Join our online Q&A on exon skipping

I recently attended the FDA Adcomm in the US.
Here are some reflections of that panel meeting and questions that I would like to put to Francesco and Sarepta:

FDA Adcomm Eteplirsen Washington April 2016

Overall I thought that there was sufficient evidence to show that eteplirsen was having a clinical benefit to patients with no or insignificant risk. However the FDA’s critical analysis raised some important questions for clinicians, researchers, biotech companies and the Duchenne community.

Biomarker evidence to FDA

There is evidence from RT-PCR that exon 51 mRNA with eteplirsen supports its mechanism. “But evidence does not show how much mRNA was produced or whether this mRNA led to production of dystrophin” Eric Bastings FDA

The proportion of muscle fibres with dystrophin by immunoflourescence was 17% +- 10%. Eric Bastings FDA: “It is not clear whether 17% constitutes an increase from baseline. Also immunoflourescence is mainly used for showing location rather than quantifying dystrophin.”

By western blot, the best quantitive measure, shows 0.9% +-0.8% dystrophin. Eric Bastings FDA questions how much this is over baseline.

FDA comment that there is no clear data to suggest a threshold when the level of dystrophin might have clinical benefit.

Muscle biopsies are an invasive method and require anaesthesia. This restricts the number of biopsies that can be taken and raises questions about the ethical need for an operation requiring anaesthetics. Exon skipping by this method does not produce an even distribution of protein. There is a chance that samples might be from muscle cells not well skipped or conversely an unrepresentative high level of protein.

Q Will clinical trials with eteplirsen still use dystrophin as a a primary outcome?

If so what methods can be employed to improve the measure of dystrophin protein and what would the target threshold be to show clinical benefit?

Clinical Evidence

No significant difference between boys treated with eteplirsen and placebo as measured by the 6mwt for study201 over 24 weeks – the only randomized study.

No significant difference between boys treated with eteplirsen and placebo as measured by the 6mwt for study202 over 48 weeks.

However, highly significant results for 6mwt 162m when compared to external controls for study 201/202.

Only two boys lost ambulation as compared to 10 out 13 in controls over 4 years.

There was agreement that 162 meters would show effect but FDA questioned if he difference might be related to other factors e.g. steroid use, physical interventions, lack of randomisation, matches between study and patient registry populations. FDA are concerned with bias introduced before, during and after the trial. The FDA also suggested that methods of collecting data using 6mwt and NSAA might be influenced by caregivers and even the boys themselves.

Q Why are measures against placebo not showing an effect even after 48 weeks?

6MWT and the NSAA are measures that do not include quality of life measures for non ambulant patients. How will future trials include non ambulant patients and what outcome measures could be included?

Patient and parent advocacy

Without doubt the evidence presented by young men and family members from real life scenarios (eg climbing in and out of a car) was very compelling and this backed up the overall evidence from Sarepta that there was some measure of clinical benefit following the use of eteplirsen. This evidence, however, was also open to accusations of bias and subjectivity.

Q How can patients and family members be involved in future trials so that the evidence that they can offer be quantified by reliable and valid measures?

Hello,

My son William was recently diagnosed with Duchenne Muscular Dystrophy. William has exon deletion 45-52. I am looking into all research which could possibly help with his condition. I am aware this is focused on exon 51. Could you inform me whether this treatment is something that could help William’s deletion in future or does he have too many exons deleted?

Many thanks,
Caroline Calvert

Hi!
We are from Croatia. Our son, Lovre is 2y,2m old, and he was diagnosed with Ullrich CMD when he was 1.5 years old. He has a dominant de nuovo mutation on COL6 A3 gene, skipping exon 16, and imunohistochemical painting has showed decreased collagen 6 in skin fibroblasts. We know that dr. Bonneman from NIH, Bethesda works on preclinical trials with exon skipping on COL6A3 (dermal skin cells). What sort of clinical trials are there in Europe in this moment, and do you think that Lovre would be a good candidate for clinical trials for exon skipping, becuse of his mutation?

Greetings from Croatia!

Regarding the message from Ms Calvert. This deletion is one that would respond to exon 53 exon skipping. There should be a Sarepta study starting to recruit soon, in addition to our SKIP NMD trial (on exon 53 skipping) in which however recruitment is over and we are now in the maintenance phase of 24 boys.
I am also aware that Biomarin has a study on skipping exon 53 and you should discuss with your phisician what is realistically available to you where you live.

Thanks so much for the doing this Q&A session! I am Leslie Guzmán, the mother of Diego Ramirez with Duchenne, he´s 11 years old and he’s walking. He has deletion 48-52, so he needs Exon 53. My question is – my husband is getting transferred with P&G to Europe. We can pick from Switzerland or UK. Could he join the trial under way that you are running?

Leslie

I agree with Ravi about needing trials for the forgotten DMD adults. My question is would it be financially viable for Sarepta to trial exon skipping in adults??

There are many factors that determine trial design. The most important of which are clinical endpoints that might be expected to respond to drug therapy (eg, performance of upper limb function and respiratory function). We currently conducting a trial in non/poorly-ambulant older boys with eteplirsen in the US. We are planning to look at this population in future studies with our future exon-skipping drugs.

Our goal is to submit an MAA for eteplirsen by the end of the year.