Correct HW, and the FDA wants multiple muscle biopsies from each child in the trial, as well. Take a piece of what little muscle the boys have, multiple times, to appease the FDA. And these boys have no drug alternative. Do it our way, boys, says the FDA, or you get nothing. Nothing.
Thedifference may be due to nothing more than the hit or miss of a small biopsy incision. No one is checking to see just how uniform production is in the body of drug-treated boys. If distribution or production is not uniform in the body, then there may be some biopsies that just don't register the dystrophin even though dystrophin is being produced in much of the body and the biopsied boys are still receiving a clinical benefit from the drug. Maybe MRIs or some other testing method will be used in the future. For now, biopsies of a teeny tiny piece of muscle in a boy, repeated by a biopsy of a teeny tiny piece of muscle in a different location of the same boy, is the best we have to prove dystrophin production. We need to be able to see the entire muscle map of the boys after treatment, not a teeny piece of it.
Variant, as Kunkel said, it's hard to say just how much dystrophin is needed to show clinical benefit. For some time, 10% of normal dystrophin was accepted as the minimum needed. I think that was due to someone's observation that Becker's patients tend to have 10-50 percent of normal dystrophin. The company has always maintained that the goal of eteplirsen and its drugsthat will be treating other exon deletions was, in effect, to transform the duchenne into the much milder becker's MD so that duchenne childrencould have longer, more normal lives. Recently, science articles appeared suggesting that maybe less than 10 percent of normal dystrophin production was needed to show a clinical benefit. That is, maybe duchenne boys could beccome becker's boys even if eteplirsen or drisapersen treatment produced less than 10 percent of the amount of dystrophin found in healthy boys. The problem is, as Kunkel pointed out in today's article, no one, including the FDA, knows for sure the threshhold amount of dystrophin needed to demonstrate a clinical benefit. What everyone should know is that Sarepta will have far better and more distinguished clinicians and scientists -perhaps the best in the world - than the FDA will have on its advisory panel. The panelists know that and will pay attention to Sarepta's experts, probably giving great weight to much of what they have to say. I expect Sarepta, through its experts, to convince the FDA that whatever percent of normal dystrophin eteplirsen is generating, it's enoughto demonstrate remarkable clinical benefit in the treated boys. I expect Sarepta and its team will rule the day on January 22nd.
Correction, some may be in phase 3, others in the new phase 2 trials. Either way, these are new boys on eteplirsen showing improvement and adding substantiation to the known miracles of eteplirsen.
Owen Jones has been on eteplirsen for 40 weeks now. No adverse reactions. 6MWT improved since baseline. Plays soccer three times longer than before eteplirsen and is taken out of the game only when the coach needs to let another child play.
Michael, age 7, and his brother Mac, age 6, both have Duchenne Muscular Dystrophy. Michael has been on eteplirsen for 30 weeks now. He can now jump 10 inches off the floor; before eteplirsen he could only manage 2 inches. He now keeps up with his friends when he runs, and can run farther and faster. Mac started on eteplirsen 10 weeks ago and already his parents are seeing some improvement. The boys have stabilized with eteplirsen treatment. There have been no side effects.
These are from written testimony of the families to the FDA in support of eteplirsen. Many more are coming.
Great article, Bill, thanks. I was not familiar with the family or the website. It amazes me, but doesn't surprise me that there are so many families with duchenne children doing everything they can to help their sons. I applaud them.
Ok. So that's merely the claim of the drisapersen inventor with no legal or factual basis to support it. I got it.
Iron, what do you mean "reads on" eteplirsen? Is the patent claiming that the inventor reduced the eteplirsen piece to actual practice? Thanks.
Pearsby, Jon has never dipped into the drisapersen vs. eteplirsen debate, nor have his postings ever been arrogant or egotistical. Sorry to see you disparage his character.
The Lancet Neurology, Volume 15, No. 1, p26–28, January 2016. Open-access article. Released this morning on line. "With increased evidence of the validity and sensitivity of magnetic resonance biomarkers in neuromuscular diseases, the path for biomarker qualification (eg, their approval by the Food and Drug Administration) should be carefully explored, with the ultimate goal of using magnetic resonance measures as surrogate endpoints in clinical trials." Best of all, it's non-invasive.
By the way, Japan just granted the drug fast-track review status last month.
jrrt. I only know that it is a morpholino. I suspect you can find details in a research article published last month in Neuromuscular Disorders Journal (published by the World Muscle Society). I don't have access to it. the article title is: Exon 53 skipping of the dystrophin gene in patients with Duchenne muscular dystrophy by systemic administration of NS-065/NCNP-01: A phase 1, dose escalation, first-in-human study.
Nisson's exon 53 trial was an exploratory trial. Trial participants were aged 5-18 years old with DMD needing exon 53 skipping, but mostly non-ambulatory. Dosing range of 1.5mg/kg, 5mg/kg, and 20 mg/kg per week, non-blinded, non-ramdonized for 12 weeks. Reading frame restored by exon 53 skipping in every dose group. Dystrophin protein production detected at 20mg/kg.
(Part 3) - From the news release: " Early analysis by NCNP detected dystrophin mRNA with the amino acid reading frame restored by exon 53 skipping in every dose group. Furthermore, the expression of dystrophin protein which appeared to have been translated from such a mRNA was detected in the high-dose group. On the basis of these results, NS-065/NCNP-01 is expected to have therapeutic efficacy in DMD.
In addition, no serious adverse events were observed throughout the study, and no subjects discontinued administration. Anemia and a slight effect on renal function have been reported as general adverse events.
NCNP is currently conducting detailed evaluations of safety and dystrophin protein expression." It is preparing for the next stage of clinical development with a view to launching this product in Japan in 2018." Nippon has USPTO exon-skipping patents that predate those of both Prosensa and Sarepta. The company could get into the patent-infringing mix at any time.
Variant -I tried to post this several minutes ago and am trying again. (part 1).
You ask, "do Asians get DMD"? Yes they do. In fact, Japan has an exon-skipping trial underway to treat it. In 2013, Japan's Nisson Shinyaku, a pharmaceutical company and food giant in Japan, launched a phase 1 trial to treat boys amenable to skipping exon 53 using morpholinos developed by Sarepta (Sarepta's morpholino patent - PMO - expired years ago).
Nisson completed the study and issued a news release earlier this year. The trial treated 10 boys who needed exon 53 skipping. I'm not sure of the dose range. The results of the trial could influence Sarepta's trials.
Even the experts get confused about dystrophin quantification, and the confusion seeps into the world's best neurology. No wonder we mere mortals are so confused. Here's an example:
In an article authored by Mendell, Flanigan, Sazani, Ed Kaye, and a score of other notables, and published in the 2013 edition of the Annals of Neurology (Ann Neurol. 2013;74:637-647), the authors introduced their article with the following: "at week 24, the 30 mg/kg eteplirsen patients were biopsied, and percentage of dystrophin positive-fibers was increased to 23% of normal; . . . . Even greater increases occurred at week 48 (52% and 48% in the 30 and 50 mg/kg cohorts, respectively), suggesting that dystrophin increases with longer treatment." Yes, that's 23% and 52% of normal, they say.
Then, in the body of the article, the authors reveal that the changes were from BASELINE! Of course, percent changes of dystrophin from normal (which the drispersen adcom panel focused upon this week) is far different from percent changes of dystrophin from baseline. Nevertheless, our best experts (and our acting CEO) confused the two in their article published in the prestigeous Annals of Neurology.
I hope our team clears it all up before the eteplirsen ADCOM.