The issue with your faulty thinking (?) is that you assume dystrophin level alone would be adequate alone to predict performance and performance measurement.
I suspect you realize it is not dystrophin level alone, but also muscle mass. Percentage of muscle versus fiber. and a host of other variables. I suspect the FDA understands this also. But you live in this world where you take pleasure in trying to mislead others.
One theory is this outbreak is in an area where ebola outbreaks are not so normal. It is possible the areas where outbreaks are more common, that the population has built up a certain amount of antibodies. Possibly this is from eating improperly prepared bush meat or mild cases passed around.
Viral transmission is a role of the dice.
Ebola can be present in sperm up to 60 days after a male has been "cured"!
One question that I have not heard the answer to is are there carriers who are not symptomatic?
If a couple of people escape from Africa and contaminate a couple of jumbo jets full of people, this could turn in to a worldwide nightmare.
Just imagine even 50 contaminated people arriving in London. How many will be on flights to the US, Hong Kong, Tokyo, Western Europe before it is recognized they have the disease.
Look at the spread of HIV and imagine, if this gets loose in a promiscuous group.
Twitter is not ablaze with this. One MD who was previously bullish is now spouting this, without giving any reason. A DMD trial update is promised next week. I suspect we will hear good things about the confimratory trial start. Maybe not great things though.
Most likely scenario is approval in 2015.
quite possibly the real emergency in the world is people like you, who are really unable to think in a rational manner. And as for ebola, bringing victims to the US should terrify you! The people responsible didn't no they had vails of the smallpox virus they failed to destroy for years. And you expect us to trust their experts?
makes sense, but one thing if I recall correctly is the primate testing used very large amount(?) of ebola to infect the primate. Therefore, I would think if they identified people by blood testing for ebola rather than waiting for symptoms, they might have reasonable candidates for proving the drug works.
The incubation period, that is, the time interval from infection with the virus to onset of symptoms, is 2 to 21 days.
And this POTUS has proceeded to do all kinds of things he couldn't do. And many of his predecessors did also.
If it's to happen, it will be because the government wants it done and the goverment will pick up the expense.
Again you remind me of a guy I fired years ago, because he couldn't find his way around obstacles.
I sure am not betting on ebola helping Sarepta, but it would be smart, if the goverment used this as a chance to prove whether their investment made sense and if this does turn into an intercontinental issue....
mauouo, if you look at the half life or Eteplirsen, it is obvious that anything resulting in Eteplirsen being in the blood stream for a higher percentage of time is likely to improve the time to increase dystrophin. It follows this would improve the 6 MWT. This might be a pump or a dosing frequency greater than once a week. Now once a bouy has increased dystrophin at some level, this probably doesn't make sense. But for that period between 12 and 24 or maybe greater weeks, the higher percentage of time the dells are exposed to the morpholino, probably the greater increase in dystrophin. And yes this will translate most likely into improved 6MWT results.
There is certainly exciting stuff going on behind the scenes. Just search the patent applications. Now if they only get DMD across hte finish line!
RP tossed mud left and right. If you read my replies to him, you will find I caught him in a number of lies.
He makes the assumption a truncated gene will not work because of some BS he spouts about evolutionary biology. We know for a fact the dystrophin gene in boys with Becker's works and that it is truncated from the normal dystrophin gene. We know that the exon skipping works in the mouse model, works in the dog model, and there are strong indications it works in human model based on the 6 MWT results.
It is hard to beleive Mendell, Muntoni, and others would be willing to risk their reputation by mistating information about dystrophin, both have had this information published in peer reviewed articles.
The Claims area of the patent to a large extent are all all that matter. The part that matters about the rest of it is 1) convincing that the invention is not prior art. 2) Enabling the invention. The mention of Sarepta's drugs were in these latter sections rather than the claims, so I give them little credence. This isn't the first device oriented patent where Cook has mentioned these. Some of these things are largely copied from patent to patent. No reason to reinvent the world in this area of the patent.
Unless Cook comes back to Sarepta for an antisense compound, I see no impact. The claims of the patent are all directed to the mechanical construction of the catheter. Besides Resten-NG and Resten-MP there are a number of compunds which there may be reason to have local delivery with such a device including FDA approved drugs: rapamycin, paclitaxel.
