What’s Really Going On Here

Posted by: Christine McSherry on December 11, 2013


As 2013 is drawing to a close and the holidays are upon us, I can’t help but think of how a year that had started with such hope and opportunity for the DMD community is now ending in disappointment, confusion and frustration.  It’s been a difficult few months for our community given the failure of drisapersen and the FDA’s recent change of position on an early NDA filing for eteplirsen.  That said, the decision on eteplirsen’s NDA filing it not yet final and there is still time for us as parents and as a community to educate and inform the FDA and Congress on the need for an early approval.  While the failure of drisapersen to achieve its clinical endpoint is not something that at this point can be changed or the outcome altered, the transference of this failure by the FDA onto eteplirsen seems both unjustified and frankly, unscientific.  While both drugs are designed to “skip over” an exon to restore the reading frame and thus dystrophin production, they do so using very different chemistries, very different doses, very different delivery methods, with very different safety profiles and it would seem…achieving very different results.

So why is the failure of drisapersen now a factor in delaying access to a drug that has shown an unprecedented ability to produce dystrophin and stabilize boys through 96 weeks?  Well, we received some of those answers directly from the FDA in the Sarepta press release.  The release essentially reprinted excerpts directly from the FDA’s pre-meeting comments and what they had to say is troubling and should be of the highest concern to all parents, patients and advocates.  Essentially, the FDA is saying that because both drisapersen and ataluren were designed to create dystrophin and because GSK/Prosensa and PTC have confirmed that they have “increased” dystrophin in their clinical trials, their clinical failures may mean that producing “small or moderate” amounts of dystrophin might not be enough to stop the disease progression.  Here is the FDA’s exact language on this matter:

“Since our last meeting, a large phase 3 trial of drisapersen, a drug with a similar mechanism of action, was reported to be negative, despite increased expression of dystrophin. The disconnect between increased expression of dystrophin and clinical efficacy for drisapersen, combined with previous negative reports for PTC124, another drug thought to act by increasing dystrophin, raises considerable doubt about the biomarker, and consequentially, its ability to reasonably likely predict clinical benefit.”

“…the quantity of dystrophin that might be necessary to be considered reasonably likely to predict clinical benefit is even less clear; small or perhaps even moderate increases are seemingly not enough, at least in the subpopulation of boys studied so far. An adequately validated quantitative assay for dystrophin now seems a prerequisite to further consideration of the biomarker as supportive of approval. Since our last meeting, our concern about the shortcomings of your current quantification methods has grown.”

I along with others have read and re-read these statements from the FDA to confirm that their opinion is the following:  Restoring a truncated, Becker like form of dystrophin, the protein that is not being produced by DMD boys due to a genetic aberration, may not actually lead to clinical benefit.  Or at least, according to the FDA’s statements, “small or moderate increases” in dystrophin may not be enough.  But I started to ask myself, what data does the FDA have to make these statements about the level of dystrophin production?  What publications, presentations, posters…or even the raw data?  It is our understanding that the FDA did not yet have ANY non-publicaly available data from GSK/Prosensa from their Phase III trial or ANY non-publically available data from PTC Therapeutics on their Phase IIb trial.  The question I asked myself was, how do they know how much dystrophin these drugs produced in these boys?  How do they know how well, in the case of drisapersen, the drug performed on actually skipping exons, which is what it was designed to do?  How can they compare the amount of dystrophin and exon skipping eteplirsen has shown through its biopsy data when the equivalent disclosures have not been made by any of the companies they are citing?

I started to look back at Sarepta’s publicly available data and realized, even going back to their Phase II study in Europe, just how transparent they were in providing individual data on each patient based on the pre and post biopsies that were taken from the boys in their trial.  Arguably, this transparency showed some weakness in their drug given the amount of exon skipping and dystrophin production in their lower dose cohorts did not seem significant enough to achieve the hoped for therapeutic benefits they had expected. The data at the time was viewed as hopeful and signaled that either a longer dosing period or higher doses (or both) could potentially show greater dystrophin production.  It was for these reasons that the company designed a Phase II study in the US using two doses (30mg/kg and 50mg/kg) significantly higher than the highest dose (20mg/kg) used in their UK study.  They also extended the duration of the study from 12 weeks to 24 weeks to understand if duration of dosing also might have an impact.  The primary endpoint for these studies was not the 6MWT, it was dystrophin production.  Sarepta was looking to answer the key question; does their drug effectively skip exons and produce dystrophin?  Both Prosensa and Sarepta (AVI Biopharma at the time) had already demonstrated that intramuscular injection of their drug could produce significant amounts of dystrophin, however, this was through direct local delivery (foot).  The question still to be answered was whether a systemically delivered drug, either through injection or IV, could produce potentially therapeutic levels of dystrophin.

