That is the theme of the data - consistent dystrophin production across all treated patients; consistent stabilization of 6MWT results for the ambulatory boys; and consistently pristine safety results. Anyone that is writing off these results as meaningless due to the small sample size just doesn't get it. When all the patients respond in a consistent manner, it doesn't matter whether the n is 12 or 120. AA is a slam dunk!
Don't people listen to these presentations - this idea that you are going to be able to put together a trial that generates 6MWT results in "direct proportion" to dystrophin measurements based on biopsies is just ludicrous. As CG has pointed out, the biopsy measurements are a sample that (1) has some measurement noise in it, regardless of where you take the sample and how many you take and (2) may not represent the dystrophin distribution throughout the body - i.e. just because the biopsy taken from their bicep says 50% doesn't mean the dystrophin in their leg muscles is exactly the same - there is no way of knowing. Beyond the dystrophin measurement issues, the 6MWT is riddled with potential measurement problems. First, there is absolutely know way of enrolling a patient population that is at exactly the same point in the disease process. While age is the most predictive factor (7 year olds will likely not show much decline over the course of a 12-18 month trial, while 11 year olds are likely to lose ambulation during the same time period). If you target patients that are 9.5 years old, does that mean they are at the exact same place in the disease - absolutely not. The company enrolled the current trial using a targeted range for baseline measurements, but that didn't prevent them from getting two boys that lost ambulation within 2 months of starting the trial. Bottom line - you could spend another decade and enroll 1,000 patients, take hundreds of biposies from each kid, trying to generate a tight correlation between dystrophin numbers and 6MWT results and it wouldn't work. The fact that certain analysts and a lot of MB posters have pushed this "correlation" issue shows how clearly they misunderstand the AA process - it doesn't require any proof of clinical benefit at all - it can be approved simply on the basis of the surrogate measurement, which only needs to be "likely" to generate a clinical benefit - not a tightly correlated result.
While Christine McSherry makes a poignant plea, what is more important is what Jenn McNary has told the FDA. As Dr Temple noted in his presentation a few weeks ago on how the FDA approaches AA decisions, he said that "patient reported outcomes" (i.e. how the drug has impacted the patients' day-to-day lives) is an important part of their decision making process when looking at rare diseases with small clinical trial populations. I hope there are a multitude of stories from all the parents talking about how their boys are getting stronger and being able to do things they previously couldn't.
Another moronic assessment - they will need to come up with a "matrix". You could study this drug in 500 boys and not come up with a reliable matrix - every boy is at a different stage of the disease, will metabolize the drug differently, have different phenotypes, etc., etc. The bottom line, which is well documented and well understood, is that DMD is defined as a lack of dystrophin production and so in accordance with the AA protocol, the production of dystrophin is "reasonably likely" to generate a clinical benefit. Will every boy "clinically respond" (as measured by the 6MWT) the same to the same levels of dystrophin production - no. But there is ample evidence that this has at a minimum slowed the progression of the disease, and if Max is any indication, if you get them early enough, perhaps stop it in its tracks (with respect to ambulation). If you are going to anchor the value of Eteplirsen on the 6MWT, how would you ever evalutate its value on a boy aged 6, let alone a boy aged 16. Again, you are looking at it with moron glasses on.
Where do you come up with these crazy thoughts? "Accelerated" means that it gets approved based on Phase II data and before the confirmatory Phase III trial is completed, which won't be until 2015. Accelerated does not mean that the FDA throws out all the normal review policies/procedures/timelines. The CEO has been clear about the timeline for the past year - get FDA guidance in Q2 (now may be Q3 due to their request for summary on dystrophin as a surrogate) and file in Q3/Q4, so approval would not come until Q1/Q2 of 2014. It amazes me how many morons can listen to him lay out this timeline over and over and then post messages on this board that AA will come by July or Oct or Dec - what is wrong with you people?
