16-02 Associate Director, Medical Writing Cambridge, Massachusetts, United States 5/20/2016
16-03 Director/Sr. Director, Medical Writing Cambridge, Massachusetts, United States 5/20/2016
16-01 Senior Director, Biometrics Cambridge, Massachusetts, United States 5/20/2016
Lack of a treatment for Exon 51 amenable skipping DMD patients
FDA reluctance to use patient registries for comparative information
FDA reluctance to use AA for diseases outside of HIV and Cancer
FDA insistence on bureaucratic control of patient access to new precision therapies
FDA lack of use of biomarkers for AA unless validated biomarkers (years of proof)
FDA contribution to high drug prices by extending valley of death for over-extensive clinical trials
Lack of treatment for 80 percent of DMD patients amendable to skipping other exons.
Something like this, depending on the broker
You need under Reg T something like a 50% initial margin. All this and the following depends on the broker. Then additional margin at say 30% will be required based
upon the changing value of the shorted stock. So say you short 1000 shares of Sarepta at 20, you would
have to have in the margin account $20,000 plus a 50% margin or $30,000 with $10K margin to start.
If the price goes up $5, to 25, the margin requirement is $25,000, plus 30% of 25, or $7,500, for a total
of $32,500, so you get a margin call for $2500 - you had $30K to start with, remember. Maybe you can come up with another $2500, so you have total account plus margin of $32,500. But it goes up another $10 per share.
Now the total value of the short position is $35,000 (1000 shares at 35) plus 30% or $10,500, so your total
margin account requirement is not 32,500, but $45,500, or another $13,000. If you don't come up with that
when requested, the broker will sell you out. The 30% maintenance margin reqt could be higher or lower depending on broker. Have a hunch some brokers will be raising the 30%. So little guys will not survive, only big deep pockets will be able to push a lot of chips in on the table as the price goes up, unless they decide to get out. Do your own diligence, but this is not a stock to short for small hands and bet against a safe, effective treatment for a significant unmet medical need which will MakeDuchenneHistory.
inadequate resources for 2 drug reviews, snow, missing adcom members, opaque and leading questions, 100 members of Congress, 24 Senators, major amendment with positive 4 year data, reports of CRO benefits from study 204 on falls. ADL, 36 experts, 6 doctors and therapists reporting patients benefitted, Adcom comments "it ameliorates the DMD phenotype" "from everything I heard today the drug works, but that wasn"t the way question was phrased". Be Reasonable
Chad Onyike asks, to what extent are we supposed to incorporate the testimony of the patients and others
the wording makes it seem a statistical question
Woodcock; We are supposed to incorporate patient viewpoints
Temple; You heard testimony from patients that tests didn't affect their level of effort
Unger: Unprecedented to have basically all the patients here. We're hearing patients improving doing
things they didn't do last year.
Romitti Q: We have 2 different groups, are we supposed to consider dystrophin results
Woodcock: this is the full approval question, not based on surrogate endpoint
(a mistaken description - dystrophin could be confirmatory evidence of single arm HC control trial)
Temple, Historical trials can be adequate and well controlled, some obvious, some not so clear.
Dunn: thats why we discussed historical controls, evidence from trials plus info from patients can be substntial evidence:
(So for 10 minutes they discuss, what does this question mean, can we consider patient and expert testimony....obviously the question unclear and basis for voting was not well defined)
Foley: Yes -clearly ameliorated the DMD phenotype.
Ovbiagele: No, but from everything I heard, this drug works
Hoffman, Green, Romittee: abstain, don't want to make a type 2 error, fearful of stalemate between
FDA and panel
Gunvalson, Dupree: Yes-can't reconcile difference between testimony boys are improving
Kryscio, Nuckolls, Kesselheim Onyike, No, not well controlled, but there seems to be more informatio from further studies showing benefits not included, use CROs like dementia (but they had 5-6 clinicians testify?)
Dunn FDA final comments: have listened very carefully, seen AdCom highly influenced by testimony, will consider very seriously
(So vote was again 6-7 with 3 abstainers sympathetic but restrained by "statistical" question-w Ovbiagele
saying drug works, basically 7 in favor of approving drug if asked based on all heard from patients & doctors)
Definition of a bear trap: Stock goes up in anticipation of approval, shorts pile on for quick .50 drop they hope, get stuck with FDA sudden decision and lose $30 per share short.
