FDA reviewer on efficacy indicates that benefit from a clinical endpoint (6MWT ) and surrogate endpoints (in their case CK levels) "appear unmet" and that dystrophin production levels were "minimal and only reliable in one study". No efficacy from the FDA's point of view and we all know the safety is horrible - can BMRN spin the AdCom to overturn these conclusions? Doubtful.
It is interesting, but also brings a lot of clarity on how little research these analysts and reporters actually do - most of their opinions and risk assessments seem completely devoid of the facts on the ground. I have read several stories or analyst assessments from yesterday that characterize the safety difference between the two drugs as "Etep having fewer side effects" - really, that is your definitive statement comparing one drug that has has zero adverse events associated with it versus one that has potentially life-threatening effects on major organ systems? If you read the FDA's safety analysis, the section on injection site reactions alone is enough to characterize Drisa as extremely toxic - 79% of the boys had reactions; 21% of the reactions were not resolved by the end of the study with some lasting up to 1,217 days. Any reasonable person who read that FDA safety assessment and has paid attention to the dozens of times SRPT has provided the pristine safety record for Etep would not write "Etep has fewer side effects" as a statement summarizing the difference in the drugs.
If you read through the FDA's detailed breakdown of the various trials and data, you will find very little data that they regard as meaningful - every trial or test seems to have some issue or qualification that renders it at best questionable and at worst indicative of a ineffective and harmful drug. Therefore, IMO, BMRN is faced with the issue of starting from scratch when it comes to proving Drisa (1) actually produces dystrophin as it was designed to do (2) produces dystrophin at a level that would provide a clinical benefit and (3) can be safely dosed in a long-term/chronic setting. It is easy to see why GSK walked away from this drug and it is alarming that BMRN thought they could spin any of this data in a positive light, let alone get it approved. Assuming Etep has a fair assessment by the FDA and they agree there is sufficient evidence that Etep can deliver on the 3 points above, I can't imagine BMRN doing anything but bailing on Drisa - they certainly are not going to get any kind of approval at this stage and what possible scenario could they pursue that they could come into the market after Etep and compete with a toxic, less effective drug? Game over!
The patient advocates will include a mom who's son was on Drisa but couldn't handle the injections and is now on Etep, but she will reportedly still advocate for Drisa's approval. Jenn McNary will also speak as an advocate for Drisa #$%$) under the banner that DMD parents need choices. When you have the CEO of SRPT speaking to the positive impact of a Drisa approval and parents that know the value of Etep jumping on that bandwagon, you have to believe the political stars are aligning for BMRN. Looks like the best we can hope for is the FDA puts a black box on the Drisa label and/or delays the approval for a REMS or further safety data from their confirmatory trial, which they have yet to launch. AF's article doesn't even speak to dystrophin production evidence and the lack thereof from BMRN - in the long run, how could they ever get the smaller Exons approved without dystrophin production evidence. Etep will own the DMD space.
The final conclusion on page 140 - "It is very disappointing that both the clinical and biomarker data for drisapersen are inconclusive at this time".
It's articles and analyst comments like this that are the reason SRPT gets no respect - the implication is that the only way it will get approved is because of political pressure. I have read very few articles or analyst comments that spoke to the efficacy and dystrophin production evidence - again, the implication being that the trial has only 12 participants, so regardless of the evidence, it can't be deemed significant or reliable. They don't even bother parsing out the evidence or analyze the approval in the context of the accelerated/conditional approval rules.
The "idea" of a historically controlled trial came from the FDA - there aren't enough patients to enroll a meaningful placebo-controlled trial, because the baseline restrictions are too tight and ultimately anyone who realizes they are in the placebo group will simply drop out midway through the trial - you can't expect parents to keep their kids on a weekly IV infusion, blood testing and multiple muscle biopsy tests when they are getting a placebo - it is unethical from so many angles. The FDA has distorted the comparability of the historical control group to come to the conclusion that the boys progress is consistent with natural history - 10 of 12 boys on Sarepta are still walking after 4 years, vs 2 out of 13 of the historical control group - how do you conclude that is the same performance? It is difficult to imagine what agenda the FDA is following here and perhaps that has been the longs biggest mistake - trusting that the FDA would act in a reasonable manner and consistent with the spirt of the AA regulations.
