53 is going on in UK at least. Remember the iphone message from Mom Zoeann Hempsall about celebrating in TGI Friday's in UK about "Ryan's" 6 mo tests (exon 53 deletion boy). This is in Jenn's stream from late Oct 2015:
"Celebrating Ryan's appointment. In an unprecedented twist, Ryan has improved in every area!! I high fived everyone in the room. He's gone from running the 10meter test in 8.9 secs to 5.4 secs in 6 months!! I'm absolutely thrilled...Today was a win...and a huge middle finger to DMD!!"
IF there are any wealthy folks in this stock---I propose new awards to be created for government officials:
First one would be the RICHARD PAZDUR MEMORIAL AWARD and would be granted to the official with the MOST blood on his hands as a result of bureaucratic activity/non-activity. (Non-DOD related). Some would be willing to nominate our friend Farkas for the first of these awards-- and the DNP (by name) as honorable mention (or, possibly for the second award).
Second, for the government 'scientist' who 'Wouldn't know clinical benefit if staring them in the face" award.
Either, or both, would be awarded as often as situations warrant.
Simp---go to it--be a doer--get it done!
lender...thanks for your hands-on input. Sounds about like what Dr Qi-Lu indicated in his Molecular Therapy--Nucleic Acids journal commentary. Though he uses WB he stated this: "....the most generally available and reliable assessment of dystrophin levels in muscles is by western blots although the data are still, arguably semiquantitative...."
Semi-quantitative and best guesstimate of total amount in specimen (vs functional location, etc.)
Elsewhere he mentioned a tenfold dilution. Is this what you guys did?
oneway...of course you're incorrect in your reading of the BDs meaning as well as on the fact(s) re WB. SRPT used RCP and WB ONLY as confirmation that what they were seeing was at the 'usual' dystrophin location on the WB test and skipped product consistent w/ such by RCP (bionerd or Jon, etc could elaborate/clarify). However, WB was NOT a primary dystrophin-production endpoint point.
From Mendell's report in Annals Neuro from 2013 (of the 48wk data): 'Dystrophin expression
and exon skipping were confirmed by RT-PCR and Western blot (representative patient results are shown in
Fig 5)." and, "Supportive measures were further provided byWestern blots prepared from serial sections from the same blocks stained using NCL-Dys1."
From the BD's, pg 72 re the 180wk bxs: "This biopsy also afforded an opportunity to examine dystrophin production using the optimized method previously described for evaluation of percent dystrophin-positive fibers. In addition, new Western blot methodology was developed in alignment with the NIH-FDA...workshop...and... the FDA." And, "Frozen archived Baseline muscle biopsy tissue from Study 201 was available for re-analyses from only a limited number of patients..."
I.e., in only 3 of 12 was there usable, still preserved excess tissue from the baseline biopsies on which to use the 'new Western blot methodology' which the FDA FINALLY got around to 'blessing' after Mar 15 (though they ignored the unanimous opinion of the importance and usefulness of IMF--probably because it was so unequivocal?)
I don't know WHY the company didn't retroactively report WB readings--maybe FDA refused to accept the single methodology (NCL-Dys1, vs 3 on wk 180 tissue). I assume that the bx testing on the follow-on pIII have been since this 'new' WB was agreed on that a difference is that FDA will have WB results by this triple methodology both baseline AND 48wk on these new boys.
alex...Only thing I know is one 'representative' picture of WB in the Mendell Jour Neuro article reporting the 48wk data. It was this picture that Qi Lu in N Carolina commented in a later paper that it certainly appeared less than 5% (if memory serves).
The paper is available in full online (or, at least, it was when last I perused it).
winter....and you think this is relevant to the etep data in what way?
Shown by Sarepta: (3 accepted methods; all three reported)
****% + fibers BOTH as % increase AND % of normal (i.e., what % of ALL fibers in the bx specimen showed dystrophin +. That is a % of normal 'n' fibers, assuming 'normal' has 100%)
****IMF % graph demonstrates BOTH % increase over baseline AND shows (vertical axis) % of normal (assuming 100% of muscle fibers in a 'normal' is expected.)
****WB: Reported as % normal (assumed to be 100%) AND showed increase over pretreatment %.
So, if Farkas, et al had a problem with this, it's too bad no one had an ink pen and the back of an envelope to show the wizards what they were (apparently, weren't) seeing. I think you could have showed this to them--I feel sure I could have as well.
