Duchenne Muscular Dystrophy (DMD)

Amondys 45TM  (casimersen) is an antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation in the DMD gene that is amenable to exon 45 skipping. Amondys 45TM approval was granted in February 2021, under the Food and Drug Administration Accelerated Approval Program.1,2

DMD is an X-linked degenerative neuromuscular disease characterized by progressive muscle weakness and degeneration.3 It is caused by framshift, or nonsense, mutations in the DMD gene, which encodes a protein, dystrophin, that is essential for muscle contraction. The mutations result in the inability of cells to produce functional dystrophin. The consequences are destabilization of the structure of muscle tissue, the formation of fibrous tissue, inflammation, and further muscle damage.4

Currently, no cure is available for DMD, and the long-term administration of glucocorticoids has been used in an effort to improve patients’ quality of life.5 Disease-modifying treatments for DMD have now been approved, including exon-skipping drugs such as Amondys 45 (casimersen), Vyondis 53TM (golodirsen), and Exondys 51 (eteplirsen).6-8 With these gene-based therapies, which have been designed to restore the production of functional dystrophin, the binding of an antisense oligonucleotide to a target exon in the pre-mRNA transcript causes that exon to be skipped during mRNA processing. A truncated yet functional protein is then produced because the reading frame has been restored.6

Mechanism of Action and Pharmacokinetics

To develop casimersen, Sarepta Therapeutics used technology based on phosphorodiamidate morpholino oligomer (PMO) chemistry. The PMO subclass consists of synthetic molecules with a 6-membered morpholino ring in their structure. The morpholino ring is substituted for the 5-membered ribofuranosyl ring found in DNA and RNA molecules.6 Casimersen is an antisense oligonucleotide with 22 subunits. The drug binds to exon 45 in the DMD gene, so that this exon is excluded when mRNA is processed. Although it is shorter, the dystrophin protein that is produced is fully functional and can compensate for the decreased protein levels in patients with DMD.1

The FDA approval of casimersen was based on the increased dystrophin production observed in patients with DMD who were treated with the drug.1 The increased production of a functional protein may be associated with a clinical benefit; however, this benefit is still to be established, and the continued approval of casimersen may be conditional.2

The recommended dose of casimersen is 30 mg/kg, administered once weekly by intravenous infusion. The drug is available in a single-dose vial at a concentration of 100 mg/2 mL (50 mg/mL); dilution in 0.9% sodium chloride is required before use. Casimersen exhibits a low level of binding to human plasma proteins (approximately 8%-32%). Peak plasma concentrations occur by the end of the infusion, and the drug is eliminated unchanged (>90%), mainly in urine. The potential for drug-drug interactions is small.1

Casimersen in Clinical Trials

The safety, tolerability, and pharmacokinetics of casimersen were evaluated in a randomized, double-blind, placebo controlled phase 1/2 trial (NTC02530905).9 The 12-week study enrolled 12 participants who had a mutation amenable to exon 45 skipping. The trial included an open-label extension that lasted for up to 132 weeks. The participants were between 7 and 21 years old and had limited ambulation or were non-ambulatory. This was a dose-titration study in which the patients were first randomized in a 2:1 ratio to receive escalating doses of the drug. In the extension study, all patients received 30 mg/kg once a week. The study showed an acceptable tolerability profile for casimersen, and no serious adverse events were described.9

Get detailed prescribing information on the Amondys 45 monograph page at MPR.

The ESSENCE trial (NCT02500381) is a randomized, double-blind, placebo-controlled phase III trial that is currently ongoing. The participants are boys between 7 and 13 years old with a confirmed mutation amenable to exon 45 skipping.6 In the interim results of this 96-week trial, the mean dystrophin levels increased from 0.93 % at baseline to 1.74 % at week 48. The patients have been treated with casimersen at a dosage of 30 mg/kg once a week. In the placebo group, the observed change in the dystrophin levels was from 0.54% to 0.76 %.1 A 100% response rate was observed in the patients treated with casimersen, which means that in 100% of the patients, it was possible to verify an increase in exon 45 skipping. The intravenous infusion of casimersen was well tolerated; adverse reactions observed in more than 20% of the participants included infections in the upper respiratory tract, cough, pyrexia, headache, arthralgia, and oropharyngeal pain.1 The increase in dystrophin levels and its correlation with a clinical benefit is, however, yet to be established. The results of the ESSENCE trial supported the accelerated approval of Amondys 45TM; continued approval may be conditional, however, depending on a confirmation of clinical benefit in confirmatory trials. The trial is expected to conclude in 2024. 

Another 2 clinical trials to evaluate the safety, tolerability, and efficacy of casimersen are ongoing.6 NCT03532542 is an open-label phase 3 extension study that is evaluating the tolerability and safety of casimersen and golodirsen in patients who have DMD with mutations amenable to exon 45 or exon 53 skipping for up to 144 weeks. NCT04179409 is a phase 2 trial to evaluate the efficacy and safety of casimersen, eteplirsen, and golodirsen in patients who have DMD with a single exon 45, exon 51, or exon 53 duplication, respectively.


1. Amondys 45 (casimersen) injection, for intravenous use: US prescribing information. US Food and Drug Administration. Revised February 2021. Accessed August 12, 2021.

2. FDA approves targeted treatment for rare Duchenne muscular dystrophy mutation. News release. US Food and Drug Administration; February 25, 2021. Accessed August 12, 2021.

3. Duchenne muscular dystrophy (DMD). Muscular Dystrophy Association. Accessed August 12, 2021.

4. Causes/inheritance. Muscular Dystrophy Association. Accessed August 12, 2021.

5. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17(3):251-267. doi:10.1016/S1474-4422(18)30024-3.

6. Shirley M. Casimersen: first approval. Drugs. 2021;81(7):875-879. doi:10.1007/s40265-021-01512-2

7. Golodirsen (Vyondys 53) for Duchenne muscular dystrophy. Med Lett Drugs Ther. 2020;62(1603):119-120. PMID:32728014

8. Lim KR, Maruyama R, Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther. 2017;11:533-545. doi:10.2147/DDDT.S97635

9. Wagner KR, Kuntz NL, Koenig E, et al. Safety, tolerability, and pharmacokinetics of casimersen in patients with Duchenne muscular dystrophy amenable to exon 45 skipping: a randomized, double-blind, placebo-controlled, dose-titration trial. Muscle Nerve. 2021; doi:10.1002/mus.27347

Reviewed by Debjyoti Talukdar, MD, on 8/12/2021.