Less than a year ago, AVI Bioscience (AVII) was a penny
stock. Yet a couple of NASDAQ non-compliance letters, a one-for-six reverse
stock split, one ticker change to SRPT and one complete reinvention to Sarapta
Therapeutics later, here we are with a
soaring stock price and market cap > $700 MM.
Investors are simply smitten with the company’s lead
compound, eteplirsen, a novel investigation drug for Duchenne Muscular
Dystrophy (DMD), which aims to help patients produce a normal amount of dystrophin,
a protein required for correct muscle function. So smitten are they, Bulls seem
confident that Sarepta will be allowed to successfully file for accelerated
approval for the drug on the basis of their single Phase 2b study. Sarepta is meeting with the FDA in Q1 13 to
discuss this.
Accelerated
Approval is a track by which FDA can allow early approval of drugs to
treat serious diseases, that fill an unmet medical need based on a surrogate
endpoint. According to the FDA’s
website, “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”.
Unlike the bulls, I think it is extremely unlikely that
Sarepta will convince the FDA that their data warrant accelerated approval. Instead,
I think it is much more likely that they will be required to perform a new pivotal
study prior to submitting the drug for FDA review. Here are some of the reasons why I think this
will happen.
The “pivotal” phase 2 data are systematically biased
AVI Biopharma conducted their phase 2b study at a one
hospital in Columbus, Ohio. This means that FDA has no idea whether or not
these results could ever be reproduced at another institution. This is a
problem in my opinion, most pivotal studies are multi-center to ensure the
results are seen consistently across multiple environments.
At 24 weeks, the study was unblinded at which point bias is inherently
introduced. This means for all measures reported after this time point,
investigators and raters know exactly which patients have received how much
treatment and at what dose. Whether or
not bulls agree, it places limitations on what can be inferred from the
results.
In July, Sarepta reported results from 36 weeks of
follow-up. They decided to exclude 2 boys from the lower dose treatment arm as
they had experienced significant worsening of their condition and could not
complete the assessments. This means all
subsequent results were reported as modified intent to treat (mITT) for 10
patients and adds further bias in favor of treatment effect. The results of the
mITT group was from only 10 patients which is a tiny sample size compared with
most pivotal studies.
Bulls argue that FDA will find dystrophin a compelling
biomarker as a surrogate end point to support accelerated approval. Let’s take a look at the data. In October
2012, Sarepta shared 48 week results. At
this time point, we have n=4 patients receiving
50mg/kg and n=2 patients receiving 30 mg/kg for 48 weeks, and the
delayed treatment group (n=4) who have been treated for 24 weeks in total.
Biopsies were repeated for all patients at this time point. After 48 weeks of eteplirsen treatment, there
was a statistically significant increase in dystrophin-positive fibers to 47%
of normal. The delayed treatment group,
also showed 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 increase observed after 24
weeks of treatment for the original cohort (which was only 22.5%).
However, when we look at the relationship between %
dystrophin-positive fibers and mean change in 6MWT, there is no clear
correlation between drug dosage, %
dystrophin-positive fibers and physical performance. Patients treated at the
lower dose of drug produce more dystrophin-positive fibers, but this does not
translate to improved physical performance on the 6MWT. Similarly, Prosensa and GSK, published
results of a phase I/II dose-escalation study demonstrating treatment with their
drug, PRO051 (a direct competitor to eteplirsen) resulted in 20-100%
dystrophin-positive fibers after only 2 weeks of treatment in some patients,
with levels maintained >70% at high doses after 7 weeks of treatment. As with eteplirsen, there was no correlation
between % dystrophin-positivity and 6MWT performance. Obviously the argument
can be made that the dystrophin is not fully functional as early as 7 weeks,
which is why GSK is in the process of conducting a phase 3 multi-center, double-blind,
randomized controlled study to investigate the effects of treatment for 48
weeks in 180 patients. The results
of that study should report 2H13.
The point I am making is that there is insufficient clinical
evidence from human studies that suggest dystrophin-positive fiber counts
predict clinical outcomes in patients with DMD.
