This is a detailed account of how the FDA lied and manipulated the public, the DMD community and the panelists during the Eteplirsen Advisory Committee (ADCOM) Meeting held earlier this year. The final FDA decision continues to be postponed at the cost of boys and their families.
This has been a crowd-sourced effort of independent minds focused on this issue at hand. We are a group of about 18 people that came together using Twitter private group messaging to help fully understand the issue. It is a result of numerous and ongoing discussions to present the true facts of the situation. This article focuses on Dystrophin levels. Additional prepared and yet to be published articles in the series focus on other FDA Adcom faults, failures, and additional laws the FDA ignored.
During the advisory committee meeting for the review of Sarepta's (NASDAQ:SRPT) Duchene Muscular Dystrophy drug Eteplirsen, the FDA made a coordinated effort to accuse Sarepta of misleading the FDA and the DMD community. DMD is caused by an absence of dystrophin, a protein that maintains muscle integrity. The FDA decided to frame the issue regarding dystrophin produced by Eteplirsen to make it look as if Sarepta had greatly overstated the Phase IIb trial results to both the FDA and DMD community.
At the heart of the issue are the two different lab techniques used to measure dystrophin, yielding two very different types of data. The first test, using immunofluorescences, looks for what is known as Percent Dystrophin-Positive Fibers (PDPF). The second test, using Western blots, looks for the total amount of dystrophin protein.
PDPF in simple terms is looking at the tissue at the cellular level and asking the question, 'are there any muscle fibers present, and if so, are they dystrophin positive', it's a yes or no question. Think of PDPF in terms of a light bulb, is it 'ON' or 'OFF'?
Western Blot measures the total amount of dystrophin protein present in the muscle tissue. Imagine mashing up all the muscle fibers from a tissue sample together and then quantifying how much total dystrophin is present. Think of total dystrophin protein as measured by WB as 'how bright is the light bulb'?
These two lab measurements produce very different data and values. Sarepta used PDPF to determine if Eteplirsen was, or was not, having an effect on dystrophin. In Sarepta's October 2012 press release, the company reported an average increase in PDPF of 47% 'of normal'. Sarepta defined 'of normal' as "determined by a pathologist who counted both the number of dystrophin positive muscle fibers and the total number of muscle fibers allowing the calculation of a percentage of dystrophin positive muscle fibers." This would be like walking around the house and counting how many light bulbs are 'ON' and dividing by the total amount of light bulbs in the house.
It is important to notice Sarepta included this definition in the Sarepta supplied Briefing Document prior to the FDA reviewers' Briefing Document preparation and full review. The Sarepta BD states:
The FDA focused on the total amount of dystrophin protein as measured by Western blot. The total amount of dystrophin protein in a DMD child, divided by the total amount of dystrophin protein in a healthy child would yield a 'percent of normal'. This method would be like turning 'ON' every light bulb in the house and measuring the total brightness then dividing that number by the maximum output potential of all the bulbs.
As you can see, these two lab methods are vastly different, as to the 'normal' they measure. One method is counting how many light bulbs are "ON'; the other is measuring how bright the light bulbs are.
During the ADCOM meeting, numerous FDA representatives mischaracterized the data presented by Sarepta, specifically, the Phase IIb 48-week data presented by Sarepta in 2012. As you review the way the FDA characterized the data, keep in mind which light bulb measurement is being considered.
FDA Division of Neurology Products, Medical Review Supervisor, Dr. Dunn set the stage when he stated, "it was our understanding that dramatic increases of dystrophin were being observed, as much as 50 percent of normal." (Copied directly from the FDA Adcom Transcript.) It is critical to note that Dr. Dunn doesn't clarify or specify which testing method he is referring to when he mentions the "50 percent of normal." However, he opened the meeting talking about "increased dystrophin expression," and thus implied the number reported was total dystrophin protein, or light bulb brightness, which is incorrect.
FDA Division of Neurology Products Medical Review Lead, Dr. Farkas was next, "instead of the expected 25 to 50 percent normal dystrophin, as was mentioned before, there was only .93 plus or minus .84 percent of normal dystrophin in the treated patients. This was measured by Western blot..." With Dr. Farkas, it is important to note he is now mixing the two completely different testing methods and testing values. Dr. Farkas states that "this was measured by Western blot," directly implying both the "expected 25 to 50 percent normal" and the "only 0.93" were both measured via Western blot, and thus both values refer to light bulb brightness; again this is incorrect.
As the FDA concluded their presentation, FDA Division of Neurology Products Medical Review Officer, Dr. Bastings reinforced, "Great hope was raised… dystrophin numbers were increased to levels as high as 50 percent of normal..." Like Dr. Dunn before, Dr. Bastings does not clarify the method of testing. However, by the time of Dr. Dunn's wrap up session, it was clear that the FDA considered "percent normal" as how bright the light bulb was.
The FDA then claims this misleading information is the reason that additional placebo controlled trials haven't started. Dr. Bastings went on to say, "Few, if any patients, would be willing to participate in a second placebo-controlled trial because they already felt so strongly that Eteplirsen was effective. This was an unfortunate situation."
