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.
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 am not sure what your point is. One issue with Drisapersen is the safety profile. The reason DMD114673 shifted to intermitent dosing is the safety profile. The beginning ages for that study were 10.2 10.8 7.9 9.1 7.4 5.8 9.8 11.9 9.5 11.3 One interesting question is why did GSK drop Drisapersen?
Looking at the treated boys other than the twins who became non ambulatory before week 24, while the dystrophin was still building, the curves for both the MITT cohort and the placebo crossover cohort are very flat.
In the Cowen presntation one slide showed this through 120 weeks. For the placebo crossover there is either only a 30 or 45 meter drop for the 108 weeks after the drug had been used on the boys for 12 weeks.. This is the 144 week data point. This is a bit astouding, because we know two or three of these boys were close to 300 meters befor the crossover occured.
For the 6 MITT boys, the drop is 27.5M at 132 weeks after the boys had been on Eteplirsen for 12 weeks.
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.
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.
The stock has been acting like the data has been leaked for quite awhile. Really the SEC needs to be investigating it, including some Yahoo posters making claims about the stock the past few weeks. It wouldn't be surprising, if some crook didn't bribe a low level person in Columbus to get the data ahead of time. With only one trial site, a janitor, secretary, maintenace person, or lots of other categories might be able to access the data and for a little moola. Shorts have been way to confident, and then helped by the WSJ printing false info.
The data while not spectacular, does not appear to be bad. There was never an initial assumption it would make the boys better, just slow the course of the disease. And it appears to be doing that.
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.
We should not be disappointed, if we don't get top line data associated with the Nice conference.
IMO the results so far are astounding! Long ago we speculated the expectation would be for a slowing of DMD. What we are seeing is a stabilization and it appears in some cases an improvement. The big question is for how long.
My guess is that Sarepta determined it was better to make internal investment in scaling to large scale. I suspect contract manufacturing may not be the dream suspected based on my experiences in other industries. If it takes customized equipment to go to large scale the contract manufacturer is going to either want you to pay for equipment up front or forever. And if the equipment won't be used at capacity for awhile they may kill you on time value of money.
Actuallly we know it takes more than 12 weeks for consistent dystrophin increase and it most likely increases through 48 weeks. We also know there is signficant dystrophin indrease at 24 weeks. If you look at the curve of the placebo cross over boys on the 6 MWT is is suggetive the were seeing some meaningful increase of dystrophin at 12 weeks on drug, which there was some but inconsistent seen in the UK testing at 12 weeks.
If you wanted to speed up the rate of dystrophin increase , higher doses may not be the answer. More frequent doses or even a pump system such as is used for insulin might make more sense. The Plasma half life according to Saoud, Mendell, Kaye, etal is about 3 hours. This means at 21 hours probably less than 1% of the drug is left in the plasma. About a third of the drug escapes through the kidneys.
It may even be that a lower dose more often would be more productive. Possibly the high concentrations increase the waste through the kidney
Of course, if you start at an early age before effects, then how quickly you build dystrophin is rather irrelevant. But starting with older boys the 24 week area is really to long.
One of Sarepta's real issues is to keep the scientists focused on the task at hand, and not going off on wild goose chases trying to optimize the pharmokinetics of a drug. These can all be explored and improved on post approval.
Please understand I know very little about what I am talking about on this topic and accept my mistakes.
I am certain the only safety measures looked at, in the Eteplirsen trial was if the boys were still alive.
Of course I jest!!!
You don't have to do all the exact same tests. You really think the folks at Children's in Columbus didn't do what was necessary to assure there weren't serious adverse effects?
If you haven't noticed Prosensa has been very slow to release any information on any increases in dystrophin. Some suspect this is because Drisapersen may not be increasing dystrophin adequately. And if an exon skipping drug doesn't increase dystrophin, then all the 6 MWT and other stuff is just BS.
Talking about safety it was interesting the Prosensa's Hans S. cherry picked trials so he could hide thrombosis in multiple presentations.
If you want to understand Prosensa, you need to understand why GSK pulled out.
No one is asking you to turn a blind eye to the fact that a second boy is now unable to perform the Gower's manuveur and stand up via that mechanism. Or the comments about the North Star Assesment.
