Last week, the New York Times reported disappointing news. A promising treatment for Duchenne failed to meet its primary endpoint in a Phase 3 clinical trial. Charley’s Fund has supported the development of this therapy, called Drisapersen. We were hopeful that the trial would be a resounding success, and that was not the case. However the news is not as dire as it may seem. It is clear that the drug had a biological effect on patients. Questions still remain — did the medicine significantly benefit a subset of patients, such as younger boys? Is the beneficial effect impactful enough to outweigh the side effects? Is there a path forward for Drisapersen despite the disappointing results of this one trial? GSK, the company developing the drug, is closely analyzing the data to answer those questions.
In the meantime, as you probably know by now, Charley’s Fund has never been the type to put all our eggs in one basket. We have also supported a company called Sarepta Therapeutics that is developing a drug called Eteplirsen. Sarepta’s drug has a similar mechanism of action as Drisapersen – the drug is designed to produce dystrophin by modifying the way the body reads the genetic code. But there are some key differences between the two products.
SAFETY: Eteplirsen’s safety profile allows it to be administered at high doses. Twelve boys have been taking the drug for two years and NO drug-related adverse effects have been noted. In contrast, Drisapersen is associated with significant side effects. Because of toxicity issues, it is difficult to administer the drug at high enough levels to overcome the variable response rate we saw in the phase 3 trial. We know from previous studies that low-dose exon skipping produces variable results. To effectively treat Duchenne, we need a drug that can be safely dosed at a high enough level to demonstrate statistically significant benefit.
EFFICACY: Eteplirsen produces dystrophin (the protein kids with Duchenne are missing) in 100% of patients who have taken the medicine. The 12 kids who have been lucky enough to take the drug for the past two years HAVE NOT DECLINED since they started producing dystrophin. “Have not declined” is a foreign term to Duchenne families. Every single day Charley declines. Last week he asked me if we can get a lower car so it will be easier for him to climb in. Yesterday I had to switch his dinner time job from “set out drinks” to “napkins and utensils” because he can no longer get a gallon of milk out of the fridge and carry it over to the table. In contrast twelve boys, now ages 9-12, have remained stable for two years while taking this drug.
Don’t get me wrong – Eteplirsen is still an experimental treatment and we still need answers. Will the data hold up when many more kids are taking the medicine? Will the dystrophin production and clinical stability we have seen over the past 2 years be maintained in the long term? Will the stellar safety profile persist after long-term administration of the medicine? There are two ways to get these answers:
1) The FDA can approve Eteplirsen on the basis that it produces dystrophin, the missing protein in Duchenne boys. That will allow all boys who are eligible for the medicine to start taking it by the middle of next year. It will also allow Sarepta to develop more medicines for other boys much more quickly than is typically possible. That means boys like Charley, who are waiting for Sarepta’s follow on compounds, will have access to these medicines much faster.
2)The FDA could require additional testing. That decision would limit this potential life-saver to a handful of boys for several more years and leave behind the vast majority of kids who could benefit from the drug. If the FDA chooses this path, some boys who could have taken a chance on Eteplirsen will die. Others will lose their ability to walk for good. Younger ones will lose their ability to jump up and down, or open a heavy door, or run around the yard with their siblings.
Every day that the FDA is equivocal on this issue means a milestone lost for children with Duchenne.
The FDA must send a clear signal to Sarepta that they support the aggressive approach the company has taken. There is virtually no risk in granting accelerated approval to Eteplirsen as soon as the company submits the New Drug Application early next year. But there is a terrible downside to not granting that approval. Or to taking more time to think about it.
I am sure that talk of clinical trials and investigational new drugs and the FDA can be hard to relate to, so here’s an analogy that I hope will help explain our situation. Your child and thousands of other kids are on the Titanic. A nearby lifeboat may save their lives. There is no guarantee, but in limited test runs the lifeboat performed incredibly well. You are as certain as you can be that the lifeboat will not fare worse than the Titanic, which you know for sure is quickly going down. Should we keep the vast majority of the children on the Titanic – with its known horrific outcome – while we select a few kids to get on the lifeboat for further testing? Or should we allow every kid the option to get into the lifeboat, which is really the only viable option when you consider the alternative?
P.S. For the record, since the NY Times didn’t print Benjy’s letter, here it is:
To the editor,
In “Gene Therapy with a Difference,” Andrew Pollack (albeit unwittingly) further stacks the odds against thousands of dying children. It is too early to describe Drisapersen as “no better than placebo.” If some children responded to the treatment — a possibility under investigation — it is certainly better than nothing. Many approved cancer drugs treat a subset of patients. In addition, calling exon skipping into question without noting key differences between the drugs in development has drastic implications. Children taking Sarepta Therapeutics’ Eteplirsen for more than two years have exhibited zero drug-related side effects. Therefore, the medicine can be administered at high enough doses to overcome the variability that may have doomed the Drisapersen trial. Mr. Pollack’s story makes Eteplirsen guilty by association. The FDA must evaluate each drug on its own merits. Thousands of young lives hang in the balance.
Benjamin Seckler, MD