Daiichi DMD trial misses primary efficacy endpoint

Daiichi Sankyo
A delay to the development of DS-5141b would see Daiichi slip further behind Sarepta. (Daiichi Sankyo)

An early-phase trial of Daiichi Sankyo’s Duchenne muscular dystrophy (DMD) drug has failed to show clear evidence of efficacy. But, buoyed by safety data and evidence of exon-skipping activity, Daiichi is pushing ahead with further development of the antisense oligonucleotide.

Daiichi enrolled six DMD patients with out-of-frame deletions amenable to correction by dystrophin gene exon 45 skipping and gave them weekly subcutaneous doses of DS-5141b for 12 weeks. Based on preclinical data, the Japanese drugmaker expected the drug to induce dystrophin mRNA exon 45 skipping and thereby improve outcomes in children with DMD. But data from the phase 1/2 trial have muddied the waters.

“The expression of dystrophin protein, the primary endpoint of efficacy, was partially identified, but was not clearly detected as a whole,” Daiichi wrote in a statement to disclose the results.


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That failure against the primary endpoint left Daiichi looking to other data points for reasons to push ahead with development. On the efficacy front, Daiichi centered in on the increased production of mRNA with exon 45 skipping of the dystrophin gene seen in all patients as a positive. The finding backs up Daiichi’s belief that DS-5141b acts on molecular machinery relevant to DMD. But the failure of this translating into expression of the vital dystrophin protein leaves questions unanswered.

The safety data are clearer, albeit with the caveat that the data set is very small. Daiichi said none of the participants dropped out or suffered clinically significant adverse events. The finding is in line with results from preclinical studies, which suggested that DS-5141b is safe and largely free from the renal toxicity issues that have affected some antisense approaches to DMD treatment.

Daiichi views the safety and mRNA production data as good enough to support further development of DS-5141b, despite the questionable evidence of its effect on expression of the dystrophin protein.

The company has yet to detail the next steps for the drug, though. Daiichi penciled in a 2020 target for the approval of DS-5141b when it started dosing patients in the phase 1/2 trial two years ago. That target is absent from its release to disclose data from the study.

A delay to the timeline would see Daiichi slip further behind Sarepta, which is due to deliver phase 3 data on a drug designed for patients amenable to exon 45 skipping next year. The drug, SRP-4045, is part of Sarepta’s attempt to build on the approval of exon 51 asset Exondys 51 by bringing a clutch of other candidates targeted at different subpopulations of DMD patients to market.  

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