On Monday, Charley turned 13 years old. Birthdays cause emotional turmoil for all Duchenne parents I know. We’re deeply grateful for every single day with our children in a way that most people thankfully are just not aware. We’re also deeply sad that each day of being older means a day of lost muscle function and a day closer to Duchenne’s inevitable, universal outcome. Every single child with Duchenne is subject to the inevitable decline and ultimate death sentence.
In July, Charley could walk 500 meters in six minutes. Three months later he could only cover 475 meters. Sadly, this decline is not a surprise. Duchenne is predictable. Duchenne is progressive. Children with the disease do not produce dystrophin, a protein necessary for muscle strength and function. Lack of dsytrophin leads to loss of ambulation, which leads to loss of upper body function, which leads to cardiac and/or pulmonary failure. Every single time.
As you can imagine, scientists have been working for decades to figure out how to get the body to produce dystrophin. Now we finally have a drug that does just that – produces the missing protein. What’s more, the 12 boys who have been lucky enough to try this drug in a clinical trial have stabilized since the dystrophin was produced in their muscle cells. We know that in these 12 boys at least, we can produce dystrophin – dystrophin that works. I will outline the crucial facts here, but if you want to help and you only have a minute, skip to the end of this blog entry right now, where it says “PLEASE HELP. “ If you have 5-10 minutes, continue reading.
Some key facts about the 12 boys:
• Four boys have IMPROVED on the 6 minute walk test over the course of two years. Stabilization alone would be cause for champagne, but in 1/3 of the boys we are seeing actual improvement – they are STRONGER than they were two years ago, unheard of in Duchenne. Could this be a fluke? Could the 6 minute walk test be unreliable? Sure, but the test was done twice each time. And the results have held up for two years. And the boys are producing dystrophin. So to look for some other unlikely reason they might be doing better against all odds (Sheer will? Happen to have great days on testing days?) is akin to looking for a zebra when a horse is staring us in the face.
• Four boys in the trial were on placebo for the first 24 weeks, then crossed over to drug. While on placebo these four boys declined, as expected. When they first started treatment they continued to decline but once the dystrophin kicked in, they stabilized. We have followed hundreds of untreated boys in natural history studies and placebo arms of other clinical trials. I’ll put my money down that there aren’t many –if any — boys aged 9-11 who started to rapidly decline, then stabilized. If they are out there, I do not know them.
• Two of the 12 boys (twin brothers) lost their ability to walk near the start of the trial, before the dystrophin had a chance to start working. Those boys remain on drug and their upper body function and breathing ability remains stable.
Yesterday Sarepta, the company developing this drug, announced that the FDA does not encourage submission of a New Drug Application (NDA) at this time. This is a direct turnaround from the FDA’s position just three months ago, when, according to Sarepta, they told the company they would accept an NDA. According to the press release Sarepta distributed yesterday morning, the FDA raised many questions about the clinical trial data and about this therapeutic approach called exon skipping.
The FDA’s change of position was most likely influenced by the recent failure of a different drug produced by Glaxo Smith Kline called drisapersen. Like eteplirsen, drisapersen is also designed to produce dystrophin via exon skipping, but a large clinical trial of drispersen did not result in stabilization or improvement in hundreds of boys. The FDA said those results call into question whether dystrophin production will lead to clinical benefit. But here’s the thing: No one knows if the kids in the failed drisapersen trial were producing dystrophin, and if they were how much of it was found in the muscle fibers. We don’t know because GSK hasn’t released that data.
If we are to compare competitive products, the recent failure of drispersen should buttress Sarepta’s case, not hurt it. Drispersen was close to what our children need, but not quite right. Due to toxicity issues, the drug could not be dosed at high enough levels to have across-the-board efficacy. In contrast, Sarepta’s drug has a stellar safety profile. In two years, not one drug-related adverse event has been reported.
This is a lot to take in, I know. But it can all be boiled down and stripped away to these essential points:
1. Eteplirsen is safe. It is possible that unknown side effects may appear once children are on the medicine for longer than two years. But every single family I know is more than willing to take that risk. Most of us currently treat our boys with poisonous steroids that result in awful side effects, just to give our children two years’ additional walking and breathing time.
2. Eteplirsen works in the 12 boys that have been treated. All 12 boys are producing dystrophin. The 10 boys who can still walk have remained stable since the dystrophin appeared in their muscles. I am putting my money down that Max can now march in the Halloween parade and Billy can now push his mom’s shopping cart when they could not do those things before starting eteplirsen treatments because they are now producing dystrophin, not because all of a sudden they just happen to be feeling great.
3. The FDA can move forward from here in three ways: a) approve eteplirsen now on an accelerated basis because it produces dystrophin, and LACK OF DYSTROPHIN CAUSES DUCHENNE. b) approve eteplirsen now because it is clear that compared to the abundant natural history data, boys treated with eteplirsen are performing MUCH better on the six minute walk test than their untreated counterparts. 3) Require longer, larger studies that will cost millions of dollars and – more important – many children’s lives. As a community, people impacted by Duchenne must come together to reinforce the reasons the FDA must accept the new drug application now. Our children’s lives depend on it.
Take it from my friend Carl, who is 26 and has Duchenne. If anyone knows the stakes, he does:
You do not need to get into any technical details. The bottom line is this: the safety data to date is perfect and the efficacy data is promising. A drug with good safety and efficacy data for a disease with NO treatment approved like Duchenne should not be DELAYED due to failure of other drugs in trials!
Charley and all children with Duchenne need your help today in the form of two quick steps:
1) Cut and paste the following message into the body of an e-mail.
2) Send the e-mail to the addresses listed below.
Thank you — this counts as a b-day gift so once you do this you are officially off the hook!
Dear Drs. Woodcock, Jenkins, Temple, Unger, Bastings and Farkas,
I understand that the FDA has reversed its previous stance on whether to consider Sarepta’s NDA for Eteplirsen. The Agency has cited the recent failure of other dystrophin-producing drugs as one reason to require that Sarepta conduct a large, placebo-controlled phase 3 study before applying for approval. I do not understand this reasoning, as we don’t even know how much, if any, dystrophin was produced by the drugs that failed to meet their primary clinical trial endpoints. In contrast, we know that Eterplisen produced dystrophin in all 12 treated patients at levels widely believed to lead to functional benefit. What’s more, the treated patients have stabilized since the dystrophin took effect. One third of the children actually improved, a clinical outcome that is unheard of in Duchenne.
I do not have a rare fatal disease, but if I had one I would want the freedom to choose a drug in consultation with my physician that has a highly favorable safety profile and early indications of efficacy. I believe the FDA’s #1 job is to protect people. While we understand there are certain risks with approving a medication studied in only 12 patients, the risk is a minimal and tolerable one compared to the certain pediatric deaths and losses of ambulation that will occur if you require several more years of study before approving this drug.
I implore you, work with Sarepta to accept the creative and aggressive confirmatory trial design they have planned. Understand that boys will die and boys will lose their ability to walk if this decision continues to be postponed.
INSERT YOUR NAME
Send the e-mail to the following FDA officials:
Be sure to cc these people:
Margaret Hamburg is the FDA Chief
Nicole Cohen is the health care policy advisor to US Rep. Joe Crowley, co-chair of the Congressional Caucus on Rare Disease