On Tuesday October 15, GSK and Prosensa conducted a conference call for the Duchenne community, especially for members that may not have been at several of the recent meetings where the two companies reviewed data on several of their clinical trials. CureDuchenne provides a recap of the webinar below.
GSK reviewed its phase 3 trial results, which was the largest Duchenne placebo controlled trial to date. There were 125 in the treatment arm and 61 in the placebo arm with the 6MWD as the primary endpoint with various secondary endpoints (NSAA, 4 stair climb, 10m walk run velocity). As many know, the trial did not meet its primary endpoint at 48 weeks nor was a treatment difference seen in the secondary endpoints. The primary endpoint result was confirmed by using a % predicted 6MWD which account for the maturing of the boys through the trial. The placebo arm of the trial seemed to follow the natural history of the boys in terms of decline in 6MWD for age. The company has also done covariate analysis looking for subgroups of boys who may benefit from drug but so far have found nothing.
The only secondary endpoint that showed any meaningfulness was drop in CK level, which indicates that the drug is doing what it is supposed to be doing at the molecular level. Safety results were as expected and consistent with other trials. Two patients dropped out due drug related adverse events. The two safety concerns were injection site reaction and renal effects. GSK said that they are pooling data across all trials that use 6 mg, both treatment and placebo arm data, and results of this aggregate analysis may yield some answers. This analysis should be completed by the end of the year. They will also be looking at the results of the open label extension study DMD114349 where, for some boys, there is up to 4 years worth of data. An amendment to the protocol has been shared with investigators and should be available shortly. Since the study is now unblended, GSK had shared the blind code and investigators and parents will be able to discuss individual results.
Next Giles Campion of Prosensa discussed the ins and outs of dystrophin quantification and reviewed the method(s) that both companies are using, and then gave an overview of Prosensa’s follow on programs and stressed their commitment to Duchenne. As was presented at WMS, dystrophin quantification is difficult for several reasons; to start with there are trace amounts of dystrophin and revertant fibers in muscle, dystrophin expression varies in different muscle groups , and expressing dystrophin levels as a percentage of control is difficult as there is no control. There are 3 methods that are commonly used; Western Blot, immunofluorescence assay (IFA) and RT-PCR. Through years of analysis and practice they have developed a computerized immunofluorescence assay that is the most accurate method as it measures over the entire membrane of the fiber, can differentiate between revertant and pre-existing dystrophin fibers through providing dystrophin fiber intensity and distribution, and is operator independent. RT-PCR and Western blot as used as confirmatory measures and as support for IFA results. They concluded that dystrophin can be used as a surrogate biomarker for Duchenne clinical trials.
He next reviewed the natural history study that Prosensa is doing in conjunction with GSK. The study plans to enroll 250 patients and will help with understanding younger boys, yield information on new biomarkers help find ways around having to use a placebo arm in clinical trials. Lastly Giles reviewed ongoing programs and reiterated Prosensa’s commitment to Duchenne. In the 044 program, preliminary analysis shows that trace dystrophin was present in all fibers, and 12 out of 21 are showing positive dystrophin response after 5 weekly injections, despite the pre-existing dystrophin. No Serious Adverse Events have been seen so far. For the 045 and 053 programs he showed their seamless design so that boys get stay on drug longer and continue on to the next dose cohort more quickly. For all the programs they are using an IV dose of 6-9 mg/kg. Most importantly, when asked what gives him confidence that these other programs will succeed in the light of drisapersen’s failure, he said that drisapersen was designed almost 15 years ago and since then they have learned a lot about sequence optimization. Newer optimization methods for the newer sequences have yielded higher skipping efficiencies in vitro when compared to drisapersen and hopefully this will translate into the clinic.
While clearly not the news the Duchenne community wanted to hear, it is clear that GSK and Prosensa are doing everything they can to get the most benefit out of these results and are committed to the program.