ru anyone that suggests predicting clinical outcome based on a single variable suggests an unfamiliarity with scientific realism! Sorry about that!
It is like predicting it will snow tomorrow because it will be cold. Cold is not adequate to predict snow! You need to understand other variables such as moisture content available for creating precipitation.
Clinical outcome is a function of numerous factors! Some of those factors:
Performance before dystrophin reached the present level.
Muscle mass in muscles being tested in the Clinical outcome of interest.
In the case of 6MWT height & probably weight.
Percentage of useless hard, fibrous or rubbery scar tissue in muscle.
Increasing dystrophin is not adequate to change the clinical outcome on a boy who has decayed.
But almost certainly increasing dystrophin is going to maintain, improve, or at the least slow the decay of the clinical outcomes.
Furthermore it may be very reasonable to suspect to see a higher increase in dystrophin in boys who have a high percentage of fat, hard, fibrous, or scar tissues in other muscles. In an ideal world dosing would be based on the amount of muscle capable of having dystrophin built in, but basing it on overall weight is a necessary compromise. And there you have the reason for the falsehood you tried to portray, unless you really don't have a mind capable of understanding the issues.
Maximum baseline for Sarepta was 400 meters + 10%. One boy was admitted who on his highest of 2 6MWT was at 437 m. 2 other boys were admitted who on their highest of two tests were about 425 and 420 meters. Do not agree with your age statement on this particular trial.
Drisapersen DMD114673 trial started off with at least 5 very healthy boys. approx 6 MWT scores -- 650, 500, 430, 410, 380. And 2 healthy boys, who might have been candidates to lose mobility in a year or so with 350 m 6MWT scores. All those boys are doing well, but there is some tapering of their 6MWT scores after the regimen was switched to intermittent. One boy started at 6MWT of 290 and is also tapering off. 2 boys started at about 250 and 260 meters. They stopped ambulating at 60 weeks.
a) The answer may be start with healthy enough boys and the drug will appear to work. b) With healthy enough boys the drug will work.
My suspicion is that there is a subset of boys where the drug will work. If there is a safe alternative is it worth the risk. I suspect GSK is concerned about the liability, especially in the US.
Bionerd and I have discussed this, he makes a very good argument the drug doesn't work.
Time will tell when the analysis are completed on the studies.
If one understands six sigma thinking, it is very clear Drisapersen will cause severe harm and kill some boys. But, I suspect most boys and parents would be willing to take the risk, if there is not a safer alternative, because it is certain duchenne will kill all the boys without a treatment that hasn't been approved. But maybe not as fast.
What do you say on the witness stand when the attorney asks you, do you really consider a drug safe when the first human trial found proteinuria in 12 of 12 boys? What do you say on the witness stand when the attorney asks you, do you really consider a drug safe when Thrombocytopenia is found on several boys in long term studies? What does the jury say when they are asked how big a check GSK should write?
In the case of Eteplirsen it is very convincing the placebo boys were in decline and the drug interdicted their decline. With the amount of time since then, it appears this is not a placebo effect.
and 21 patients in UK trial, though lower doses.
get a clue regulatoryclueless! Calling yourself regulatory expert is a hilarious halloween costume!
I am not sure Eteplirsen and Sarepta have to be on the first page of PPMD fro Pat F and the team there being valuable to the boys and the companies and drugs that may cure the boys.
Read Pat Furlong's May 20th blog: "Continuing the Quest for Accelerated Approval"
The we have the Decode duchenne project10/23
The FDA meetings.
I think she may have a more important roll than jumping up and down like a mindless bot shouting eteplirsen!
I suggest you all give her a bunch more rope and be cautious agitating what may be a quiet, but very important advocate for eteplirsen's approval!
CSR would be nice if EU and ROW (non FDA) was just a cash stream where Sarepta didn't have to expend resources and had cash coming in. lots more exons and lots of other things to be done. Lots of cash tied up in manufacturing. Streamline, become profitable, and then find other arenas to become profitable in.
The beauty of ISIS is Crooke has found other companies to pay for his explorations. The ISIS shareholders may never see the payoff of the home run ball Sarepta may have, but they have not been subject to much of the dilution, going out of business concerns, sub dollar share pricing of Sarepta's predeccesor.
"AVI-7100 administered intraperitoneally at 10 mg/kg resulted in statistically significant reductions in the combined daily average viral titer through peak viral load (days 1-3) versus saline control (p=0.0012) and Tamiflu control (p=0.0103) by up to 3.9 log."
"Maximum reductions in the cumulative average viral titer of 5.1 log versus saline control and 4.52 log versus Tamiflu control were observed through day 5, but statistical analysis at this time point was not possible due to limited animal numbers. "
"Seven days after infection, microscopic examinations of the ferrets' lungs were done to assess the extent of regional tissue damage.
Pathology scores in both studies revealed only mild damage in the AVI-7100 treated ferrets, while damage was severe in both Tamiflu and saline controls."
24 Aug 2010
CDC estimates that from the 1976-1977 season to the 2006-2007 flu season, flu-associated deaths ranged from a low of about 3,000 to a high of about 49,000 people.
