FDA Approves Amondys 45 for Duchenne Patients Amenable to Exon 45 Skipping

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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The U.S. Food and Drug Administration (FDA) has conditionally approved Amondys 45 — formerly known as casimersen — by Sarepta Therapeutics as the first treatment for people with Duchenne muscular dystrophy (DMD) amenable to exon 45 skipping.

Accelerated, or conditional, approval is granted to a medication whose immediate availability fulfills an unmet medical need, provided early evidence of its benefits outweigh potential risks.

Amondys 45’s continued use, and full approval, requires further verification of clinical benefit in the global, confirmatory Phase 3 ESSENCE study (NCT02500381), whose preliminary data supported today’s FDA decision.

That ongoing trial, which is expected to conclude in 2024, is evaluating the therapy’s safety and effectiveness in people with DMD-causing mutations amenable to exon 45 skipping.

“This is an important day for Sarepta and, far more importantly, for the patients that we serve. After years of scientific commitment, investment and development, the approval of Amondys 45, Sarepta’s third approved RNA therapy, offers treatment to the 8% of the DMD community who have a confirmed exon 45 amenable mutation,” Doug Ingram, Sarepta’s president and CEO, said in a press release.

“Along with our other approved RNA therapies, we can now offer treatment options for nearly 30% of Duchenne patients in the U.S. And our commitment to bring therapies to the greatest percentage of the DMD community as soon as possible continues,” Ingram added.

Amondys 45 is given through once-weekly intravenous infusions at a dose of 30 mg/kg of body weight, and will carry a U.S. list price similar to other Sarepta exon-skipping therapies, the company said.

The decision comes six months after the FDA accepted and granted priority review to Amondys 45’s regulatory application.

DMD is caused by no, or very little, production of dystrophin, a protein essential for muscle strength, due to mutations in the DMD gene. Most commonly, these mutations lead to the absence of one of more exons in the DMD gene’s messenger RNA (mRNA), the intermediate molecule derived from DNA that guides protein production.

Exons are like pieces of a puzzle that contain information to produce proteins. When one or more exons are missing, the remaining exons might not fit together properly, affecting how the dystrophin protein is produced.

Exon skipping therapies such as Amondys 45 work by driving a cell’s protein-making machinery to skip over mismatched exons, allowing those that again fit together to attach — like in a puzzle — and enable the production of a shorter but functional version of dystrophin.

This is achieved with antisense oligonucleotides (ASOs), lab-made molecules designed to be complementary to a specific region in the intermediate mRNA.

Kidney toxicity has been observed after administration of some ASOs, the FDA noted in its approval decision, although not in trials of Amondys 45. Still, the agency recommends that kidney function be monitored in Duchenne patients using the therapy.

In the ESSENCE trial, the most common side effects observed (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 targets the estimated 8% of DMD patients with disease-causing mutations amenable to exon 45 skipping, and works to stabilize or slow the progression of their disease.

The two other Sarepta exon-skipping therapies available in the U.S. are Vyondys 53 (golodirsen) for people with mutations amenable to exon 53 skipping, and Exondys 51 (eteplirsen) for those amenable to the skipping of exon 51.

The Sarepta-sponsored ESSENCE study, in addition to evaluating Amondys 45, is also serving as a post-marketing confirmatory trial for Vyondys 53, whose accelerated approval was granted by the FDA in December 2019.

The Phase 3 trial, which opened in September 2016, aims to enroll up to 222 Duchenne patients amenable to exon 45 or exon 53 skipping.

Participants are randomly assigned, 2:1, to either treatment or a matching placebo for 96 weeks (nearly two years), after which all are being given the therapy for another 48 weeks (about one year) in an open-label trial extension.

ESSENCE’s main goal is to assess changes in patients’ muscular strength and ability through the six-minute walk test, which measures how far a person can walk in six minutes on a hard flat surface.

Preliminary trial data from the first 43 participants — 27 assigned to Amondys 45 and 16 to a placebo; all ages 7 to 20 — were confirmed by the FDA in its approval announcement. Findings showed that, after 48 weeks, those given the treatment experienced a significant increase in dystrophin levels in muscle biopsies, compared both with measures taken at the study’s start and with those in the placebo group.

The agency also noted that ESSENCE is continuing and Amondys 45’s clinical benefit, including in muscular strength and ability, is not yet established.

Still, Amondys 45 “provides a targeted treatment option for Duchenne muscular dystrophy patients with this confirmed mutation,” said Eric Bastings, MD, deputy director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Decades of research and commitment have fueled and now accelerate our progress towards new treatments for Duchenne,” said Marissa Penrod, founder of Team Joseph and parent of an 18-year old with Duchenne.

“The extraordinary diligence and persistence of the Duchenne community — patients and families, clinicians and researchers — have led us to today’s approval, where we now have exon-skipping treatments for almost a third of those with Duchenne,” Penrod added.

Parent Project Muscular Dystrophy (PPMD) also welcomed the FDA decision, and reported on its website that DMD patients eligible for Amondys 45 treatment can learn more about the therapy and its access through the patient assistance program SareptAssist or by calling 1-888-727-3782.