The ultimate irony could be that Drisapersen is approved by the EMA while SRPT and Eteplirsen go down in flames because of a hidebound, close minded, unqualified FDA review. Biomarin is optimistic that Kyndrisa ("Kind" Drisapersen) will get a favorable review in Europe which is a bigger market than the US.
So the drug that Farkas said would "kill children if used widely" may end up being marketed while the drug that has harmed no one and has obvious benefits never sees commercialization. That's FDA protecting us from safe and ineffective drugs.
Is this some sick episode of The Twilight Zone!?! This decision will impact a generation of DMD boys.
Who you gonna believe? A desk bound ophthalmologist or a neuromuscular pathologist with over 27 years of clinical experience in DMD? In less than three minutes Dr. Anne Connolloy gave a more objective picture of the biochemical and clinical impact of Eteplirsen than the two plus hours the FDA team had...
“I know well the difference between Duchenne and Becker muscular dystrophy as I have cared for more than a hundred and fifty boys and men with these disorders. If I have a question whether a boy has Duchenne or Becker I do in fact assess the number of dystrophin positive fibers. In the recent FDA briefing it was stated that the percent positive fibers is not a reliable way to quantify dystrophin. Not only do I disagree with you I ask you to review those biopsies carefully and note that the fibers with dystrophin are larger and more frequent than any biopsy I’ve ever seen with revertant fibers. I believe these dystrophin fibers are driving the clinical effect. Furthermore, because Justin and Cole are so much stronger than I would have expected, if I met them for the first time today I would have suggested they have muscle biopsies. When I consider the post Eteplirsen biopsies and their physical examinations I would have to classify them as having Becker muscular dystrophy. Thus, I do believe that dystrophin positive fibers are a clear biomarker for strength and rescue of muscle.”
Based on all natural history that you and I have reviewed he should have stopped walking by age thirteen. At age 16 and a half, after recovery from a femur fracture, he is still walking.
My second patient, Cole, was 10 years old when he started the trial and has also done well despite a fracture at age 11 and a half requiring a cast and no weight bearing for eight weeks. He has regained the ability to walk and continues to do so at 14 and three quarters years. They are both exceptionally bright.
These two teenage boys do not require someone to feed them, take notes, or take them to the bathroom. While I am a strong advocate of corticosteroids, make no mistake about this fact, corticosteroids whatever the regimen do not explain the data here. Be careful of type 2 error.
She just made finished at exactly 2 minute and 59 seconds when Caleb “The Axe” Alexander cut off the mic.
This is all you need to know about whether Eteplirsen works or not. Alexander, whose eyes were glazed over at this point, was probably busy playing games on his lap top during the testimony.
I’m a neurologist at Washington University in St Louis and I’ve worked with children and adults with neuromuscular disorders for 27 years. I have been a consultant for Sarepta, but stand to gain nothing financially from approval. Please consider what I have to say from the perspective of a clinical researcher in Duchenne dystrophy, a neuromuscular pathologist, and finally with their permission I speak for Justin and Cole who I’ve followed for three and a half years in the extension study.
I know well the difference between Duchenne and Becker muscular dystrophy as I have cared for more than a hundred and fifty boys and men with these disorders. If I have a question whether a boy has Duchenne or Becker I do in fact assess the number of dystrophin positive fibers. In the recent FDA briefing it was stated that the percent positive fibers is not a reliable way to quantify dystrophin. Not only do I disagree with you I ask you to review those biopsies carefully and note that the fibers with dystrophin are larger and more frequent than any biopsy I’ve ever seen with revertant fibers. I believe these dystrophin fibers are driving the clinical effect. Furthermore, because Justin and Cole are so much stronger than I would have expected, if I met them for the first time today I would have suggested they have muscle biopsies. When I consider the post Eteplirsen biopsies and their physical examinations I would have to classify them as having Becker muscular dystrophy. Thus, I do believe that dystrophin positive fibers are a clear biomarker for strength and rescue of muscle.
Now a minute on behalf of Justin and Cole. I have followed Justin since the age of three and treated with intermittent , twice weekly steroids. However, at the age of 11 when he entered the study he had difficulty getting off the ground and I timed him at 26 seconds and he subsequently lost the ability to get off the ground.
One of the most pathetic things about the Farkas review is the ridiculous skepticism over the objectivity of the 6MWT. I wonder how Farkas would react to an AdCom questioning the objectivity of an eye chart exam? Questioning the objectivity of 6MWT shouldn't even be in the mix with these results. The tests were conducted by physical therapists that are the experts in conducting 6MWT. On the other hand, almost all of the Drisapersen tests were conducted by centers with no training in the conduct of 6MWT and almost no experience with DMD. Bienaime said exactly this during a conference call. Yet Farkas used the Drisapersen data as a comparison. Properly conducted 6MWT supervised by PT's experienced with DMD is the best clinical endpoint for DMD progression in boys that can walk, period. An AdCom shouldn't even be allowed to question that. It's like debating if the earth is round or not.
