Last updated March 9, 2022, by Teresa Carvalho, MS
Fact-checked by José Lopes, PhD
DS-5141 is an exon skipping therapy being developed by Daiichi Sankyo and the Orphan Disease Treatment Institute in Tokyo to treat people with Duchenne muscular dystrophy (DMD) amenable to exon 45 skipping.
How DS-5141 works
DMD is caused by mutations in the DMD gene, which provides instructions for making a protein called dystrophin that is key for muscle health during movement. When the DMD gene is “read,” the genetic code, made of introns and exons, is copied into a temporary molecule called messenger RNA. The introns are then removed and the remaining exons are spliced together to form a mature protein coding sequence.
Certain mutations can result in a frameshift, a situation in which the DNA code gets out of alignment, causing all subsequent parts to be read incorrectly.
DS-5141 works by binding to exon 45, so that genetic code is “re-aligned” and the cell’s machinery can continue reading the messenger RNA. The protein that is produced is a shorter but functional form of dystrophin.
DS-5141 in clinical trials
A Phase 1/2 clinical trial of DS-5141 (NCT02667483) was conducted in seven boys with Duchenne amenable to exon 45 skipping in Japan.
In the first part, study participants were given subcutaneous (under the skin) injections of DS-5141 once a week for two weeks. Doses ranged from 0.1 mg/kg to 6 mg/kg. In the second part, two selected doses of DS-5141 from part one were administrated once weekly for 12 weeks, and then over 48 weeks in its extension.
The trial’s goal was to evaluate DS-5141’s safety, tolerability, and pharmacokinetics (the movement into, through and out of the body). Early evidence of effectiveness was evaluated through production of the dystrophin protein and of messenger RNA with exon 45 skipping.
Results showed that dystrophin was detected in some, but not all, of the treated patients treated with DS-5141, while messenger RNA with exon 45 skipping was detected in all participants. No serious adverse events were reported and no patients discontinued treatment.
More recent data demonstrated a “clear increase” in dystrophin production in several boys. Messenger RNA with exon 45 skipping was again seen in all participants and the safety profile continued to be good, with no clinically significant adverse events.
An open-label Phase 2 study (NCT04433234), also in Japan, is evaluating the safety and efficacy of long-term treatment with DS-5141 in eight DMD patients, including those who completed the previous trial. Boys, ages 5 and older, are being given 2 mg/kg or 6 mg/kg once weekly for about two years.
Its primary goals address safety, measured in reported adverse events or side effects, and treatment efficacy. Effectiveness evaluations include changes in the distance walked during six minutes, a common assessment of motor function, and time to stand, and time to walk or run 10 meters. The study is also assessing changes in the NorthStar Ambulatory Assessment Score, a standard measure of DMD severity in ambulatory patients. A secondary goal is to determine DS-5141 levels in the blood.
The trial is expected to end in March 2023.
Other information
DS-5141 received a SAKIGAKE designation from Japan regulators in April 2017, which is intended to support the development and speed the review of potential therapies for serious and life-threatening diseases. Treatments given this designation are likely to be more quickly made available to patients in Japan than elsewhere, if approved.
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