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Sarepta Therapeutics, Inc. Message Board

  • iloveallahgod iloveallahgod Apr 9, 2014 6:58 AM Flag

    Truncated Dystrophin Above 10 Percent in Eteplirsen Patients?

    Has Sarepta Disclosed 10 percent or more of truncated dystrophin in any of its eteplirsen patients? Qi-long Lu says this is the threshold amount of functional dystrophin based on studies of Becker MD patients. He says the publicly available information from Sarepta does not show this level of dystrophin production.

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    • Don't know why you're getting thumbs down--it's what he said. He also indicated that there was initially a strong statement concerning the safety and effect of etep--but was modified by objection of some reviewers who argued that other groups and even non treated DMD boys COULD show comparable stabilization.

      This is why I argued about Hoffman's (and others) 'hand-waving' assertion of such in his recent article. And why I asked him if he was one of the reviewers of Lu's paper, and if so, did he ask for the change in language. His wording was so similar to the final Lu language that I strongly suspect this is true.

      This, IMO, is the critical issue, because such a postulate as the 10% is ONLY 'true' IF the clinical data from etep's boys is NOT significantly different from drisa or natural history. If it IS different than those,, then the postulate will fail (re. the 10% being a threshold) and itself would have to be reworked.

      In other words, folks like Hoffman are arguing circularly in a catch-22 kind of situation wrt etep. I.e., we postulate that 10% is necessary; therefore if etep is less than 10% then the clinical data have to be wrong. This is disingenuous in that it discards provable hypotheses (that stability of etep IS clinically significant) for non-verified hypotheses--threshold level of dystrophin on testing/type of testing, etc.

      Meanwhile, wrong assumptions persist and the boys are caught in the middle.


      • 4 Replies to jrrt1
      • JRRT, I'm not sure Lu had access to the last biopsy data at the time of his article. If one takes into consideration the latest research that suggests that all oligos enter myocytes via myogenesis in the DMD pathology, a biopsy post 96 weeks should reveal greater/ + fibers/ total dystrophin. In the myogenic hypothesis low single digit number of cells undergo myogenesis due to injury, stress and/or inflammation every year. If true a 100% increase in total dystrophin in injured myocytes should be expected. There is one major flaw in the collection of these samples. Not every single-point sample is of inflamed muscle tissue. It is this tissue which undergoes myogenesis hence increased oligo myogenic cell entry.

        Sentiment: Strong Buy

      • I fear, while sound, your reasoning is too complicated for the politicians running the FDA to grasp. They would rather allow those with obvious ulterior motives muddle the process with erroneous, self serving interpretations than be swayed by the truth.

      • Thanks, jrrt1. Good response.

      • jrrt - Just read the article - it confirms what was discussed on this board before regarding the failure of the Drisa trial does not show a disconnect between dystrophin production and clinical benefit, because Drisa's dystrophin measures were weak and inconsistent. With respect to whether Etep can achieve this magical 10% threshold as measured via Western Blot, he bases his conclusion on "one sample", while casually acknowledging that given the preclinical studies, it is not surprising that Etep showed dystrophin production via Western Blot, while Drisa did not. Regardless of whether Etep generated 10%+ levels in any of the boys in the current study, that does not mean the clinical efficacy data should be dismissed. Longer term follow up on the Phase II boys (possibly even another biopsy down the road) may show the 10% level is achieved over time or future studies may show you need to increase the dosage to get to a 10% level. There are so many things to learn about the use of Etep that will take decades of research, but the idea is that until you have all the answers, it should be kept off the market is idiotic.

    • Wrong - all the boys in the study showed at least 20% dystrophin at 48 weeks. Who is this Lu and where are you getting this quote?

      • 2 Replies to tredleon
      • Truncated dystrophin or dystophin positive fibers? Big difference. Qi-long Lu is one of the top researches in the country studying DMD. He is in North Carolina. This is what he said in a published article last month: "it is reasonable to postulate that significant improvement in the disease phenotype by exon skipping will require expression of truncated dystrophin to at least 10% of normal levels with wide distribution. Such levels of dystrophin have not so far been convincingly demonstrated in any of the systemic trials of exon skipping and read-through treatments". "Nevertheless, the levels of dystrophin [in the eteplirsen trial] were limited, clearly below 10% by western blot, and from only one sample (judged from the image presented in the publication) despite the high percentage of dystrophin positive fibers reported." I am surprised that you are unfamiliar with Lu's work.

      • tred...
        Lu was the lead author in the recently published Nature article discussed a couple of weeks ago.


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