) -- Many investors are smitten with

Sarepta Therapeutics

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and its lead compound, eteplirsen, a novel experimental drug for Duchenne Muscular Dystrophy (DMD), which aims to help patients produce a normal amount of dystrophin, a protein required for correct muscle function. Sarepta bulls are so smitten with the company that they believe FDA will allow eteplirsen to be filed for accelerated approval on the basis of a single phase IIb study. Sarepta is meeting with FDA in the first quarter to discuss this issue.

Under accelerated approval regulations, FDA allows the early approval of drugs to treat serious disease that fill unmet medical needs. The approvals are based on clinical trials that assess efficacy using surrogate endpoints. "The FDA bases its decision on whether to accept the proposed surrogate endpoint on the scientific support for that endpoint. The studies that demonstrate the effect of the drug on the surrogate endpoint must be

adequate and well-controlled studies

, the

only basis under law

for a finding that a drug is effective," the FDA's regulations state.

Emphasis mine.

Unlike the bulls, I believe Sarepta is extremely unlikely to convince FDA the eteplirsen data warrant accelerated approval. Instead, it's much more likely Sarepta will be required to perform a new, larger pivotal study prior to submitting eteplirsen for FDA review. Here are some of the reasons why I believe a denial of accelerated approval for eteplirsen is the more likely outcome of this quarter's FDA-Sarepta meeting:

The "pivotal" eteplirsen phase II data are systematically biased.

Sarepta conducted their phase IIb study at one hospital in Columbus, Ohio. This means FDA has no idea whether or not these results could ever be reproduced at another healthcare institution. Most pivotal studies are conducted at multiple hospitals to ensure consistency and reproducibility of results. Multi-center studies are less susceptible to biases, inadvertent or not. The single-center eteplirsen phase IIb study is problematic in my opinion.

After 24 weeks of treatment, the eteplirsen study was unblinded, at which point bias was introduced into all future results. For all measures of efficacy reported after this time point, investigators and raters knew exactly which patients had received how much eteplirsen and at what dose. Whether or not bulls agree, unblinding of the eteplirsen study placed limitations on what could be inferred from the results after 24 weeks.

In July, Sarepta reported results from 36 weeks of follow-up in the study. Two patients were excluded from the analysis of the lower-dose eteplirsen treatment arm because they experienced significant worsening in their ability to walk and could not complete assessments. Because these patients were excluded, all subsequent results were reported as modified intent to treat (mITT) for 10 patients (down from 12 patients on an ITT basis)-- adding more bias favoring the treatment effect of eteplirsen. Data from 10 patients is tiny for a pivotal study used to determine efficacy and safety of an investigational drug, accelerated approval or not.

Bulls argue FDA will find dystrophin a compelling surrogate endpoint to support accelerated approval. Let's take a look at the data. In October 2012, Sarepta shared 48-week results from the eteplirsen phase IIb study. At this time point, four patients received eteplirsen 50 mg/kg and two patients received eteplirsen 30 mg/kg. Another four patients in the "control arm" of the study were treated with placebo for 24 weeks followed by 24 weeks of eteplirsen.

These patients crossed over from placebo to eteplirsen when the study was unblinded.

Muscle biopsies were repeated for all patients at 48 weeks. As reported by Sarepta, there was a statistically significant increase in dystrophin-positive fibers to 47% of normal in the six patients treated with eteplirsen since the start of the study. The placebo/delayed treatment patients also showed a significant increase of dystrophin-positive fibers to 38.3% of normal after just 24 weeks of therapy. This is surprising as it's nearly double the dystrophin increase observed after 24 weeks of treatment for the active treatment patients (which was only 22.5%.)

However, when we look at the relationship between percentage of dystrophin-positive fibers and mean change in the six-minute walk test (6MWT), there is no clear correlation between eteplirsen dose, percentage of dystrophin-positive fibers and 6MWT performance.

Patients treated at the lower 30 mg eteplirsen dose produced more dystrophin-positive fibers, but this benefit in the surrogate or biomarker endpoint did not translate to improved physical performance on the 6MWT.




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published results of a phase I/II dose-escalation study demonstrating treatment with their DMD drug PRO051 that resulted in 20-100% dystrophin-positive fibers after only two weeks of treatment in some patients, with levels maintained at greater than 70% after seven weeks of treatment for higher doses of the drug. As with eteplirsen, there was no correlation between percent dystrophin-positivity and 6MWT performance. Obviously, the argument can be made that the dystrophin is not fully functional as early as seven weeks, which is why Glaxo is conducting a phase III multi-center, double-blind, randomized controlled study of PRO051 to investigate the effects of treatment for 48 weeks in 180 DMDpatients. The results of this phase III study should report in the second half of the year.