Yes, this is in % of dystrophin + fibers. Mendell's group had a very high %+ baseline so 'only' about 6-700% increase up to ~50-+/-%. The rereads had a much lower %+ baseline and lower post-rx %+ to (from memory) 15-25% of normal. However, this % increase was well over 10x due to lower denominator and was thus into the 1500-1700% + increase over baseline. Couldn't be seen by the eye-doctor, I guess!
OTOH, the subsarcolemmal % of normal (by IMF) increased from baseline of ~9% to ~23-24% of normal for a 140% increase over baseline. Again, the test was discounted and ignored by DNP though it a universally supported, even the primary, test recommended by DMD experts and indicated as such at the FDA-sponsored symposium on dystrophin.
The boys/families and the company talk data, the DNP did a lot of hand-waving away of things that no DMD expert would allow and instead played the emotional (they've been picking on us, momma!) and a 'keep your eye on the pea' shell game.
clash...."Did all the clinical DMD experts in the world show up....?" Rhetorical question, right?
The more pertinent question, if you can answer it for us is: "Has there been ANY DMC clinician-experts who are on record--verbally or in writing; that after reviewing the 'totality' of the data that etep has NO benefit and produces NO dystrophin and SHOULD be rejected? (Such being defined as docs who are the week-in, week-out medical caregivers for duchenne pts).
I'd think the DNP--and also you(?) ron, could at least leak ONE such, if it exists, right? Get on it now, OK? As honest as you think yourself to be, IF there's not ANY (and I don't know, though I've not heard of one), then I'm sure you'd be willing to state publicly that there are NO such DMD experts, right?
(And NO, neither you, nor your buddies Bastings or Dunn, or any doc on the AdComm qualifies! Oh, and no lab rats (e.g., EH) either--we're talking about real DMD doctors who treat the patients.
Ready, set, go!
One thousand, two thousand, three thousand................
starfe...it case it wasn't clear before then, the release of the BDs in Jan made it clear it WASN'T CG---it really HAS been the DNP this whole time.
winter---for some AdComm votes and staff analyses, overruling is the only rational approach. This is one--on clinical, scientific, FDASIA and several other grounds, IMO.
The FDA surely must understand--at least at CDER director level that the reputation of the FDA wrt answering, "Has benefit been shown?"; and, "Has safety been shown?" has already been damaged by this 'botched' staff analysis and subsequent doubling-down at the committee meeting. If they don't overrule, no one who understands the story/data will be able to look at ANY future staff analyses/AdComms as being of unassailable quality sufficient to justify the control given them in life/death decisions wrt drug approval.
That, of course, leaves out liberal arts majors like AF and 'journalists' like Herper--the latter doesn't seem to be clued in enough for anything other than and obsequious, knee-bending attitude to the FDA staff's voice as being infallible as last word.
Someone asked about those scientists in DMD who DIDN"T sign the letter--implying that such would mean they were opposed to approval. My comment to that is that the FDA should be asked to show if there was even ONE letter from a clinician who regularly treats DMD and who has familiarized himself with the data for etep, who express OPPOSITION to approval.
Those who DID sign put their professional reputations on the line opposing an agency which, either directly, or indirectly could do a large amount of harm related to future funding, drug developments/approvals, etc. I can't imagine a more strongly worded rebuke of the DNP staff, nor stronger support being expressed in such a situation with a potentially vindictive bureaucracy in a document which was to be made public.
Can the FDA CRL etep. Yep, Bastings/Farkas would in a milli-second, I believe. Hopefully, SCIENCE will rule and LAW will rule the day against emotions (hurt feelings and vindictiveness of DNP staff) and etep will be granted approval (and, PBOs dropped!).
Ahh, maury....you're back and in form again: basically, malignant ignorance personified; as well as a through-and-through bigot.
Oh, I hope you aren't one of those who are defacing memorials around the country. Or, if you are, that some of the families whose brothers, sons, fathers they go to honor don't see you doing it. Or, if you are, and they do, I hope (for their sakes---I don't think I care what happens to you) that any damage they do to you isn't irreparable.
klink....if it WERE the 'real' RF posting, then it must mean he's no longer an FDA employee, right?
The thought of that almost makes up for a dollar down on a long-weekend Friday, right?