NOTE: Some edits were made (10/27/12) after eagle eyed commenter Richard Trent pointed out some flaws in my summary which I have tried to correct below.
Sarepta Pharamaceuticals recently released data about a very small trial of eteplirsen in boys with Duchenne muscular dystrophy. This medication operates by inactivating an “off switch” in the gene for dystrophin. Dystrophin is the muscle protein affected in Duchenne and Becker muscular dystrophy. Defects in the protein result in muscle breakdown, worsening muscle strength, breathing and heart problems, and eventually death. The only current treatment is oral corticosteroid therapy, which has significant side effects, including weight gain, mood problems, and decreased growth.
The trial in 12 boys with the disease showed promise in increasing a measure called the six-minute walk test. Boys on the higher dose of the drug had a 5% improvement in the distance that they could walk compared to boy not on the medication. Boys who were in the placebo arm had an approximately 17% decline. (They also received the study drug halfway through the trial, without apparent benefit).
This is great news, but I think that we have to take it with a bit of caution, for several reasons.
- Twelve patients is a very small trial, even for a relatively rare disorder like Duchenne.
- The benefit seen was relatively modest.
- Patients in the lower dose group did not see a benefit although the levels of dystrophin in the muscles of these boys increased substantially. These boys were excluded from the analysis but the FDA may not agree with this. Moreover, this lack of a dose-response is concerning to me as it raises the possibility that these effects may disappear in a larger trial.
The New York Times has a good article summarizing these results. Here is a reaction from the Jett Foundation which supports our clinic. You can find my recommendations for the care of boys with muscular dystrophy under ten. Here is a remembrance of a patient who died from this terrible disease.
Doc, I think you misread the press release. Boys on the drug showed an improvement of 21 m after 48 weeks on the drug. Boys who were on placebo for 24 weeks and then on the drug for the next 24 weeks had a decline of 68 m so the improvement is a lot more than 5%, 89M.
Dear Richard– thanks for pointing this out. I’ve endeavored to correct this above. I am troubled by the lack of a dose response relationship in this trial; I am looking forward to reading more than an abstract and press release.
Doc,
1) Were the p<=.016 did not exclude the 2 boys because they quit walking! The 89 meter benefit was a comparison between the 50mg/kg cohort and the placebo group. Therefore this is completely clean comparison.
2) From their time on dosage week 24 to week week 36 the placebo of the crossover group showed an improvement 10 meters -78 meters to -68 meters. This suggests an improvement or a slowing of progression of the disease. If you examine the chart of the placebo crossover boys you will observe from week 0 to week 36 the placebo group were loosing distance walked at a rate of 2.17 meters per week. This would suggest at week 148 they should be at a loss of about 104 meters. Therefore a loss of 68 meters is actually a gain of 36 meters over the distance expected for normal disease progression! And someone suggests the drug is not having an effect on the placebo/delayed group?
In reality a more meaningful slope would be about -4.09 meters per week, the slope derived from week 36 to week 48 which would suggest an additional 23 meters or 59 meters total gained by the crossover from placebo to drug.
I feel more comfortable accepting the conservative 36 meters, because the 6 MWT, as are all tests of physical abilities a noisy test. In reality I would expect the slope of decline on a weekly basis to increase as the disease progresses based on other data I have seen.
Therefore, this statement "They also received the study drug halfway through the trial, without apparent benefit" has been proven completely false beyond a shadow of a doubt!
If you do not realize the reason the placebo group continued to show decline from, trial week 24 to trial week 36, I will explain. If you review the data in AAN presentation on eteplirsen, you will find at 12 weeks the drug had not caused a significant increase in dystrophin. Then when the biopsy was conducted at week 24 on the 30 mg/kg cohort, consistent and significant dystrophin increase was shown in all 4 dosed subjects. Therefore the expectation would be for normal disease progression from week 0 to week 12 and some, but not full improvement to occur by week 24, if viewed in 12 week increments.
This really explains the two twins excluded from the 30mg/kg cohort and from an analysis of combined 30 mg/kg and 50 mg/kg cohorts along with why there was not an instant change in the placebo delayed boys.
As you now realize Andrew Pollack's New York Times story was extremely poor as is your follow on story.
We should also examine the meaning of N=12. My estimate and it is the highest estimate I have seen is there are 2090 boys in the US who could benefit from an eteplirsen approval. This means 12/2090 gives you 0.57%.
This means the trial is being conducted on an extremely high percentage of the boys who would benefit from the skipping of exon 51. Depending on the labeling, it could be the trial was conducted on as high as 2% of the intended population.
The opposing story to this is the GSK trial is being conducted on hundreds of kids, Very true. Why because in the first 12 boy 5 week trial of the GSK/Prosensa drug, proteinuria was found in 100% of the boys. There were also several other treatment related adverse event.
Two trials of Sarepta have failed to identify any treatment related adverse events.
Wow, thanks so much for your insight! I was not at the AAN conference do have been relying on secondary sources. This is terrific.