What interested me as I went back and read the press releases, old presentations and published papers is how little information has actually been released in relation to the number of biopsies taken in the many trials targeting dystrophin production.  As I looked into this disclosure issue more, I actually became more disturbed than intrigued.  A pattern seems to have emerged early on from both PTC Therapeutics and Prosensa.  That pattern is an almost astonishing level of non-disclosure regarding publication or release of details behind the hundreds of biopsies they collected from hundreds of DMD boys.  The numbers speak for themselves.  In PTC’s Phase IIb study, they took before and after biopsies from 174 DMD and BMD boys (yes, there were both in this trial).  That’s just under 350 procedures in this one trial where anesthesia was used on these boys in order to allow for the surgical removal of a muscle sample.  Clearly PTC, Prosensa, GSK and Sarepta know that they need the information from these biopsies to know if their drug is working, not working or how well it is working.  Why else would they put young DMD boys through two or three surgeries and how else would they get IRB approval if this wasn’t necessary?

But if these biopsies are so important as they can tell us about how and if these drugs are working, then why haven’t we seen them?  Why haven’t we as parents, whose children were subjected to these procedures in the hope that one or all of these drugs would work, seen the individual biopsy data?  More to the point, why have almost ALL of these biopsies remained undisclosed?  PTC initially stated that they were having “quantification problems” with their evaluation of the biopsies from their Phase IIb, but it has been over 3 years and all we are given or provided are some generalizations about how much dystrophin they produced.  Don’t believe me, look for yourselves and try to find where the data from these biopsies has even been released or even detailed information from them disclosed.  Even in the most recent presentation to investors at the Deutche Bank conference, PTC has a slide that is meant to demonstrate that their drug is effective at creating dystrophin, yet this is a single slide with no detail or information on the patient it came from.  Its also a slide from their Phase IIa study, not the Phase IIb, from which they collected over 300 biopsies with half of those taken after 48 week of treatment, not 28 days.  Where are those slides?  There should be dozens of them!

But PTC is not alone, in going back to releases, statements and Q & A’s with Prosensa, the same pattern emerges.  They admitted to needing more time for analysis and that they were having quantification issues.  How is it that they were supposed to release their Ex US data in Q4 of 2012, but then announced they would not release it until Q4 2013?  Only to then surprise the community with the release the 6MWT data in April at a non-DMD conference.  Now that we were given some top line data on exon skipping from that Phase II trial as well as dystrophin production upon the Phase III failure, it looks like this biopsy data would have been predictive that drisapersen was not a very robust drug.  Shouldn’t the community, patients, parents and others have seen this biopsy derived data sooner?  Amazingly, there is hardly any discussion or information out there regarding the biopsies taken in the Phase III study or their other Phase II.  Why are GSK, Prosensa and PTC not discussing biopsy data that would show whether their drugs are working or not working when the clinical measurements of their drug are not meeting their endpoints?

Looking for any significant or detailed disclosures from biopsies from GSK/Prosensa in other earlier trials yields nearly the same result.  They have likely taken over 800 muscle biopsies from DMD boys in their trials, but how many have we seen?  Maybe a handful scattered through a few papers and presentations. These are the data that would tell us if the drug is working or not.  Put aside all the arguments and debates about quantification methods, it wasn’t hard to see if dystrophin was being produced when they did intramuscular injections and published the proof concept papers that lead to these systemic delivery trials.  And it wasn’t hard for Sarepta (AVI) to see that they didn’t produce the levels they wanted in many of the boys in their UK trial, but did so in their US trial based on higher doses and longer duration dosing (they did not see robust dystrophin production at 12 weeks).  So why are we not being shown these biopsies and the data and analysis generated from them?

Why has such vital information not been shown and analyzed in detail?  Why are we still seeing new papers with new conclusions being derived from the Phase IIb ataluren trial over 3 years after it concluded?  Why instead are we not seeing the same type of detailed data release and analysis from these 700 plus biopsies so the DMD community and the many researchers from around the world can review, analyze and learn from this data?  It seem almost unprecedented that this much important data for a rare disease remains undisclosed or disclosed with some general summary or percentage rather than detailed data…or even individual patient data.

There are lots of questions here, but few answers.  As a community, we need to be concerned that a potentially effective treatment, such as eteplirsen, may become victim to the failures or shortcoming over other drugs or drug trials.  More troubling is whether the FDA is making conclusions about these drugs and their ability to produce dystrophin without either the data or expertise to analyze it and understand it.  We have a lot riding on the FDA’s ability to understand these issues, to insure that they are not making uninformed or less than informed assumptions and that ALL data that may support the research community understanding these issues be released in detail.  We don’t have time to waste and their certainly should be no patience or tolerance for companies who do not provide transparency and access to needed data so that we can answer these questions and insure that the FDA and others are using the best information possible as they make important, life altering/saving decisions, including their near term decision on eteplirsen.  Please join me in asking Glaxo, Prosensa and PTC to put forward the biopsy data they have collected from over 500 boys so that our community, our families and the FDA can make informed decisions based on real data.


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