Possibly a more interesting patent 8,785,410 Iversen , et al. July 22, 2014 Antisense composition and method for treating muscle atrophy
makes a lot of sense. reimbursement and a possible drisapersen approval or the twon unnowns once Eteplirsen approved. Insurance may push cheapest drug
Winterlion had made some estimates of population and adoption rates. He stated he didn't have a source for his 1500 population.
Exon 51 skippable population US and adoption rate
Exon 51 skippable population US and adaption rate
Dawson James (Nov 2012) estimated US 2015 population as 1904. growing to 1952 in 2020.
Brad Loncar estimated population as 2000 in his blog.
Sarepta used an estimate of 1950 patients opportunity in the US in their 2013 JMP presntation.
WinterLion had made an independent estimate of 1500 without explaining his method.
A few years ago I created a model and estimated the population as 2090 with 93 births per year based on 2.173 Million male births per year in US.
Updating based on 2012 live male births of 1.976 Million male births per year in US, my population estimtate drops to 1,901 in US. with 84 births per year. Furthemore I think 2113 is a more liely 2020 estimate than the 2,500 I previously expected.
DawsonJames estimated the following US adoption rates: 2015 - 0%, 2016 -40 %, 2017 - 65%, 2018 - 90%, 2019 - 93%, 2020 - 96% Assuming Drispaersen is not approved in the US, these are probably reasonable adoption rates.
In rare diseases, there is typically a high rate of adoption. Of course this depends on reimbursement, which will be dictated by various insurance models.
Winterlion had made an adoption estimate of 50%, but did not make clear his timing, but thought that was remarkable. I disagree.
I posted some info on IV. post 10161. The ATS which is referenced in one of the Natural History study recommends a 30 M course with cones at each end in a 100 foot hard surfaced hallway. They also report some data on a continuous course and on a treadmill and do not recommend either.
rarediseases dot org - if you were to look at the various associates of this group who puplished "Quantum of Effectiveness" You would find this isn't the single carnk, which you are, babbling your highly biased agenda. i would suggest you forget about Eteplirsen, forget about duchenne and get on with your life.instead of putting forth your spewing of #$%$. You really need to be critical of your own bias.
If you really beleived what you have stated, you would take each example in "Quantum of Effectiveness" and see, if you can find inconsistencies.
What the paper I referenced demonstrates is the FDA has a wide range of flexibility to do the right thing. Sometimes based on scientific judgement (something which you demonstrate massive ignorance or) and administrative and or case by case flexibility. I pointed out a few examples at your urging walking in to your trap of trying to put a few facts on the table (so you can do your usual trick of trying to deny facts, which is another area you demonstrate massive ignorance of.) I am trying to understand why I don't have you and your aliases on ignore.
I have cited many things previously on IV. But a few more:
Albendazole - Albenza - - "due to the very limited data avialable ... the statistical conclusion toward the efficacy .. of [Albendazole} can not be reached" Approved 1996
Alglucerase - Ceredase -“no well-controlled studies were conducted” ...."This approval illustrated FDA'a ability to exercise scientific judgement as well as to extend itself in aiding a sponsor with compiling the NDA...“
Alpha1 – Proteinase Inhibitor (Human) - Prolastin - "approved labeling cites one uncontrolled study
of 19 subjects, all with the same phenotypic variant of this deficiency, the most severally affected variant of which there are many variants" ...demonstrates "case by case flexibility" or "administrative flexibility"
Artemether/Lumefantrine - Coartem April 2009 FDA noted only two trials conducted at single center in China with single racial group. One study p=.49. Capsule arm p=.675. Tablet arm p =.16 However, there were other non-primary endpoints that showed the value of the combination over both monotherapy components. Therefore, this approval required an exercise of scientific judgment.
Ganciclovir Sodium - Cytovene - Ganciclovir Sodium - FDA urged and sponsor had agreed to conduct a prospective, randomized, no-treatment controlled study; however, the NDA ended up being approved on a post hoc, retrospective review of a case series of subjects treated by one physician.
