Thank you for the opportunity to speak today. My name is Dr. Tracy Rupp: I was previously a clinical pharmacist and pediatric nutritionist at Duke University Medical Center and am now a senior fellow at the National Center for Health Research. Our research center analyzes scientific and medical data and provides objective health information to patients, providers and policy makers. Our Center does not accept funding from the drug or medical device industry and I have no conflicts of interest.
We strongly support a drug regulatory process that gets safe and effective new treatments to patients as quickly as possible. And patients with Duchenne muscular dystrophy don’t have time to spare. This is a devastating condition that usually leaves young boys wheel-chair bound by their teens and facing the end of life at a time when other young men are entering the prime of their lives. For a disease with no cures and with such catastrophic consequences, we understand that patients are often willing to accept treatments that carry more risk. However, to be able to accept a drug with risky side effects, we must have good evidence that the drug is effective.
Unfortunately, we don’t have substantial evidence that drisapersen is effective but we do have evidence that the drug has life-threatening side effects. We do not recommend approval of drisapersen because we cannot say it has a favorable risk-benefit profile.
Drisapersen was thought to exert its beneficial effects by increasing levels of dystrophin. However, a number of biomarker studies found that drisapersen does not significantly increase dystrophin levels beyond those of untreated patients.
Similarly, the clinical trials, including the large phase 3 trial, did not find that the drug was effective at increasing the distance participants could walk in 6 minutes. One of the phase 2 studies (#117) had inconsistent findings and poor statistical strength. The second phase 2 study (#876) did not find a significant difference between treatment and placebo groups in the distance walked. Likewise, the larger phase 3 study (#044) also did not find a significant improvement in the 6-minute walk distance in boys who received drisapersen.
The sponsor claims that post-hoc subgroup analysis show the drug is effective in younger boys. But, it should be noted that this analysis is no longer statistically significant if one of the patients is removed from the analysis. This patient was no longer able to participate so his values were entered as zeros. This type of analysis can only be said to be hypothesis-generating. This hypothesis must be tested in a double-blind, randomized, placebo-controlled trial of sufficient size to know whether it is actually true.
In summary, neither the biomarker studies nor the clinical endpoint studies show that drisapersen is effective. Since these studies were very thorough and carefully planned, if the drug had a positive effect it would have been apparent.
Not only is the drug ineffective, but it is also unsafe. Drisapersen has life-threatening side effects, including the potential to cause platelet counts so low that fatal, spontaneous brain or lung hemorrhage could occur. It also causes kidney, skin, and vascular damage. Studies indicate the risk of adverse effects increases with time and are not always anticipated. This is very concerning for drisapersen since patients would require life-long therapy.
In conclusion, I am deeply disappointed that drisapersen is neither safe nor effective. Patients and their caregivers have literally invested their lives in the hope that this drug would have a profound impact. But patients with Duchenne’s deserve more than false hope. They deserve safe and effective treatments. Of course, there are some patients for whom drisapersen may have been effective, but they are the exception rather than the rule – AND patients can be badly harmed before they find out whether they are one of the few patients who might benefit. We urge the drug’s sponsor and the FDA to make drisapersen available to these patients through the Expanded Access Program as appropriate, while continuing to collect information to better predict who might benefit and who is likely to be harmed.
Thank you for the opportunity to comment today and for consideration of our views.