Geez, OMG, if Janet Woodcock approves Eteplirsen there will be a flood of NDA’s of drugs where FDA has been yanking around the sponsor for over 4 years, sending mixed signals, not settling on endpoints, where the Agency changes its mind, even debates the utility of a proven endpoint at an AdCom, an AdCom made up of completely unqualified personnel, with no experience or knowledge of the underlying disorder, and a review team equally inexperienced, biased and confused, where the complete review ignores the opinions of every expert in the field, making inappropriate comparisons, ignoring FDASIA and the patient reports of clinically significant responses, for an orphan disease with no FDA approved drug, a disease that has a clinically dismal course, requiring extremely expensive supportive care. Just imagine the precedent!!! FDA must make an example of these boys and show them that the Agency isn’t gonna be pushed around even when their review makes no damn sense. Bureaucracy, dogmatic adherence to clinical trial protocol and pursuit of the most unambiguous endpoint is the goal. Remember; always treat the patient like a guinea pig no matter how long it takes and how many lives are wasted. So what if 95% of orphan diseases have no FDA approved drug and one out of ten Americans has an orphan disease. So what if the drug is completely safe. Protocol is all that matters.
These are uncharted waters in biotech. My mistake was not comprehending how ridiculous the review process can get. While its obvious that the Farkas team is incompetent and even stupid, it appears that once assigned a case it's impossible to overrule or reassign a review in the FDA's labyrinthine bureaucratic mess. This review is so full of holes that under normal circumstances in any other organization it would have been shredded and the authors fired but this is FDA. Sarepta will be able to destroy the credibility of the Farkas effort because it's just plain stupid. The question is will the panel "get it"?
For me holding shares is just too risky. OTOH calls make sense. Monday's gonna be a no holds barred, full contact, mma cage fight.
Grey has nailed it. DNP is totally dysfunctional. This is more about protecting egos then protecting the lives of kids with DMD. My issue now with the AdCom is that often these panels reflect the bias of the division that selects them. Hate to say it but if Jesus were to testify in favor of approval it would still be an uphill fight.
The tragedy is that Eteplirsen works. The profession is convinced of that. So it's now gonna take until 2020 before this hidebound organization approves the only drug that has ever changed the course of DMD. What a tragedy. As an investment SRPT is now a loser in my opinion. FDA should be burned to the ground. I lost my shirt on this but kids with DMD are losing their lives.
Sentiment: Strong Sell
Not only that but it stops the rest of the pipeline in its tracks. If Eteplirsen gets a CRL there will be no exon skipping drug on the market until 2020. The original results came out in Oct 2012. How's that for accelerated approval. This delay is all on FDA who said maybe, then no, then maybe then delayed then produced one of the most unscientically sound set of pathetic briefing documents ever cranked out by the Agency. They owe it to the DMD and rare disease community to be as accommodating as they can possibly be because thus far they have majorly botched this whole process.
External stuff means nothing because you say so, right Simp.
Excellent argument. Hard to find fault there.
Using your infallible logic then if 36 world renown experts in DMD said Eteplirsen was snake oil that would have no impact on the panel. And if 25% of Capitol Hill said ignore FDASIA that would also have no influence.
For that matter if FDA's own policy under PADUFA V is to give more consideration to patient testimony that would mean nothing to the panel as well. Right...
"In PDUFA V, FDA also committed to a new initiative called Patient-Focused Drug Development with the goal of obtaining the patient perspective on certain disease areas during the five year period of PDUFA V. Assessment of a product’s benefits and risks involves an analysis of the severity of the condition treated and the current treatment options available for the given disease. This information is a critical aspect of FDA’s decision-making as it establishes the context in which the regulatory decision is made. FDA believes that drug development and FDA’s review process could benefit from a more systematic and expansive approach to obtaining the patient perspective on disease severity and current available options in a therapeutic area."
Great article in Barron's, "Showdown for Sarepta Therapeutics Shares". You can read it on Investorvillage.
This paragraph has a critical mistake, though...
"If the FDA fails to approve eteplirsen in May, Sarepta shares could be headed back down to $10. A rejection would diminish but not doom eteplirsen’s prospects, since the company has an ongoing confirmatory Phase 3 trial involving the drug with results likely in 2017 or 2018. If the Phase 3 data are favorable, Sarepta could seek FDA approval at that time."
