World Muscle Society Congress: Next Generation Exon-Skipping & Clinical Trial Updates

The World Muscle Society Meeting in Monterey, California saw reports on a number of topics of interest to the community. On Thursday poster sessions covered advances in the next generation of exon-skipping and updates on various clinical trials.

Next Generation Exon-Skipping

Several laboratories presented data on ways to modify the ribonucleic acid “backbones” of antisense oligonucleotides to increase their efficiency. For example, Dr. Dominic Well’s group from the Royal Veterinary College London demonstrated that adding a short piece of a protein called Pip6a can improve the efficiency of exon-skipping in mice that lack dystrophin. Pip6a, known as a “cell-penetrating peptide,” helps move the antisense oligo into muscle cells. Mice treated with these peptide-conjugated oligos showed improved strength and function compared to mice treated with regular oligos.

At the same time, Dr. Sue Fletcher demonstrated that exon skipping can correct metabolic abnormalities in the hearts of mice that lack dystrophin. In separate work, Dr. Fletcher has developed oligos to skip almost all exons in humans, including multi-skips of two to four exons. “The double exon skip is working very efficiently,” she said. “We have also looked at trying to repair very large duplications by removing multiple exons to put the gene back into frame—we can’t take out all of the duplication, but we can reduce the size.” Dr. Fletcher’s laboratory also collaborated with Dr. Kevin Flanigan to develop approaches to skipping duplications of exon 2 and exons 17 and 18.

Dr. Flanigan’s laboratory was able to show skipping of single duplications of exons 2, 12, 18, 21, and 44 and also skipping of double duplications of exons 3-4 and exons 8-9. He concludes that exon-skipping is a feasible approach to restoring dystrophin protein in those with single or double exon duplication mutations.

Clinical Trial Updates

Dr. Brenda Wong reported the results of a six month study of human insulin-like growth factor-1 (IGF-1) in Duchenne.  Participants included 17 boys with Duchenne and 21 boys without Duchenne—all received the drug in this open-label study. Although the drug did improve problems with insulin resistance, no improvement in function (six minute timed walk test) was seen. Dr. Meilan Rutter, who was involved in the study, suggested that perhaps a longer treatment period would have shown a difference in strength.

Another look by Dr. Craig McDonald at the data from the Ataluren phase 2b study that was halted in March of 2010 suggests that the low dose participants, but not high dose participants, show a statistically significant slower rate of decline than those on placebo. The revised analysis calculated a “percent predicted 6 minute walk distance” based on age and height rather than using absolute numbers.

Sarepta (download Sarepta's poster presentation) showed stabilization of walking for all ambulatory subjects at 96 weeks on eteplirsen. The same data was recently reported in a press release.

Dr. Ed Kaye of Sarepta clarified that the company currently has five months of additional data beyond the 96-week point that has not yet been reported due to the lag time required for analysis of the data, and to that end he stated that all the ambulatory boys in the study are still ambulatory now. Commenting on these results in a separate presentation, Dr. Francesco Muntoni said “[without eteplirsen] this is not what happens in my clinic.” He further suggested that these results show that the duration of treatment is more important than the dose. Sarepta is submitting a New Drug Application on the strength of the phase 2 data and in parallel planning a phase III confirmatory study, which is slated to begin in at the end of the first quarter of 2014. 

Directly across the aisle from the Sarepta poster, GSK described the results of the dystrophin analysis in its 48-week phase II study of drisapersen (this was the study that laid the groundwork for the recent phase III study that failed to reach significance). * Participants were assigned to either a continuous dosing regimen, an intermittent dosing regimen, or a placebo matched to one of the two regimens. At 24 weeks, muscle biopsies were obtained from all participants. GSK used two different approaches to determine how much dystrophin was being made in the muscle—immunofluorescence and Western blots—and they also quantified the resulting amount of RNA message missing exon 51. The immunofluorescence technique they used measured the amount of dystrophin across at least 1,000 fibers.  Overall, the combination of these three measurements (the “composite biomarker score”) showed a slight trend for an increase at 24 weeks. At 25 weeks, participants on the continuous dosing schedule showed a statistically significant improvement in their loss of walking ability, but by 49 weeks this difference became a non-significant trend toward a benefit from the drug. Although the company couldn’t detect a linear relationship between the composite biomarker score and walking ability, they did detect an overall “clustering” of boys in the drisapersen arms with higher biomarker scores.**

*Prosensa will host a conference call on Tuesday, October 8, 2013 at 11:00 a.m. ET / 5:00 p.m. CET to discuss the recently-presented data on drisapersen. View the call-in information.

**Note that Dr. Natalie Goemens will provide more detail about the phase III drisapersen study at a talk on Saturday

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