BMRN received a "tough" review because their safety data was horrendous and their efficacy data was inconsistent and sketchy, at best. SRPT's safety data is pristine - what would a tough review of the lack of any adverse events look like? The FDA and/or panel may raise doubts about the comparability of the 6MWT and other performance measures against historical controls, but there is a difference between raising a doubt and dismissing the data outright, which is what the FDA did to BMRN's attempts to find evidence of 6MWT benefit from their trials. In addition, most of the secondary performance measures by BMRN showed no benefit, while SRPT's secondary measures show stability and/or advantage over historical controls.. When it comes to dystrophin production, the FDA already had a tough review of SRPT's original dystrophin data and challenged them to re-score the measures and do a 4th biopsy - by all accounts, that data confirmed the methods and results - what is there to be tough on there?
BMRN created. Their efficacy data was so full of holes and their safety profile was so horrible, this drug should never have been submitted, but as was noted numerous times on this board, the FDA's acceptance/filing of their NDA was no indication of the quality of Drisa - it simply meant they had met all the requirements documentation for a NDA. You could tell the AdCom members were desperate to find any positive thread to the data, but it just wasn't there. I actually felt bad for the FDA staffers who had to get up and publicly display how worthless BMRN's data was - they were put in a horrible position of trashing the hopes of the few patients who actually believed in the drug.
The one interaction that to me epitomized how desperate BMRN was to fool someone into believing in Drisa was during the discussion of dystrophin production. The FDA staffers made it pretty clear from the start of the analysis that the dystrophin increases that BMRN was reporting were small percentage increases (less than 5% increases) from baseline readings that were less than 1% of normal muscle tissue. In other words, BMRN was trying to rationalize that an increase from say 0.5% of normal at baseline to a post-treatment reading of 0.502% was meaningful. When one of the AdCom members asked if they had analyzed whether the increases in dystrophin correlated to any increases in 6MWT performance, they actually had a chart prepared - even the idiot AF commented "why didn't they show this earlier"? Answer - because anyone that believes that a .002 increase in % of dystrophin positive fibers would correlate to anything is a moron. The fact that BMRN put a chart together answering a question only a moron would find meaningful says a lot.
The downside to this whole debacle is that regardless of how strong the case is for Etep's conditional approval, it is now soiled by being linked in the minds of many analysts and "experts" as a drug that is similar to Drisa - What A Mess!
More paranoid, vacuous drivel from simp - what else is new?! Instead of posting a laboriously lengthy message to get a single point across (Etep's briefing docs may not be glowing), why don't you give one or two specific areas where the FDA may find the data on Etep lacking or inconclusive? If the board were to post a briefing doc on the accuracy/relevance of your posts over the past few years, it would be as bad and conclusive as BMRN's!
usagary - a confirmatory trial is only required if conditional approval is given - if the Drisa is given full approval, there is no requirement for a confirmatory trial. BMRN has put the FDA in a box, because if they give them conditional approval and require them to do a confirmatory study, their ability to enroll that study (at least in the US) would be severely compromised by the approval of Etep. Frankly, given the "messy" clinical benefit data and horrible safety profile, the FDA should kick Drisa to the curb, but it doesn't seem like that is in the cards?
pearsby - you are the definition of a "moot point" - you raise issues that are clear to everyone on this board and act as if they are going to be a surprise to the FDA or AdCom - do you really think the AdCom members don't know the scope of the trials/data they are going to be asked to review? The issue for the FDA and AdCom is whether the limited current data warrant accelerated approval with the expectation that the confirmatory trial will validate any open issues. The reality (as a number on this board have pointed out) is that the clinical significance of Etep won't be known for 5-10 years - i.e. will it keep boys that start early ambulatory, will it stabilize the pulmonary and upper body muscles of boys that are already non-ambulatory and allow them to live with some function into middle age, etc., etc. The idea that a 100 patient trial (let alone a 12 patient trial) will provide all the answers on the clinical value of Etep is senseless - the only question for the AdCom and FDA is whether the evidence supports the case that Etep is "REASONABLY LIKELY" to provide clinical benefit to the boys. The dystrophin data, the 6MWT data vs natural history and heard the declarations from parents and doctors that Etep definitely is working are enough for most reasonable people to conclude that Etep warrants accelerated approval - questioning whether the FDA and AdCom will be reasonable is an easy, but useless exercise.
ru - I thought gave up beating this dead horse. It is more than clear to everyone except you that the AA protocol in the rare, fatal disease space is not the same as a "conventional" drug approval. The FDASIA regulations speak to the limitations of small, uncontrolled trial data from a statistical standpoint and how the FDA has flexibility in how they approach the analysis of the various clinical data. To the extent statistical significance can be established, that is a bonus (which SRPT has done with much of the dystrophin data), but it is clear that the FDA has the ability to assess various clinical endpoints and non-clinical evidence (i.e. patient reported outcomes) in determining whether the drug is "reasonably likely" to provide clinical benefit.