5 to 20% of the US population get the flu every year.
***** Unreal amount of product required!
***** But if 3,000 to 49,000 die from flu related illness every year, how many are in expensive hospitalizations per year. How many people have long term and costly recovery?
***** When will manufacturing be ready? What would be the cost of scale-up? Doesn't this really need a deep deep pockets partnership
***** Unlike the West Nile Virus, finding sick patients to treat is not an issue!
***** Treating .1% of US population might yield gross revenue of $2 billion dollars, estimating drug sales at $8,000 per dose! Some of the other work on infectious diseases suggests that after a treatment there might be an immunity, will it happen with influenza? How long will it last if it does.
*****more than 200,000 people in the United States are hospitalized each year for respiratory and heart conditions illnesses associated with seasonal influenza virus infections.
**** How soon will infectious potential terminate?
What this news told us is, there were certainly no outliers! Many of us were fairly certain from the p values, but some of us also new some smart statisticians and felt much better seeing where the minimums and maximums were. Anyone who thought they saw this data since week 24 data is wrong or they had access to non public information.
There is still lots of data that Sarepta can share when they want - pulmonary, and all kinds of strength tests. I suspect some of it they are holding close to the vest for future scientific papers and conferences.
The clinical trial group can probably transfer 108 week 6 MWT data to Sarepta anytime they ask for it. What may be amazing about that data is it very well show continued recovery of the boy with the broken ankle.
The beauty of Marburg and other government programs is they pay part of the tab on the basic science such as PMO +. They also help to cover the overhead. Influenza causes between 3,000 and 49,000 deaths per year in the US. If it wasn't for the Ebola and Marburg work there probably wouldn't be an influenza drug in safety trials.
My Libertarian leanings are uncomfortable with this, but if it is going to happen better it happen with a competent company I own stock in.
the patent situation must still be resolved, but worst case is that is probably a licensing issue. If Drisapersen has truly failed, then it raises the question if the University of Leiden patents truly enable.
So far they haven't indicated they have manufactured the lots they need for stability testing. I would be pleased, but surprised if they completed an NDA filing in 2013. But, if they announced a rolling NDA and submission of some parts in 2013 it would not be surprising.
They could give a signal as to what happened at the next data collection. Data was probably collected mid September for 108 weeks. Don't have to give details. A signal continued stability, further recovery of boy with broken ankle, continued safety. My expectation is they won't do any of these. All are probably within Mendell's knowledge base. As someone else said pulmonary data. Lots of possibilities.
No, I have no RNA stock, but have a tiny position in their calls. just a gamble.
I really don't change my view on a company based on whether I won stock or options or not.
I leave the pumping and dumping to those who want to play that game. I have often said negative things about AVII while being long the stock.
Balance is what we need in this world.
I am guessing Drisapersen will work in some patients without damage, but right now there is no way to know which boys it will work in at the 6mg/kg level and who will not be damaged by it
Recall in the UK study of Eteplirsen there were dramatic differences in individual patients in cohorts 4,5, and 6 in respect to dystrophin increase.
The data GSK has released on dystrophin, where it is clear a significant number of boys showed no dystrophin increase suggests there is something besides the drug in the equation of how much dystrophin will be made. If Prosensa and GSK can figure that out, then maybe there will be a relatively safely treatable population.
There will always be a signficant risk though.
I suspect GSK has recognized it may be a nightmare drug in the US's litigious society. Maybe in some countries the risk is more acceptable today. US may be where the big profits are likely to be made.
@ianestepan "At the DIA conference $GSK said that the risk benefit of drisapersen does not justify patients being dosed currently"
There was a Drisaperesen Trial Participant Open Facebook group. There were a number of messages that sounded like parents were convinced the drug was working. That group is now closed and the messages are no longer visible. It also appears to me the membership was shrunk dramatically.
Some parents made it sound like they were unable to comment before because of their agreements with GSK, but that when GSK stopped dosing they felt like they could comment.
The most probable reason RNA's exon skipping drug appears to be failing is they are unable to dose above 6mg/kg and even that is iffy due to the toxic effects of the backbone they chose. Sarepta is dosing at 30 and 50 mg/kg with no side effects.
12 of 12 patients in Sarepta trial show significant dystrophin. In the GSK/Prosensa trial Phase 2 only 59 % of the patients showed increased dystrophin by the lowest possible measure, a measure so low that 1 of the placebo patients showed increased dystrophin.
From prospectus "We conducted a subsequent Phase I/II dose-ranging safety study in which drisapersen was administered to 12 patients subcutaneously, once weekly for 5 weeks. The study, initiated in March 2008 and conducted at two European clinical centers, demonstrated that drisapersen was well-tolerated in all patients and novel dystrophin expression was detected in each treated patient." There is a document on web that suggest one of these boys had a damaged biopsy and therefore the statement in prospectus may not be true.
What they didn't state was dystrophin levels and possibly hid the fact that the levels were inadequate to expect improvement.
In the phase II data GSK released, they used the lowest possible standard and showed only 59% of the boys with increased dystrophin.
The class action lawyers will probably be circling Prosensa.