To that end, it is entirely unknown what the correct dose or dosing frequency
should even be for this eteplirsen based on early study results. I doubt FDA
will be persuaded otherwise. Furthermore, if GSK are required to demonstrate
efficacy under blinded, controlled conditions so why should the regulatory
hurdle be any lower for Sarepta? Bulls
argue that GSK is conducting a phase 3 study due to their drug’s safety
profile. FDA requires a drug demonstrate both safety and efficacy. A review of
PRO051’s phase1 /2data 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 the sponsor under blinded, controlled conditions. In fact,
if Sarepta were to repeat this trial with adequate power for 48 weeks under double-blind
conditions, it is possible that absolute benefit could be modest.
Bulls argue that FDA will allow for accelerated approval
because the drug is safe and tolerable. I’m the first to agree that we need to
get more medications to market where there are no other viable options, but it would
simply be unprecedented for FDA to award Sarepta accelerated approval on the
basis of this open-label signal. The regulatory precedent for accelerated
approval is very clear:
Orphan drugs are held to the same statutory requirements for
demonstrating effectiveness and safety as regular applications.
Orphan drugs must: Demonstrate substantial evidence of
effectiveness/clinical benefit (21CFR 314.50)
Substantial evidence of benefit requires: Adequate and well-controlled clinical
study(ies) (§314.126)
“Study has been
designed well enough so as to be able “to distinguish the effect of a drug from
other influences, such as spontaneous change…, placebo effect, or biased
observation” (§314.126)”.
This study is neither well-controlled, nor adequate given
that its single-center with only 10 patients completing assessments at 48 weeks.
Being entirely open-label past 24 weeks, it is riddled with potentially biased
observations.
But wait, Sarepta bulls feel FDA will be swept away by
patient advocates demanding quicker approval of treatments. When did Federal agencies become so nimble
and responsive to emotional demands from the public? They didn’t. And while I
have immense sympathy for families living with loved ones suffering with rare
diseases, I look at the situation objectively, as will FDA.
As an example of FDA’s stoic position on ensuring regulatory
standards are upheld under all circumstances, Bulls should take a look at the
regulatory history for Vyndaqel for the treatment of the rare and universally
fatal disorder, transthyretin familial amyloid polyneuropathy (TTR-FAP) for
which there are no approved drugs. The US prevalence of TTR-FAP is only 2,500,
yet Pfizer still managed to submit a single multi-center, global, randomized,
controlled study enrolling N=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, countless patients, caregivers and advocates begged,
wept and pleaded with FDA directly to approve this drug, especially on the
basis of its’ benign safety profile.
They wanted hope where there was none.
Sadly, hope wasn’t enough. FDA
issued a complete response letter to the sponsor requesting the completion of a second efficacy study to
establish substantial evidence of effectiveness prior to an approval. More recently, patients and advocates
suffering with chronic fatigue syndrome have extensively lobbied the FDA to
approve Hemispherx’ Ampligen, a potential first in class treatment for a
chronic, debilitating condition. The
agency received “hundreds of letters, emails, and testimonies” in
support of approval. One patient even went on a hunger strike, but to no avail.
On February 5, 2013, Hemispherx was issued a complete response letter citing
that there were insufficient safety and efficacy data to approve the
product.
In any future
regulatory meeting to discuss accelerated approval, FDA will be presented with single-center
data on 12 patients. Blinded observations were available up to 24 weeks of
therapy with no significant differences
between treatment and placebo at this time point. FDA then has to evaluate open-label
observations for the 10 patients who could actually complete assessments, 6 of
whom were treated for 48 weeks and the other 4 patients who received treatment for
24 weeks. In my opinion there is nothing adequate and well-controlled in this
data and the evidence of effectiveness is questionable due to bias, and there
are simply not enough patients treated at the dose the company is seeking an
indication for, to establish comprehensive safety. In the extremely unlikely
event the FDA granted accelerated approval, an FDA Advisory Committee would likely
shoot this application down and demand more robust data.
Disclosure: The
author owns May puts $SRPT
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