BMRN attempted to muddy the dystrophin-as-surrogate waters by claiming their drug showed a clinical benefit without the evidence of dystrophin production. GSK's horrible execution of the their Drisa trials, where a significant portion of the biopsies were unreadable, is one of the reasons the FDA back-pedaled on Etep. If RNA/GSK just fessed up to the fact that their drug wasn't working and acknowledged that they couldn't safely dose it at high enough levels to produce dystrophin, that may have left a cleaner clinical review path for Etep and we would have been approved by now.
I fail to understand all the handwringing over the trial size, as if 3+ years into the process of pursuing accelerated approval the FDA is going to suddenly say "oh, you only have data on 12 patients"? A small N is a problem if there are safety signals that need to be weeded out in a larger population - not the case here. A small N is a problem if there is inconsistent pk/pd and other biomarker activity - not the case here. A small N is a problem if there is inconsistent clinical benefit - assuming you accept the rationale for the twins, not the case here. Most importantly, a small N is a problem if you are seeking full approval - not the case here.
The quote in the Business Journal was him commending the FDA on how they handled the Drisa review. I've listened to every presentation and conference call over the last 4 years and I don't recall CG ever disparaging the FDA - he may have expressed frustration with the process and their start and stop decisions, but he was mostly disciplined in his comments about the FDA and how the company needed to work with them. CG was a scapegoat for people who though the FDA was making decisions based on personality conflicts with CG - if you look at the evidence, the FDA's decisions were based on ignorance and bad analysis.
nerd - My thoughts exactly - the FDA looked for reasons why the data might not make sense, instead of discussing the rationalization of why the data could be meaningful. Two examples stuck out in my mind - they noted that the four 50mg patients did not show dystrophin production in the week 12 biopsy, whereas the four 30mg patients showed increased levels at 24 weeks - their conclusion was not to question whether SRPT's assessment that it takes time for dystrophin levels to be generated was reasonable, but rather to dismiss the 24 week data as unreliable. The second was the assessment of the comparison of the historical control data - they surmised that higher use of steroids, physical therapy and aggressive management by the parents could account for the differences in the 6MWT scores, without having any clear evidence that was the case. Granted, their job is to be skeptical and to find flaws in the way the trials are conducted and clinical endpoints measured, but to speculate on reasons why the data should be questioned without having evidence to conclude one way or the other is not very scientific.
gig - "the law and the punishment in this country are too soft"? The US by far has the highest incarceration rate than any western nation - who exactly are we being soft on? And when you say "religions do not do the killing, evil people do", there is only one religion in the modern world that preaches to the destruction of "infidels". Of course it takes a "sick mind" to do these terrorist acts, but when a sick mind is brought up under a violent ideology, do the math!
I would find it hard to believe that Drisa gets anything but a CRL with additional study requirements, which will likely never take place if Etep is approved. The delusional Driss-pumping analysts hide behind the idea that the FDA doesn't have to follow the direction of the AdCom, which was overwhelmingly negative, but they fail to point out that the FDA crafted the AdCom review and questions in a way that left the AdCom members no wiggle room to do otherwise - it was the FDA's review that was harsh and unequivocal - no evidence of efficacy and "life threatening" safety issues.
You can speak to risk-benefit all you want, but given Farkas' commentary on the safety, do you really think he is going to have his legacy be that he approved a drug that led to the death of a boy because some undefinable class of boys are able to tolerate the drug? If political/parent pressure were going to have any effect on the FDA decision, it would have been evident in the FDA's AdCom review - they would have left the door open for the AdCom members to consider the "totality" of the data and patient reported outcomes - they didn't, because they made it perfectly clear that the safety issues were too significant to risk against the lack of efficacy, from both a clinical and dystrophin-production standpoint.
IMO they delayed the PDUFA because they are debating on whether to leave the door open for BMRN to continue studying the drug - how do you justify allowing a company to pursue studies in a drug that is toxic, when you are on the verge of approving a superior drug with a pristine safety record?
dylacha - "without dystrophin data this does not get approved". In one sense you are correct - if SRPT's data was as incomplete and flimsy as BMRN's data, we would be in the same boat - a significant portion of the biopsies BMRN performed in their Phase III trial were deemed unreadable and those that were readable provided very inconsistent and conflicting evidence of whether any new dystrophin was being produced. SRPT's data package on dystrophin is complete for all 12 boys (except one that opted out of the final biopsy) and the results are consistent and validated. The question of what level of dystrophin is required for clinical benefit is something no expert has an answer for, but any reasonable person would conclude from the data that Etep is definitely generating the production of new dystrophin and the clinical data from 6MWT and other functional measures are meaningfully positive - combine that with the safety profile and the declarations form parents and doctors and that is more than enough for AA.