The confirmatory trial won't be finished until May 2019 which means approval wouldn't happen until 1st Q of 2020 at the earliest!
So AdCom members have to ask themselves, "Can we in good conscience delay this drug and the rest of the pipeline for almost another four years because we don't have incontrovertible evidence of efficacy or do we agree with the experts and approve it now?" Basically accelerated approval or death sentence for DMD boys.
Members of the Supreme Court go so far as to plagiarize amici briefs when they make decisions (see: The Influence of Amicus Curiae Briefs on U.S. Supreme Court Opinion Content).
I think it's ridiculous to think that FDA Advisory Committees don't heavily weigh the opinions of expert testimony as well.
The percentage of members that signed the House letter was 25% (109/435). The percentage of Senators that signed their letter was 24% (24/100). Percentage of both houses was 25% (133/535). Pretty much a bipartisan mix. How often do you see that these days?
As for whether or not the panel will listen to outside experts an interesting read is Dr. Joel Perlmutter's report on his testimony before an FDA AdCom. He felt that his testimony was misunderstood and that the panel voted contrary to his position. He also felt that he was extremely qualified to give advice and says he's "hard nosed" about evidence. He feels that the AdComs need to listen to outside experts especially experts that focus on the evidence. Perlmutter's is now a member of the AdCom so he's now on the other side of the table. He'll listen to outside experts but he's no pushover.
Signatories of the Senate letter...
Senators Wicker and Klobuchar, cosigners of the letter include Kelly Ayotte, R-N.H., John Barrasso, R-Wyo., Michael Bennet, D-Colo., Richard Blumenthal, D-Conn., Barbara Boxer, D-Calif., Sherrod Brown, D-Ohio, Maria Cantwell, D-Wash., Shelley Moore Capito, R-W.Va., Bill Cassidy, R-La., Susan Collins, R-Maine, Chris #$%$, D-Del., Tom Cotton, R-Ark., Angus King, I-Maine, James Lankford, R-Okla., Edward Markey, D-Mass., Robert Menendez, D-N.J., Lisa Murkowski, R-Alaska, Chris Murphy, D-Conn., Marco Rubio, R-Fla., Jeff Sessions, R-Ala., Charles Schumer, D-N.Y., and Elizabeth Warren, D-Mass.
My bet is that Briefing Documents 2.0 are slightly positive in an almost patronizing way. The positive nod will say something to the effect that, "Relative to the historic control submitted by the sponsor there is an indication of efficacy and given the limited exposure thus far the drug seems to be relatively safe."
They will qualify this by saying that "Historic controls are notoriously biased and only when compared to a true placebo control can a drug's efficacy be accurately measured. Furthermore, a wider population needs to be exposed to this chemistry before we can be confident that it will have no untoward effects."
The Farkas horse manure about the better physical therapy and more consistent use of steroids in the Eteplirsen boys will be thrown out because it was pure, unadulterated horse manure and the idiotic conjectures about the dystrophin analysis will be tossed. The document will admit that de novo dystrophin was produced but be ambivalent about its impact.
Basically the documents will admit that there do appear to be signs of efficacy that need to be corroborated by a confirmatory trial. The panel will get the message that Eteplirsen is safe and effective but FDA wants everybody to know that they're in charge.
That, plus some fired up advocates, overwhelming, enthusiastic support from the experts in DMD, FDASIA and Congressional intent, and the fact that delay will mean waiting until 2020 (results mid '19 for confirmatory with approval 1st to 2nd Q '20) will result in a positive AdCom.
13 million shares traded on the 5th and 6th and the share price takes off because Joe Edelman says SRPT's a buy!?! Come on now. How much of a tell do folks need? FDA policy is to give the briefing documents to the AdCom panel and the sponsor 14 business days before the meeting. That's the 5th or 6th depending on how you count it. Chances are pretty good that briefing documents edition 2.0 are mildly positive. Do people really think that Farkas and the rest of the review team want to go down in a self righteous blaze of glory? It's gonna be four years of efficacy and safety, advocate pressure, Congressional pressure and the enthusiastic support of almost every respected expert in the field versus an arrogant, condescending regulatory traffic cop. Give me a break. PADUFA's aren't extended for frivolous reasons. Board members don't blow 2 1/2 million bucks for kicks and Joe Edelman doesn't control the tape. And Farkas ain't the head honcho at FDA. FDA isn't gonna make these kids wait now until late 2019 at the earliest to have access to Eteplirsen. Some people may need a voice coming from a burning bush to tell them what to do but all the signs are saying buy.
