I was thinking the same thing - when the AdCom brought up the idea that the ISRs were effectively unblinding the study and asked whether the boys with ISR performed better on the 6MWT - how is a boy in pain and/or with an ulcer on his leg or butt supposed to perform better?
copp - I agree on the face of it that the Etep data is strong enough to get conditional approval without an AdCom, but I think the FDA wants to avoid any controversy and put the process out in the open. It is such a politically charged decision and there are so many "vested" interests at play, any sign of favoritism or working outside the designated process would put them in an unfavorable light. I was actually impressed how emphatically they exposed Drisa's flaws - hopefully they will be equally impressive in acknowledging Etep's distinct advantages to Drisa and make it the case book example of FDASIA that it deserves.
jrrt - In the case of Drisa, I think the FDA just wanted the data and their breakdown out in the open. The case made by BMRN for their data vs the FDA's interpretation of the data was night and day - if the FDA had rejected Drisa behind closed doors, the parent groups would have gone crazy. I agree that they did not want any wiggle room from the AdCom members to interpret the data in a positive manner - the questions were set up to focus on the true flaws in the data and not to look for any potential silver linings (there were none).
One of the most shocking comments from one of the AdCom members was a woman (Gunvalson) who said if she was a DMD mom, she would accept the 10M benefit computed for Drisa from the Phase III trial. Obviously, this was an emotional statement, because it truly ignored the reality of that reported 10M benefit, in that it came from a trial with a P-value of 0.42, which means that the value was statistically meaningless. You would hope someone on an AdCom would understand basic statistical concepts, but if she didn't, the FDA was validated in not letting emotions come into play with a simple approval vote.
Exactly - I wish I had picked this up when it was below $2, but anything below $2.50 is still a bargain. With the offering, they have enough cash to get them to a couple of milestones that should push this over $5 in the second half of 2016.
thig - in my head I agree, but I sense that the AdCom will become "reactionary" to some of these issues. I am not worried about the N=12 issue - the N is only a problem if your data is inconsistent - BMRN was arguing to look at subsets while ignoring the other patients for reasons that upon analysis didn't hold up. I am worried that the dystrophin production evidence may not sway, simply because it was noted several times that Becker patients typically have dystrophin positive fibers of 50%+ - I don't believe SRPT's positive fiber counts made it to that range. Many AdCom members were questioning not only what level of positive fibers were necessary to provide benefit, but how could they be sure the dystrophin being produced by Exon-skip was functional. I know SRPT has additional tests and data on these issues - let's just hope they are convincing.
Regardless, I still believe that SRPT's safety profile and efficacy data is sufficient for a conditional approval and the progress they have made in the confirmatory trial should seal that decision.
BTW - A long day and a celebratory IPA caused me to add a decimal place in my example of BMRN's dystrophin production fantasy - the 4% increase from a baseline of 0.5% would be 0.52% The point is still valid - their dystrophin production numbers were a joke - it is hard to believe they were discussed at all, although several AdCom members noted how unethical it was for all the useless biopsies they took from these boys - in their P3 trial only 44% of the biopsies were able to be read.
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!
The scary part is the trigger was the investment by one of the more vile characters in the hedge fund space - given this guy's track record as a scumbag, who in their right mind is jumping in thinking he has any ability to do anything but rape the shareholders?
"repeatedly raised concerns" about N=12? If they had any problem with N=12 in the context of an accelerated approval they would have closed the door years ago - I don't recall any correspondence or communications where N=12 was deemed a problem. When it comes to dystrophin production, what the FDA expressed was ignorance - they challenged SRPT with false accusations of how their methods were lacking (without providing any specifics), but then SRPT proved them wrong with the re-reads and the 4th biopsies.
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!
It's a textbook example of how toxic Drisa is - if it can cause that much damage to the skin, just think what internal damage it can inflict over years of dosing?
Amen md - as Jenn has stated, Etep could have and should have been approved two years ago. Any analyst that dismisses the "limited" data on Etep as unworthy of approval is both clueless to the clinical evidence, dismissive of reams of anecdotal evidence, and insensitive to the irreversible destruction of DMD - to think the FDA would take another step back after all the hoops they made SRPT jump through (which they have done successfully) is just plain stupid.
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!
Normally it can take a couple of quarters, but my impression is that SRPT has been putting all the necessary people and procedures in place to launch immediately, so I would guess no later than 3/31/16?
Read the Barron's article - they think BMRN will be able to squeeze royalties out of SRPT. I know the patent issues are not finalized either in Europe or US over exon 51, but I believe that SRPT has the ability to market Etep in the US without interference until the patent issue is final - from what I understand, that is not the case in Europe - BMRN can block Etep unless their patent is deemed invalid. Does anyone know for sure?
As AF points out, the vote is not even a traditional yes or no on efficacy and safety (two separate votes) - instead they are asking them to vote on whether the 3 separate trials either strengthen, weaken or have no effect on approval and then a separate vote on whether safety strengthens, weakens or has no effect on approval - this is a very unique format and completely dismisses the pooled analysis that BMRN portrayed in today's press release. Given the FDA's issues and conclusions on the separate trials and the even worse assessment of safety, it is hard to imagine many "strengthen" votes?
A poster yesterday proposed that it was manipulation by hedge funds that knew the briefing docs were bad and they were forcing the price down to take out retail investors with stop loss orders - I hate to believe that kind of manipulation takes place, but what other explanation is there?
After reading the results of the preclinical (i.e. animal studies) it is hard to believe the FDA ever gave RNA approval to test this drug on humans - the safety profile is horrendous. At this stage, there is no way Drisa is going to get full approval and without a confirmatory study ready to go, the prospects of a conditional approval are weak at best. I think BMRN tosses drisa in the trash can and tries to screw SRPT over patent issues at this stage.
Did you see the pictures of the injection site reactions - I thought it just caused swelling and redness - these kids are getting open sores/skin ulcers from this drug. On another note the FDA reviewer on safety proposed monthly monitoring of liver function (vs BMRN's proposed 6 months). The only good thing for BMRN is there is no REMS, primarily because they assume these kids will be seeing their docs weekly for the injections and any issues can be dealt with on their weekly visits.
The final conclusion on page 140 - "It is very disappointing that both the clinical and biomarker data for drisapersen are inconclusive at this time".