You are the one that is blind to the facts - Fact #1 - no DMD patient ever has or ever will begin sponaneously producing dystrophin, so the placebo aspect of dystrophin production measures is meaningless. Fact #2 - the lack of dystrophin is clinically accepted as the reason patients lose muscle strength, so dystrophin production as a surrogate endpoint is a lock. Fact#3 - any holes you want to shoot in the 6MWT results are meaningless, because they don't have to prove clinical effectiveness in order to get accelerated approval. All your ranting about controlled trials don't mean a thing in the rare disease space - the FDA has enormous flexibility in determining the evidence that can be considered in an accelerated approval filing. While you focus on two patients that deteriorated prior to their dystrophin levels being impacted, there are 10 others that are stabilizing on their 6MWT measures and as the FDA official noted in a recent presentation, "patient reported outcomes" (i.e. anecdotal evidence on how the drug has impacted the patients' lives) is a very important consideration in accelerated approval filings with limited patient populations. Combine that with a pristine safety profile and accelerated approval is a slam dunk. Time for you to move on.
That's just stupid - most countries will pay a fraction of inflated US cost of the drug, and an initial price of $350K in the US may be reasonable when there are 4,000 patients, but as exons are added and patients start living longer, the price will come down.
What a moron - The Street is a quantitative analysis rating that shouldn't even be used on biotechs - they haven't "reviewed" anything about the company, its pipeline or market potential. The fact that you would spout off about this downgrade proves you haven't either.
Thanks for the insight, and while it would be interesting to see the specific stats on the SD patients, ultimately the only stat that matters is whether OS is extended. Given that metastatic disease is what typically kills most cancer victims, you would hope that if Reo is delaying/stopping the progression of metastatic tumors, there should be a meaningful impact on OS. If that concept plays out in the H&N trial and these various Phase II trials show impressive PR/SD stats in late stage patients like this trial did, then we have a blockbuster.
dtic - I think you nailed it - even minimal responses in small number of refractory patients who have failed numerous prior therapies is probably not going to drive any spike in the share price, but it is the first step toward a path of getting TH-302 to be a front-line therapy in combination with a number of different agents and a number of different indications. Ultimately, these smaller trials (many not sponsored by the company or Merck) will lead to significant off-label use when TH-302 is ultimately approved in STS - unfortunately that won't be until 2015, but the storyline of the breadth of market potential of TH-302 will continue in the interim.
zwerp - what you said is perfectly reasonable, but what exactly do you think could be "latter contradicted by new evidence"? Even if in the long run there are some safety issues that crop up with Eteplirsen, do you think that would prevent most parents from wanting their children on the drug. When it comes to efficacy, you have 100% of patients generating meaningful dystrophin levels - the odds that the production of dystrophin will be contradicted going forward is negligible. The only efficacy issue is what are the limits of the drug to restore muscle capacity (the early evidence is that you need to get the dystrophin in before the muscle wastes away to incapacity) and what the impact will be on patients starting treatment at various ages. IOW, the risk/benefit profile here is pointing toward minimal risk and high potential benefit and I doubt the FDA's reputation would be tainted by granting an AA - that is what the confirmatory trial is for - to weed out any residual risk.
Where do you guys come up with this idea that the manufacturing is a major issue - they have already utilized CMO's to shift to "mid-scale" manufacturing in order to produce the supply necessary for the confirmatory trial and he has stated that once they get a nod from the FDA if AA is feasible, they are ready to shift that to "large scale". The market for this drug in the US is less than 5,000 patients, the CEO has stated on numerous occasions that the manufacturing process is straight-forward and scalable (which they have proven with their mid-scale shift), so other than your own paranoia, what is driving your conclusion that manufacturing capacity is the "best argument" against AA?
The naysayers will write off these moms meeting w the FDA as meaningless, but the recent FDA presentation on AA by Dr. Temple confirmed that "patient reported outcomes" (i.e. how the drug has impacted the daily lives of the patients) are becoming more and more important to them in assessing approvals in rare diseases, where the trials provide limited statistical support because of the small patient enrollments. These meetings are not about "anecdotal evidence" that will be tossed aside when it comes down to a decision - they are providing the FDA critical information that could sway the decision. IMO, the dystrophin production data combined with the pristine safety record are sufficient for an AA, so when you add the moms speaking about how their children are flourishing on this drug, it is a slam dunk.