Grey, many thanks for your due diligence. Were you able to find any stats or specific instances dealing with major amendments and their outcomes? Here's the guidance which indicates how significant an amendment can be...
"If the applicant submits a major amendment(s) (refer to Section XVI.B for additional information on major amendments) and the review division chooses to review such amendment(s) during that review cycle, the planned review timeline initially communicated will generally no longer be applicable. Consistent with the underlying principles articulated in the GRMP guidance FDA’s decision to extend the review clock should, except in rare circumstances, be limited to occasions where review of the new information could address outstanding deficiencies in the application and lead to approval in the current review cycle."
Now, back to The Masters.
Good article. If Eteplirsen is delayed again, I can just see a member of Congress pointing to this report, "AN FDA REPORT CARD: Wide Variance in Performance Found Among Agency’s Drug Review Divisions," and absolutely excoriating FDA...
"Ms. Woodcock, you mean to tell this committee that the Agency couldn't follow the guidance outlined in FDASIA and give conditional approval to perhaps the only drug that has ever shown any promise in Duchenne!?! A review that ignored the entreaties of dying children and their families. A review that ignored the detailed advice of the world's experts in DMD. A review that ignored the Agency's own guidance on 6MWT, dystrophin quantification and use of a historic control. Instead, under your guidance and supervision you put the fate of these children's lives in the hands of a review team with absolutely no experience in DMD!?! Americans pay outrageous sums for drugs and medical care yet this FDA division can't give timely guidance or approval to a drug that is as safe as mother's milk!?! I'll quote from the study...
"Our study finds, notably, considerable variation among the divisions. In fact, the median time for approval at the slow- est division is three times as long as the approval time at the fastest. The slowest, the Neurology division, took nearly 600 days to approve a drug, and the two fastest units, Oncology and Anti-Viral, took under 200 days...
An examination of numerous variables suggests that the performance of the leading divisions cannot be explained by a lower workload, differences in the type and complexity of the drugs under review, or a diminution in safety. Indeed, Oncology and Anti-Viral had a relatively higher workload than other units while the divisions that appeared to be below-average performers (Cardiovascular/Renal, Neurology, and Psychiatry) had a lower workload."
If Eteplirsen is delayed again it ain't gonna be pretty for Janet Woodcock, DNP or FDA.
The roster is here...
Peripheral and Central Nervous System Drugs Advisory Committee Roster
There are three vacancies so maybe they'll recruit some more folks. The Docs on the roster are experts, just none of them are DMD experts. None of them have any experience with DMD. They're all well published in their fields, dementia, stroke, etc.
During the Drisapersen AdCom I recall that they started to discuss the possibility of a hint of efficacy only to have Farkas jump in with both feet and declare that kids would die from Drisapersen if approved. So I take that as a sign that these folks are empathetic to what the boys are faced with. Given that everyone of the panel members is well published and have extensive resumes in their fields I would hope that the opinions of experts in DMD would make a favorable impression. Otherwise this group is a black box.
I'm an investor. I bought AVII/SRPT to make a buck. If you got a problem with that vote for Bernie. BUT I'm not blind to the frustration that the kids and their families are going thru. And if they're using every tactic they can to get Eteplirsen approved I applaud them. Patronizing, sanctimonious idiots like AF who lecture us that the greater good will be served by a more rigorous review don't have a clue. I'll take my lead from Drs Wilton, Kunkel and Mendell, the 36 experts, real life world renown experts (Wilton and Kunkel among them), the data, 4 years of it, and boys/men like Ricky Tsang. Excerpts from his letter to FDA follow. There's finally something that works for these kids but clowns like Farkas and Marciniak are the gatekeepers!?! Even FDA isn't that messed up. Adult supervision will prevail. Finally...
"No. Eteplirsen will not benefit me, at all, but you must understand that my goals have changed ever since I was diagnosed with heart failure in July of 2011. I am no longer determined to be cured, but solely advocate for the sake of the next generation. I don’t want them to share my fate.
While I am alive still, the agony is unbearable. I have nerve damage from the tracheostomy and my stoma has been burning like fire and acid combined for a decade. My back throbs in soreness because the spinal fusion rods are pushing through. My chest is in torture from the constant pressure of the safety strap, while my heart feels like it is being stabbed by a knife. My butt is numb resulting from sitting all the time, and my joints are aching as we speak. My feeding tube site bleeds every night and with all the unbearable pain, a migraine is always with me...
At this point, it shouldn’t be up to people behind desks to decide our fate; those who don’t have one or more dying child at home. It should be up to the parents. They are capable of choosing for their own children."