The FDA was successful in influencing the panel into believing Sarepta had hoodwinked the FDA and the DMD community. During the comment period on why Advisory Committee Panel Member, Dr. Onyike had voted "No," he commented directly to the audience on hand, "I also hope you would consider, as a community, participating fully in controlled trials so that you're not in this position in the future."
During the ADCOM panel's discussion period for the first question, the committee chair Dr. Alexander, clearly shows the effects the FDA had on the panel. He comments, "In the clinical development program, there were estimates that dystrophin levels may have increased as much as 20 to 50 percent, which I think we would all argue or believe or feel would be incredible results relative to, for example, what we're seeing here. Now, I'm referring to the actual quantification with Western blot, and that clearly was a pivotal event that appears to have had a very profound impact on the subsequent decisions that the sponsor and the FDA reached regarding the next steps in the development program."
Dr. Alexander reveals the consequences of the lies told by the FDA. His statement identically mirrors the logic of the FDA. Dr. Alexander clearly confuses the difference between the "20 to 50 percent" as reported by PDPF (how many bulbs are ON) and the 0.93 percent total dystrophin protein as measured by WB (the brightness of the light bulbs). By reinforcing the expectation of a value as high as 50 percent, the actual values become a 'failure' in comparison even though the WB numbers were in fact statistically significant.
So what did Sarepta actually say about the Phase IIb 48-week data? Sarepta released a PR on October 3rd, 2012 regarding the results of the 48-week data. Sarepta reported the data as "Percent Dystrophin-positive Fibers" (how many light bulbs are ON). On October 13th, 2012, the data was presented by the study's lead author, Dr. Mendell, at the World Muscle Society meeting in Perth, Australia. Again, Dr. Mendell presented the data as PDPF. The critical point is both Sarepta and Dr. Mendell reported the data as "percent dystrophin-positive fibers," or PDPF, not total dystrophin production as measured by Western blot.
Is it somehow possible the FDA thought the original 2012 data was in fact a measurement of total dystrophin protein? I believe Dr. Bastings answered that question during the ADCOM when he stated "Just between 2013 and 2015, FDA held 13 formal meetings with the applicant about eteplirsen." The FDA knew exactly what data they had and what data they were looking at.
The FDA had a clear opinion regarding PDPF, as expressed by the clinical team leader Dr. Farkas, "PDPF does not mean a normal amount of dystrophin, a functional amount, or really any specific amount of dystrophin." The FDA obviously knew the 2012 data was presented as PDPF by Sarepta, they obviously disliked PDPF, yet the FDA continued to claim that they were duped by Sarepta via the PDPF data.
It is important to notice Dr. Farkas does in fact know the meaning of PDPF and his understanding was known prior to the Adcom as shown in his statement:
In 2012, Sarepta basically said "wow, look we did it, we were able to turn half the lights in the house ON!" (A 50% increase in PDPF). This effect had never been seen before, or since, in any other treatment and shows Eteplirsen does indeed have an effect on dystrophin, the very thing absent in patients with DMD. The FDA claims that they were told, and deceived the Adcom panel to believe, "Originally we were told all the lights in the house are on, at half brightness, when in reality all the lights were only at 1% brightness."
The issue is rather complex, and can be hard to follow, and that's exactly what the FDA wanted. Rather than helping simplify the data, the FDA used the complexity of the data to confuse people and shift the blame. Weaving a story that rather than the FDA dragging their feet for more than three years on the first real treatment for DMD, it was Sarepta that had misled the FDA and the DMD community.
It's appalling, if not criminal, the way the FDA purposefully distorted the facts to the Adcom panelists and the DMD community. Dr. Farkas made it a point both at the start and at the end of his clinical presentation that "it's really important to take a close look at what you're being told." While Dr. Farkas was addressing the DMD community, maybe he should heed his own advice.
Credits and appreciation for this article go to @StunningFeline, @BosCaptn, and many others from the independent group.
We have attempted to stick to the facts of the FDA faults, failures, and delays. At the same time, it is difficult to even speculate on the reasons behind the FDA decisions. So with that in mind, we leave it up to FDA oversight influence, political figures, and the future to determine the answers.
The FDA has numerous times shown aggravation with the company. In fact, many times over the course of the Adcom in April, FDA reviewers came back to the issue of what was said or what was known in the past instead of only dealing with the safety or efficacy of the drug at hand. If you believe the FDA will continue to stonewall you may want to sit on the sidelines and it is a valid short thesis.
In our view, the stock continues to be a buy with a price target of over $60. The Adcom created fear and doubt yet the additional delay and request for additional Western Blot data is an indication Etpelirsen will receive FDA approval. The approval is imminent but the timing is unclear. The early quarterly release is also an indicator approval could come in early August. Short Interest, remains extremely high although it is decreasing slowly. On August 2, the confirmatory trial, ESSENSE, changed to "Recruiting" status indicating the trial has initiated.
Disclosure: I am/we are long SRPT.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.