The Significance Of The Sarepta Approval


The FDA’s granting of Accelerated Approval (AAP) for Sarepta’s eteplirsen for Duchenne Muscular Dystrophy (DMD) marks a clear turning point in thinking at the FDA. DMD, not unlike ALS, poses very real challenges to the traditional clinical trial process. With a small disease population (13% of an already-small DMD population who have the particular genetic abnormality the drug targets) consisting of young boys, the option of a large Phase 3 randomized double blind placebo concurrent control trial that can produce a p-value of less than 0.05 (the chance of the result being random and not connected to the drug) is untenable from both a practical and financial point of view. That being said, reliance on the old norm doesn’t even begin to address the ethical concerns of giving young boys placebos in the face of a crippling and fatal disease.

In this case, the manufacturer opted for a very small single arm trial and utilized two European studies of DMD natural history as a control. The trial participants’ feedback proclaimed efficacy. Traditionalists roared back “placebo effect”. Patient and parent advocacy groups as well as Right To Try proponents screamed foul and the battle lines were drawn.

Last spring the FDA conducted a long-awaited hearing of an advisory panel which, on a close vote, declined to find “efficacy” and recommended against AAP. What happened next was quite remarkable and indeed a rare instance of the exercise of forward-thinking judgment on the part of government officials, principally Dr. Robert Califf (the FDA commissioner) and Dr. Janet Woodcock (head of the FDA’s Center for Drug Review). They utilized the flexibility afforded them by Congress many years ago to grant Accelerated Approval to the drug, subject to a Phase 4 confirmatory trial. In other words the patients could get access to the medication, the manufacturer could recover its investment and make a profit, and the FDA could continue to assess efficacy and control access to the drug. That might just be what Congress intended – a novel possibility.

While AAP is not uncommon in the areas of oncology and HIV, this represents the first use of AAP in the case of a neurodegenerative disease. Everyone wins except the long-time FDA staff members who still complain, calling eteplirsen an “elegant placebo”. Perhaps it is time for them to move on and for patients to stop dying in slow and very non-elegant clinical trials.

What does this mean for ALS? In four short letters “HOPE”. We strongly believe ALS patients and drug and biologic manufacturers are in a much better position to take advantage of this path and the FDA’s openness to use it, something HopeNowForALS has been championing for the past several years. Some points to consider are:

  • The heterogeneity of ALS and the non-linear progression patterns of most patients present similar but different problems to DMD, but they also make the current randomized double-blind placebo-control trial more likely to produce Type 1 (false positive) or Type 2 (false negative) errors than produce an accurate assessment of the treatment;
  • In many ALS trials, blood, cerebrospinal fluid, and other tests can conclusively show biologic effect in patients (eg reductions in markers of inflammation, etc.) just like dystrophin levels did in DMD patients. When those effects are shown there is even more reason to consider alternatives to concurrent placebo controls;
  • With the records of thousands of placebo patients from ALS trials housed in the ProAct database, we are in a much better position to construct highly statistically powered homogeneous controls than even the DMD investigators were. This way it is possible to create a highly-powered matched control on a patient-by-patient basis for those in the treatment arm, thereby establishing expected mean progression with accuracy previously thought impossible. Predictive progression algorithms offer yet another alternative to the traditional concurrent placebo control;
  • While not a perfect solution, these advances, along with better ideas on patient stratification within trials, will prove extremely meaningful in reducing statistical noise. With that noise reduction, both Type 1 and Type 2 errors are dramatically reduced in ALS trials. In short, they are a better and smarter alternative to the status quo. It just takes courage and intelligence to recognize these things, like that exhibited by Drs. Califf and Wooodcock.

Treatments in development like tirasemtive, NurOwn, NP001, Radicut, and others on the horizon can utilize these 21st century innovations to present their case for AAP in a strong and intelligent way to the FDA, without either bankrupting themselves or delaying the process for years at time while they seek investments from the capital markets to conduct still-flawed and expensive Phase 3 trials. Even more innovative trial designs have now become possible, utilizing more robust run-in data on trial participants who participate in Precision Medicine Programs like the ALS-TDI program. It’s now time for “big data” to meet “big science” at the intersection of ALS and take advantage of this extraordinary opportunity the FDA has put within our reach.

We applaud Dr. Califf and Dr. Woodcock for recognizing there is more than one way to construct an adequate trial control group, and promise to keep working with them. We pledge our every effort in pushing HopeNowForALS to take its place as an agent for change in clinical trial design for this deadly and monstrous disease.

Robert Hebron
Hope NOW for ALS

Board of Directors:

Bob Hebron (ALS caregiver, NJ)
Jehad Majed (ALS caregiver, MI)
Linda Clark (widowed ALS caregiver, CA)
Eric Valor (person with ALS, CA)
Dr. Stephen Finger (person with ALS, SC)
Jay Smith (person with ALS, TX)

Email: info@hopenowforals