the exons 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 that occurs in these patients.
Amondys 45 in clinical trials
A randomized, placebo-controlled Phase 1 study (NCT02530905) evaluated the safety, tolerability, and pharmacokinetics — the therapy’s movement into, through, and out of the body — of Amondys 45 in 12 patients with advanced-stage DMD with mutations amenable to exon 45 skipping.
The study found that Amondys 45 was safe and well-tolerated, showing little to no accumulation in the blood with the weekly dose of 30 mg/kg of body weight.
A Phase 3, double-blind 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.
The trial, in boys with DMD amenable to skipping of exon 45 (Amondys 45) or exon 53 (Vyondys 53), is taking place at clinical sites in the U.S., Europe, Canada, Australia, and Israel. Participants randomly receive either active treatment or a placebo as a once-weekly infusion into the bloodstream for up to 96 weeks, or just short of two years. This phase is followed by an open-label extension phase. Here, all patients will receive active treatment for up to 48 weeks, or a little less than one year.
The study’s main outcome measure 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 April 2024.
Results from an interim analysis after 48 weeks showed that mean dystrophin protein levels in the Amondys 45 treatment group increased to a statistically significant 1.74% of normal compared with 0.93% at baseline.
When the researchers tested a sample of 22 DMD patients who received Amondys 45, all showed an increase in the levels of messenger RNA (produced from the DMD gene) in which exon 45 was skipped compared with their baseline levels. Moreover, there was a statistically significant positive association between exon 45 skipping and dystrophin protein production.
A Phase 3, open-label, extension study (NCT03532542) is now enrolling 260 DMD male participants, ages 7 to 23, by invitation. Its aim is to evaluate the long-term safety of Amondys 45 and Vyondys 53. This study is expected to complete in August 2026.
Amondys 45 is delivered by intravenous (into-a-vein) infusion over 35 to 60 minutes, available in single-dose vials containing 100 mg/2 mL. The recommended dose is 30 mg/kg taken once weekly.
The treatment may cause kidney toxicity. For this reason, several measures of kidney function should be monitored before starting Amondys 45, such as blood levels of cystatin C and urine protein-to-creatinine ratio — ways to assess kidney function and protein in urine — as well as a urine dipstick test, which tests urinary appearance and content.
The most common side effects are upper respiratory tract infections, cough, fever, headache, joint pain, and pain in the mouth and throat.
Additional information may be found on the treatment’s label.
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.