The only thing that could prevent/delay an AA is a manufacturing issue, so unless the CEO has been minimizing the potential complications of getting up to "large-scale" production, AA should be a slam dunk.
zwerp - why do you get caught up into all this hand-wringing over whether the nod from the FDA on allowing an AA submission will happen in 1 month vs 3 months? If you really listened to the call, you would know that they have to have another meeting with the FDA after filing the additional information requested - his hope was that meeting could happen before the end of Q2, based on his perception that the FDA was being very flexible with their scheduling. Given that statement, why would you start speculating whether an AA "allowance" could happen "much sooner" - does a month or two difference in the timing really change your perception of the value of this company? Besides , it is not clear whether they will have a formal answer until after the CMC meeting, which won't happen until Q3.
It is as impressive as any of the clinical data. Brady is on the verge of turning 12, the time when he would normally be losing the ability to walk, and performing a test (getting to his feet from sitting on the floor) twice as quickly as he did when he was 6 years old. People getting caught up in the "n" or dose dependency or linear relationships between dystrophin and 6MWT just don't get it - the impact this drug has had on these boys is borderline miraculous, something that I'm sure is being impressed upon the FDA by the families and will carry as much weight as any of the clinical data.
simp - way to dissect the drop - it was precisely because of the delay in the pending meeting - NOT! For someone who seems to hang on every word/nuance coming out of the company, how can you say they never guided to a June meeting. CG has previously said on more than one occasion that they were hoping to have a meeting scheduled before the end of Q2 after submitting the responses to the first meeting in May.
There could be a placebo effect in the 6MWT for a month or two, but not for over a year.
Whether the increased dystrophin is functional or whether higher dosing will prove beneficial in a larger patient population are questions for the confirmatory trial. There is a reason they call it "conditional" approval - the nuances of how the drug works at different dose levels for different aged boys could take decades to understand, but denying patients the drug until those nuances are worked out would be unethical. There is ample evidence that this drug is meaningfully effective - is it a total cure that is going to bring boys out of wheelchairs, probably not. But the early signs are that preventing/delaying deterioration may be possible, which provides even a greater argument for accelerated approval, because the longer you wait, the more unrecoverable damage will be done to these boys.
One thing is clear - this company puts out horrible press releases, which leave more questions raised than answered. It seems reasonable to shift directions to combine Reo with "emerging" treatments and more focused/targeted patient groups - the planned 2nd stage of the trial assessing the impact of PFS and OS would probably take 2+ years to complete, so if you generate good results in combo with an outdated drug regiment, it would be a waste of time and money. This is especially true for a Phase II trial - with a Phase III trial, you can get an SPA that gives you the basis for approval, so if during the trial a new "standard of care" emerges, you can still get approval and do some combo testing with the new drug while the existing trial finishes up. This is what is going on with THLD - their drug is designed to complement conventional chemo agents and is in a Phase III trial with gemcitabine in pancreatic cancer - they have an SPA that sets the rules for approval, regardless of how the numbers may compare to other emerging treatments. Meanwhile it looks like Abraxane is going to be approved in combo with gem and may become the standard of care for pancreatic cancer by the time TH-302's trial is completed in 2015. In the mean time, the company (or independent investigators) will be able to do small trials to determine dosing regiments with TH-302 in combo with gem and Abraxane, so the pancreatic market opportunity will not be lost.
This discussion about a "delay" is all in your heads. CG said back in late Apr/early May that they "hoped" to have the follow-up meeting before the end of Q2. His "confusion" about when or what form the follow-up will be is because there is no formal roadmap here - he is guessing based on his experience and feedback to-date that the FDA will want to meet again to provide a formal answer and now he is hedging that maybe that meeting will not take place until early Q3. The difference between his hope back in early May and his current guess about the timing is less than a 30-day window - anyone who is characterizing this as a "delay" is because of your own speculative expectations about what the FDA would do and when - his "confusion" was simply trying to answer questions that were premised as if there was some formal timetable or protocol that had shifted - there wasn't.