#MDA2021 — Amondys 45 Safe and Well-tolerated in Phase 1/2 Trial

Editor’s note: The Muscular Dystrophy News Today team is providing in-depth coverage of the 2021 MDA Virtual Clinical and Scientific Conference, March 15–18. Go here to read the latest stories from the conference.

Treatment with Amondys 45 was safe and well-tolerated, showing little to no evidence of accumulation in the blood with the approved weekly dosing, in patients with Duchenne muscular dystrophy (DMD) taking part in a Phase 1/2 clinical trial.

The results, “Casimersen Treatment in Eligible Patients With Duchenne Muscular Dystrophy: Safety, Tolerability, and Pharmacokinetics Over 144 Weeks of Treatment,” were presented this week as a poster at the 2021 MDA Virtual Clinical & Scientific Conference.

DMD is caused by lack of, or very little, production of dystrophin, a protein essential for muscle strength. Most frequently, the DMD gene mutations that result in Duchenne lead to the absence of one of more exons in messenger RNA, the intermediate molecule derived from DNA that guides protein production. Exons act as genetic puzzle pieces, carrying protein-building instructions. When one or more are are missing, the remaining exons might not fit together properly.

Amondys 45, previously known as casimersen, directs muscle cells to skip exon 45 when making dystrophin, enabling remaining exons to attach and resulting in a shorter but still functional version of dystrophin. The therapy, marketed by Sarepta Therapeutics, was approved conditionally in the U.S. for the treatment of DMD patients amenable to exon 45 skipping.

Study 4045–101 (NCT02530905) enrolled 12 male patients ages 7 to 21 — mean age 13.6 — and assigned them randomly to receive either increasing intravenous (into the vein) doses of Amondys 45 (eight participants), or placebo (four participants), for 12 weeks, before entering an extension period in which all received 30 mg/kg of Amondys 45 for up to 132 weeks (about 2.5 years).

Boys and young men included in the study were either on a stable dose of oral corticosteroids or had not received any for at least 24 weeks before beginning the study.

All participants had DMD mutations amenable to exon 45 skipping and were either not able to walk independently or had limited mobility, as measured by a mean distance of 39 meters (about 128 feet) on the 6-minute walking test.

Eleven patients — all of those first given Amondys 45 and three of those receiving placebo — completed the study.

All participants experienced at least one adverse event (side effect). Most were deemed mild in severity and two related to treatment with Amondys 45 — one case of moderate iron deficiency and one of flushing.

Three patients on Amondys 45 experienced a total of five serious adverse events, but these were not considered treatment-related and resolved during the study period.

Overall, the most common side effects included common cold, procedural pain, cough, headache, upper respiratory tract infection, and vomiting. No patient left the study early or reduced dosage on account of an adverse event.

The study revealed no evidence of kidney toxicity, or any potential heart-related issues. The investigators observed no patterns, trends, or abnormalities in clinical health measures, and no deaths were recorded.

All pharmacokinetic parameters — measures of how the medication moves into, through and out of the body — for Amondys 45 at 30 mg/kg remained similar between weeks seven and 60. According to the scientists, this suggests little to no accumulation in blood pasma with weekly dosing.

The U.S. Food and Drug Administration recently granted Amondys 45 conditional approval, based on the preliminary results of the Phase 3 ESSENCE trial (NCT02500381) in males with DMD.  This study, expected to conclude in 2024, has shown a significant increase in dystrophin levels in muscle biopsies at 48 weeks, compared both with measures taken at the study’s start and with those in the placebo group.