I'm even more confident that eteplirsen will be granted AA and here's why. Janet Woodcock won the efficacy standard battle for AA and that standard is reasonably likely to convey a clinical benefit. Woodcock knew she had the votes of the FDA for AA approval but some suggested that since Sarepta has P-3 dystrophin data from phase III trial let's make sure the P-3 dystrophin data is consistent with the Phase II dystrophin data. If it is AA is assured.
I've read the debate of quantified dystrophin as % of normal and it is stupid. Comparing DMD exon 51 WB measurements to normal boys is preposterous especially considering no one knows at what level increase results in a clinical benefit. The only human data that supports a measurement with clinical benefit is Sarepta's WB of 0.9% of normal. The only way to conclude anything is to compare dystrophin measurements to baseline and try and correlate increases in physical clinical functions like 6MWT etc. Anyone that places any weight in Farkas's analysis and/or knowledge of DMD pathophysiology is delusional. Sorry for being so harsh but I can't take it.
The initiation of this trial is scheduled to dose it's first participant in July which means that they began screening boys for this trial in May. Is the FDA awaiting to announce AA on the day Sarepta doses it's first patient? Maybe. The FDA is on record as requiring this trial to "start" before granting AA for eteplirsen. Many in biotech world define the initiation of a clinical trial as the first patient dosed. I contend that once the FDA approves the first clinical site and they begin screening that trial has been initiated. We are about to find out. If Sarepta announces the start of the Essence trial this Tuesday that would be the clearest signal yet that the FDA will grant AA later that afternoon.
Long, I'm in the camp that believes that AA is announced this week. A week ago I calculated when the Ad Hoc panel's written decision was due. 35 business days from the DPO filing is August 24th, the same day as the PDUFA 90 day expiration. I always believe that the 90 day extension was fungible. The DPO process is not. The decision could come late afternoon on the 24th or in the am of the 25th. The FDA will release a PR announcing AA for eteplirsen. I strongly believe that the FDA will approve eteplirsen because I cannot think of 1 CRL scenario that explains the extended delay that Sarepta has experienced in it's AA FDA pathway. There are also rumors that the dystrophin WB's were slightly better then the 4th biopsy results.
Janney analyst Debit Chattopadhyay made positive comments on today's Essence recruitment update. A conclusion he reaches is profound. He states that since Sarepta has not received a CRL 2 month post new 13 patient Western Blots he concludes that this data is within "mechanistic" dystrophin levels consistent with increased levels. He believes AA will be announced in August.
Santhera's DMD drug Raxone's mechanism-of-action is that it restores ATP [energy molecule] generation. It also has antioxidant properties. There is no direct biomarker linkage that reliably is predictive of a clinical benefit for DMD, unlike dystrophin restoration. An analogy would be if we were to conduct a clinical trial testing the herb Ginseng. Ginseng helps stimulate ATP production in the mitochondria. Ginseng has been proven to increase ATP production. Should a nutraceutical company file an AA application for Ginseng for DMD? Of course not. This analogy illustrates how ridiculous the comparisons and extrapolations are for eteplirsen and Raxone. Apples-to-oranges.
One of the big red flags from Farkas's briefing doc's analysis is that he concluded, not based on historic exon 51 baseline 6MWT data, but that age only criteria was more comparative, then the matched control Sarepta used which included baseline 6MWT, steroid usage and genotype. Farkas used the mixed control to fit into a conclusion he already made.
I believe Sarepta shares are under pressure today because of Janney's analyst Debit C. comments on the WSJ article on the possibility of a DPO. For the record I believe Debit C. is one of the best biotech analysts but he is misreading the Differing Professional Opinion FDA guidelines on DPO's. He claims that the filers of the DPO [aka Farkas] can appeal the decision to the FDA commissioner and if that happens he would favor placebo -controlled studies for AA approval. The DPO is decided by a panel set up by the Director of Drug Development and Research, Janet Woodcock, and she ultimately makes the decision. The filer can appeal to the FDA commissioner BUT can only file an appeal based on violations of DPO procedures and rules. The Director's decision is not appealable per se. It becomes appealable if she violates the DPO rules. This is a rare mistake by Debit C. analyst at Janney.