So that they can differentiate Eteplirsen showing no risk and some benefits when they grant AA. Sample Eteplirsen Benefit risk in Sarepta presentation and on twitter.
Things that take time
1. Labeling see guidance on labeling for AA
2. writing final structured risk benefit - released with approval
3. agreement on confirmatory trials timing/controls/size
Yes, it may sell a ton of stock, to BigPHarma - see story from Fitch Drug approvals driving targeted acquisitions in US pharma, says Fitch PFE, BMY both would be looking closely at marketable drugs and PMO IP and pipeline
When you check, as you should the updated PCNS materials on the FDA updated Advisory Committee
three days ago, when first post, had them like this
Jett Foundation presentation
then yesterday they changed the order to
Jett Foundation Presentation
TODAY May 17, they changed it AGAIN
Guest Presentation for Sarepta - leaving off the name Jett Foundation.
Slides from Advisory Committee presentations
Just weird, or somebody with too much time on their hands, or somebody
really sweating the way the materials are being presented.
Sec 506 EXPEDITED APPROVAL OF DRUGS FOR SERIOUS OR LIFETHREATENING DISEASE OR CONDITIONS
(b) ACCELERATED APPROVAL OF A DRUG FOR A SERIOUS OR LIFE-THREATENING DISEASE OR CONDITION, INCLUDING A FAST TRACK PRODUCT.----
(1) IN GENERAL
(A) ACCELERATED APPROVAL. ---The Secretary may approve an application for approval of a product for a serious or life-threatening condition....upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.....
Woodcock on April 25 There is agreement that eteplirsen has achieved its pharmacodynamic objective -ie production of dystrophin
1. Eteplirsen has "an effect"
2. The effect, by pcr, PDPF and WB, is on dystrophin production.
3. (a)36 scientists, including Kunkel McDonald, supported view that remedying dystrophin deficiency will
have clinical benefit. (b)Kathryn Wagner testified that Patient 006, Patient H, whom she treated, with 2.47% WB and 20% PDPF, had stable 400 6wt for four years. It is undeniable that dystrophin is likely to predict clinical benefit
(c) The article, What Can We Learn From Clinical Trials of Exon Skipping for DMD, Lu, Cirak, Partridge, 11 Mar 2014 notes the correction to FDA's prior view that there is a "disconnect between increased expression of dystrophin and clinical efficacy." Stabilization of the motor function in DMD boys participating in Eteplirsen extension study has now being observed over 2 years....dystrophin protein level...is a fundamental biomarker to be taken into account....
(2016 -now FOUR YEARS OF STABILIZATION OF MOTOR FUNCTION)
21 CFR 14.22
(d) Unless the committee charter provides otherwise, a quorum
for an advisory committee is a majority of the current voting
members of the committee, except as provided in 14.125(c) for
TEPRSSC. Any matter before the advisory committee is to be
decided by a majority vote of the voting members present at
the time, except that the designated Federal official may
require that any final report be voted upon by all current
voting members of the committee. Any current voting member of
the committee may file a separate report with additional or
and do they tell these people they can file their own reports with additional views?
Exon skipping was just an idea
But the patient community funded studies
They identified 2 O'me and PMO as potential therapies
Patients described the race against time in 2009 - Treat DMD
FDASIA provided a surrogate pathway to approval in 2012
FDA mistakenly asserted no link between dystrophin and function in 2013 based on results from a first
generation AON, while Eteplirsen PMO is a second generation antisense molecule
FDA finally accepted a rolling Eteplirsen NDA in 2015
Sarepta provided additional safety data from new patients being dosed N = 111
The first Eteplirsen AdCom was delayed because FDA didn't have resources
to do two at once.
The Eteplirsen Adcom was delayed again by Washington Weather
The 4 year ambulation data came in in January
Trials of follow on Exons are enrolled in the treatment arm, controls doing recruitment
This delayed the PDUFA to May as a Major Amendment
Major Amendments should only be used except in rare cases, for approval
FDA cannot delay the PDUFA again, because of the Major Amendment 3 month add on
Now is the time to fix Exon 51 DMD
Then 45, 53, 8, .........
Added: Apr 27, 2016 10:50 am
This is a request for information (RFI). It is not a solicitation for proposals, proposal abstracts, or quotations. The purpose of this notice is to:
1) Gather information on oseltamivir intent to manufacture over the next 3-5 years.