Laronidase - Aldurazyme April 2003 single randomized placebo controlled trial of 45 patients. 2 primary endpoints - forced vital capacity was statistically signficant. 6 MWT was not statistically signficant p=.07. Only one of four secondary endpoints was statistically signficant.
Mecasermin Recombinant - Increlex- August 2005 FDA permitted sponsor to pool post-hoc five small clinical trials.
There are many examples of the FDA doing the right thing, even if involved studies that were not well controlled and post-hoc analysis.
My calculations show 93 boys in US born amenable to skipping exon 51, with a current population. Once treatment starts on a large scale, the exon 51 amenable population will probably grow to 2500 boys in 5 years. The early pulmonary results suggest the assumption when I made these calculation a couple years ago is correct, Assumption: The drug will extend lives.
On the other hand I expect some will not be treated for a variiety of reasons.
I suspect 70 boys born in US amenable to exon 51 skipping is on low side.
And I think Jim has as much right as anyone to make their views clear. There is freedom of speech. People can choose to use the ignore function, for individuals and there are a number of people I often put on ignore.
Based on the FDASIA law and the historical precedent described in "Quantum of Effectiveness" I think the FDA went off the reservation in 3Q2013 and is directly responsible for a number of lives lost. If they had stated earlier what they finally determined late in 1Q2014, then the push to start other trials would have been felt earlier and might of happened.
By the same token Sarepta should have been more proactive in expanding the testing in some fashion as soon as there was clear demonstration of efficacy.
The difference is the FDA should work for the people of the US. Sarepta is a public company owned by the stockholders and has no primary responsibility to anyone other than the stockholders until such time as they are able to sell a product.
I suspect the other stockholders would agree with me, Sarepta should move forward and gain approval of a drug and put in place plans to produce it and distribute it with resonable haste.
Understand, the 144 week data is really much much better than the market evaluated it. Sarepta screwed up the communication! The 144 week data possibly points to a change is slope, but right now is on the same slow decline as the boys had before. The boys in the placebo crossover went on the drug in week 25. The earliest any effect could be expected from the drug is weeks 36. And we know the boys would have a substantial increase in dystrophin after week 36. The placebo delayed boys on average only lost 45 meters to the present. So over this 108 week period the boys lost 45 meters on average, less than .5 meters per week. Yes, they may have a drastic slope change at some point, but until there is confirmation it happened, it didn't happen. And understand the drug and also the Prosensa drug were never inteded to be cures, but just to slow the progression. Natural History data proves that has been accomplished!
And it the 132 weeks since the 30/50 mg/kg MITT group has started tp have an effective amout of drug in their system, they have only lost 27.5 meters! A loss of .25 meters per week.
Natural History for boys on steroids over age 7 suggests the boy will on average lose between 1 and 2 meters per week.
Yes, approval is likely on the present data set. Even, if the next point does turn South a year or 2 longer ambulation from a drug with a spectacular safety profile is enough to justify approval.
NDA filed 2014. Adcom late Q1 2015 to mid Q2 2015. Approval ( Accelerated or Full) Q3 2015. Only confirmatory trial required and FDA is insisting it be started before approval. Ignoring precedent in rare diseases and the FDASIA law.
Most likely there will be commercial sales in 2015, 2016 latest unless there is a stumbling block. FDA knows they screwed up in 3Q2013 and are unlikely to repeat it.
Those who don't beleive this should search for "Quantum of Effectiveness" Google should bring it up. Read about the examples of other drugs approved for rare diseases,
The reason Eteplirsen doesn't have AA already is Sarepta hasn't submitted an NDA. The FDA can't do much other than give guidance until the NDA is submitted. And the FDA guidance is start some other trials, either confirmatory and/or other exons. Hopefully Sarepta keeps their nose to the grind stone and starts both in 2H2014. Those don't have to be completed for approval They may not have to provide any data other than the drug is safe at that point in time.
If the FDA review of the dystrophin measurment process goes well, there is a possibility it could be accepted as a surrogate biomarker. PPMD has recommended such. At that point the 6 MWT and the lung function become confirming and there is a possibilty the FDA could reach the correct decision, which is full approval.
When you read Quantum of Effectiveness, you will find the FDA has the power and has shown the willingness in historical precedent to ignore all the #$%$ RU and Pasteur and a few others spout about.