Starting to believe that the current AA decision delay is related to ongoing Sarepta/FDA labeling discussions. Accelerated Approval based on a surrogate endpoint is a more difficult process per the FDA's own guidance. If this is the cause of the current protraction then it means AA has already been decided. Dystrophin western Blot quantification values would not be leaked but Labeling discussions could be leaked because it involves, from Sarepta's perspective, the entire regulatory team plus....I expect the share price to continue to climb until AA announcement
If one looks at where we are today regarding the circuitous route to AA like a bizarre briefing doc, a Sarepta addendum [response], another briefing doc to address addendum, an adcom, a controversial vote, a few voting members who voted NO wanted to vote Yes but due to the deliberately confusing way the voting questions were posed they voted No, extension of the PDUFA deadline,, additional data request, a possible DPO, a possible process appeals and I believe professional malfeasance and bias by Farkas and Bastings and we have the perfect storm for Sarepta to transmit the new dystrophin data confidentially. There is no way Janet Woodcock would disagree with the confidential submission of data. I know that many investors can't get over the fact that all data must be disclosed but don't forget that during the Adcom, confidential P3 safety data was submitted to the DNP panel. Based on the interpretation that ALL data has to be reported by the sponsor why wasn't this data disclosed by Sarepta? There is a FDA form that that must be filled out by the sponsor and approved by CIDER Director and if I get time I will post it. There are tens of thousands of FDA forms.
Chris Marai actually thinks it's possible that the younger boys might have greater dystrophin production by Western Blot then the older boys in the Phase II trial. Why is he the only biotech analyst to posit that opinion? Just last week Wall Street speculators were pushing the idea that dystrophin baseline quantification numbers for the 13 boys from Phase III trial would be higher so their conclusions were that it would be more difficult for statistically significant dystrophin production over baseline at 48 weeks. This was the reason for last week's decline. For those who try to interpret "Wall Street's" wisdom on data interpretation please stop. Many of these guys have no clue.
In 1962 the FDA was granted regulatory authority to assess the efficacy of new drugs. The efficacy standard adopted by the FDA was "substantial evidence" that the sponsor proved clinical efficacy. "Substantial evidence" standard includes in it's definition "well-controlled trials". At this time there was no Orphan Drug designations or AA pathways. Subsequent laws passed by Congress created incentives to the drug industry for drug development investment in rare diseases. Many have read the 2008/2012 AA laws and the FDA's guidance to the drug industry. The phrase or standard of "substantial evidence" from "well controlled trials" only applied for full regulatory approval and rightly so. "Substantial evidence" applies to full approval including confirmatory trials post-AA [interim] approval. Substantial evidence is not only a level of proof of efficacy but this evidence must be demonstrated in a well controlled trial. How does this original definition fit into a conditional AA / surrogate endpoint pathway for rare diseases? It doesn't and the FDA is cognizant of this fact by allowing CIDER to use significant regulatory flexibility in conditionally approving rare disease drugs via AA. They have used "historical controls" instead of "well-controlled" studies to approve AA eligible drugs. There goes the "substantial evidence" definition that some narrowly read FDA watchers use for AA. The FDA has approved drug[s] for AA based on 1 or 2 trials for rare diseases that doesn't come close to the definition of "substantial evidence" from "well-controlled" trials. The FDA ubiquitously applies statistical significance standard of a clinical endpoint to approve a drug. This is exactly why Janet Woodcock/CIDER Director will grant AA to eteplirsen.She will base her decision on a statistical significant increase on a surrogate marker, dystrophin. She will also apply "flexibility" given to her under statute and FDA's own guidance for AA and appropriately use a match historical control
Cops, Kaye presented slide confirming that Essence trial is confirmatory for eteplirsen. Public acknowledgement.
Next interesting aspect of the eteplirsen AA approval, a/k/a The Long and Winding Road, will be Woodcocks Press Release on said approval. I will be looking for whether she inserts the AA efficacy standard into PR. For me this would signal that the delay and disagreement and possible DPO between the Director of Drug Evaluation [JW] and the Team Leader [Farkas} was based on the standard. We will never know for sure.
I would buy more because there is a general misunderstanding of the DPO process. I believe that a DPO is a very bullish signal because one would only file a DPO request AFTER, in this case, the Director of Drug Development and Research over ruled the Adcom's recommendation. In this case the adcom voted 6-7 on dystrophin against.
The longer it takes for the FDA to issue their AA decision the more likely it is a DPO hearing. It could take up to 35 days to schedule and hear the different professional opinion. i don't believe they would have scheduled a DPO if it were only a difference on whether eteplirsen was granted AA. It is much more likely that it is a 'regulatory difference" because the standard is that it will significantly damage the FDA and since eteplirsen safety profile is pristine it is impossible to make the case that AA approval reaches that bar so it has to be the efficacy standard. Farkas insists the AA standard is the exact same as the 1962 statute, substantial evidence. Follow-on statutes 2008/2012 FDASIA/AA changed the standard to reasonable likely to confer a benefit. Janet Woodcock believes and is intent on using the AA standard for DMD. The laws and FDA's own guidance to the drug industry supports Woodcock's interpretation of AA standard. Woodcock will not lose this argument because she is the boss of Drug research @ the FDA