2) Better understand the capacity to provide various formulations of oseltamivir to support influenza preparedness efforts over the next 3-5 years.
3) Make use of this information to inform acquisition strategies for influenza antiviral drugs that may be used to support influenza preparedness and response efforts.
show data beyond the initial 12 boys, including a significant reduction in falls for a patient who started the drug in mid Nov 2014, so there is additional functional support beyond the 201/202 studies. The PROs and Clinician reports are powerful evidence of a significant clinical and quality of life benefit from eteplirsen. Evidence of eteplirsen producing dystrophin and/or clinical benefits like 6Mwt and LOA benefit are adequate, given regulatory flexibility, for Accelerated Approval. #MakeDuchenneHistory will the FDA says Yoda.
It ameliorated the phenotype. That's exactly what Regan Foley, the one smart pediatric neurologist said in her vote for accelerated approval. Of course, Romitti was on the right side too, even if he couldn't figure out which button to push.
As this article notes, "the dystrophin levels needed for improvement of muscle pathology, function, and overall vitality are not known....these findings suggest the dystrophin levels needed to benefit vitality and functioning of patients with DMD might be lower than those needed for full protection against muscle damage." That is, some benefit, not asymptomatic Beckers, but some significant clinical benefit can come from dystrophin production if clearly shown, like patient 6, Example H given by Dr Kathrryn Wagner, 2.47% WB, 20% PDPF by IF, and stable at 400 6Mwt over four years.
The claim by FDA reviewing staff that the WB was below the level necessary for BMD is clearly wrong, unscientific, and unsupported by the literature above, and the 12 boys clinical results, 1)You don't need to get to asymptomatic BMD for a benefit, and 2) duration is more important than dose, so start dosing all Exon 51 amendable patients without further delay, FDA.
Oh, and the 4 year non-LOA is an Intermediate Clinical Endpoint (ICE), like a surrogate, adequate for accelerated approval.
If you buy on margin they can automatically lend those shares, but if shares are fully paid they have to get your approval
lots of interesting tidbits - is practising insertion, removal on a porkchop OK; how many psychiatrists does it take to do a probuphine implant; one study participant was lost because incarcerated for duration of study; is this a superior study or a non-inferior study result rems rems rems but on balance, vote for approval lots of talk of opiod crisis which was a key holdup in Califf approval askinh for new fda dirction
Ortho and Rehab devices Apr 20 Transcript is instructive: Panel had multiple MDs (Drs who treat and see patients) ortho surgeons expert in field Heckman, Finnegan,Kelly, Golish Bailey, PfefferTr. 7-9; device for great toe arthritis, results based on patient satisfaction and FAAM pp.24-26, 43-45; Visual Analog scale for pain p. 35;but study included lesser forms of arthritis -Grade 2 Coughlin; there was "limited literature to determine what success was" using composite scales of pain and FAAM p. 64; Questions around use of patient-reported outcomes p. 68 (but agreed with FDA) (so FDA CAN AGREE TO USE PRO'S IF THEY WANT TO) BUT Bboth device and arthrodesis were effective in reducing pain & increasing function, so non-inferiority depended on safety p. 98(&p. 111); Agency asked panel whether favorable benefit risk was demonstrated p. 106; Q considered real functional outcomes like return to work or return to play? (as opposed to PRO scales) p. 111 What is substantial evidence of effectiveness: OSMA (Mfrs Assn) p. 127-129 reasonable assurance of safety when probable benefits outweight probable risk; Effective when based on scientific evidence it "provides clinically significant results in a significant portion of patient population" but FAAM is subjective scoring p. 160; we have an implant with a proud failure rate of 10% at 2 years p. 186; Q Panel CAN STILL VOTE IN FAVOR EVEN IF NOT STATISTICALLY SIGNIFICANT, TRUE, FDA? p. 199; first time ortho use of materials should not be non-inferiority study p. 203; OUTSIDE ORTHOPEDIC SURGERY ACTUAL GOLD STANDARDS INCLUDE SURROGATE OUTCOMES p. 213 (don't look at changing surey answers, FDA tools should give objective measures) Patients will have impression of increased mobility, when levels of function same or worse p. 227; superiority of treatments should result in a better quality of life demonstrated by real functional outcomes p. 237 ; panel should look at reasonable assurance of safety, effectiveness and risk benefit p252