The point I'm making is there is insufficient clinical evidence from human studies to conclude with reasonable confidence that dystrophin-positive fiber counts predict clinical outcomes (6MWT performance) in DMD patients. To that end, it is entirely unknown what the correct dose or dosing frequency should even be for eteplirsen based on early study results. I doubt FDA will be persuaded otherwise.

Furthermore, if Glaxo was required to demonstrate efficacy of PRO015 under blinded, controlled conditions, why should the regulatory hurdle be any lower for Sarepta? Bulls argue Glaxo is conducting the phase 3 study due to concerns about PRO015's safety profile. FDA requires a drug demonstrate both safety and efficacy. A review of PRO051's phase I/II data do not suggest there are any concerning safety signals compared with eteplirsen's safety early data.

The fact remains that eteplirsen's open-label "placebo-adjusted" benefit has never been demonstrated by Sarepta under blinded, controlled conditions. If Sarepta were to repeat this trial with adequate power for 48 weeks under double-blind conditions, it's possible the absolute benefit of eteplirsen in DMD patients could be modest.

Bulls argue FDA will allow for accelerated approval because the drug is safe and tolerable. I'm the first to agree we need to get more medications to patients who have no other viable treatment options, but it would simply be unprecedented for FDA to award Sarepta accelerated approval on the basis of a faint and unclear efficacy signal from a small, open-label phase IIb study. DMD is a rare, orphan disease but the FDA holds these drugs to the same statutory requirements for demonstrating effectiveness and safety as regular drug applications.

When Sarepta unblinded the eteplirsen study at 24 weeks, the data collected after that time point became confounded with potential biases. The biases -- and the modest sample size -- render the data useless for the purposes of FDA determining substantial evidence of effectiveness or clinical benefit.

Sarepta bulls argue FDA will be swayed by DMD patients and their advocates demanding fast eteplirsen approval. But since when have federal agencies become so nimble and responsive to the emotional demands of the public? They haven't. While I have immense sympathy for families living with loved ones suffering from rare diseases, I look at the regulatory situation objectively, as will FDA.

Vyndagel for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP), a rare and fatal disease, is an example of FDA's stoic position ensuring regulatory standards are upheld under all circumstances.

The U.S. prevalence of TTR-FAP is only 2,500, yet


(PFE) - Get Pfizer Inc. Report

still managed to submit a single multi-center, global, randomized, controlled study enrolling 128 patients as the basis for their submission. The drug was extremely well tolerated in the pivotal study with a placebo-like side effect profile. During the open public hearing session of an FDA advisory committee meeting to review the application in May 2012, patients, caregivers and advocates begged and pleaded with FDA directly to approve Vyndagel, citing specifically the drug's benign safety profile.

FDA ignored these pleas and rejected Pfizer's Vyndagel application, requesting a second efficacy study be conducted to establish the drug's efficacy prior to an approval. More recently, patients and advocates suffering with chronic fatigue syndrome lobbied the FDA to approve

Hemispherx Biopharma's


Ampligen. The agency received hundreds of letters, emails, and testimonies in support of Ampligen approval. One patient even went on a hunger strike, but to no avail. On Feb. 5, 2013, Hemispherx was issued a complete response letter citing insufficient safety and efficacy data to approve the product.

When Sarepta meets with FDA this quarter, the company will show regulators eteplirsen data from a single-center study encompassing 12 patients. Blinded data from this study are only available up to 24 weeks, at which point there were no significant differrences in measures of efficacy between eteplirsen and placebo. FDA will also be presented data from the study taken after 24 weeks. These data are unblinded, exclude two patients from the active treatment arm and include a placebo group that was switched over to eteplirsen treatment.

In my opinion, there is nothing adequate and well-controlled in these eteplirsen data. Evidence of efficacy is questionable due to bias. The small number of patients treated at limited eteplirsen doses are insufficent to assess safety comprehensively. In the extremely unlikely event FDA allows Sarepta to seek accelerated approval of eteplirsen, an FDA advisory committee would likely shoot the application down and demand more robust data prior to any approval.

Disclosure: Chaudhry owns May puts in Sarepta.

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Aafia Chaudhry M.D. is a founding partner at Noesis LLC, an investment-management firm focused on the pharmaceutical and biotechnology sectors. She originally trained in general surgery prior to transitioning into the health-care industry. Aafia has been an active life-sciences investor for the past nine years and is an expert in pharmaceutical life-cycle management strategy. She was formerly president of 81qd, a strategic data-analytics consultancy, and most recently served as vice president of strategic market planning at WebMD Health Corp.