If you don't understand, the point of exon skipping drugs be it Eteplirsen or Drisapersen is to slow the progression of the disease by increasing dystrophin. It is not to cure the disease. It is to change it into a progression more similiar to Becker's MD.
It is very clear this is happening in the Eteplirsen case. There is mixed evidence as to whether it is happening in the Drisapersen case. The 177 week data looked promising, but many of the boys had a much higher baseline than in Eteplirsen's 12 person trial. In the Drisapersen phase III, the conclusion was that it wasn't effective. And after much playing they concluded, if they treat boys early it is effective. Of course this is the most difficult case to prove, because in the younger boys their 6 MWT scores and other measures are increasing until around 7 years.
Jerry Mendell the lead investigator on the Sarepta trial has suggested the Drsiapersen phas III may have failed due to inexpe
"MULTIFUNCTIONAL" - What does it mean? Manufacturing and warehouse? Multiple steps of manufacturing? Manufacturing, laboratory, office, and warehouse?
How much mfg space Corvallis? 1,000 sq ft? But it is small scale. How many times the capacity? What is Corvallis capacity? 30 boys 30mg/kg dose? Reason I guess this high is they have been supporting development other exons and some DOD, but we know some DOD PMO--X was outsourced.
If I recall right mid scale was 3-5 times small scale and large scale was 3-5 times mid scale, so roughly 16 times. I suspect large scale doesn't take 16 times the space.
Just playing with thoughts to guess how much of US eteplirsen capacity or how much more is accounted for in this space.
"$25 million in acquisition costs and planned enhancements" PLANNED ENHANCEMENTS!
Recall CG said at one time process was similar to mfg peptides.
I suspect the only secrets will be possibly trade secrets in how to manufacture at large scale or higher. The sequences will be patent protected and therefore not secret. The targeted exons will be disclosed most likely as clinical trials or amended with clinical trials dot gov.
The bad news is this is a phase 1 safety trial. If someone decided they wanted drug under 2 animal rule for stockpiling, it would be good news. Most likely unless we see a worse flu than in past few years, this will go no where unless someone decides to do a test in infected adults. Since the government chose to do a phase 1, maybe they will do a phase 2 or 3 in sick adults. Recall this drug works on conserved region and is probably effacious against most flu strains. If they chose to do a trial against various flu strains, they could recruit quickly and have a guick answer.
All that said, I doubt it goes anywhere quickly.
On the other hand Sarepta is probably funded to where they could do a phase 2, if they decided to make it a priority.
What would it take to attract a partner for this?
The 2 approved drugs for influenza take about a day off the course of the flu! But took massive testing to accomplish this.
The real cost of influenza is the cases where it turns into pnuemonia.
I still have to think of this as unlikely scenario.
But human proof of the antiviral capability of the PMO-X and the manufacturing capability might open an entire new world for this technology and Sarepta.
1) Agree w. jrrt comments.
2) CG knows if Sarepta does all the correct work going forward in filing the NDA approval is almost certain. In many regards, the 144 and 168 week data are irrelevant to the case. Unfortunately, it is relevant to the investor community. And it may be relevant to whether approval is granted on the present data sets. And even much more importantly the continued ambulation of the boys is to themselves, their parents, and the world as a whole.
3) There well may have been learnings in the scaling from the present small scale that can support little more than a dozen boys to the mid scale that made the move to large scale a better fit to internal manufacturing. Or possibly an opportunity to good to pass up. Or likely a bit of both. I think144 week data irrelevant to the decision.
ROFLMAO! The fact this isn't incorporated is not a demonstration of incompetence. More likely it is a demonstration of competence! To have incorporated another theraphy at the same time would have delayed the trial by a year or more.
Should there be a trial with this combined with Eteplirsen or Drisapersen? Possibly. Do you really thing CG designed the trial by himself?
A half assed trial change was put together by Avi and Cook a few years ago where they made a change to the PPMO from the PMO on a drug eluting stent and possibly caused the trial's failure.
The 120 wk data shows the miracles available through modern science and the work of dedicated pioneers. Summerton, Weller, Iverson, Kole, and Wilton to name a few in the development of the Morpholino antisense, and its application to exon skipping for DMD. There are many other names that should be there to do this tribute justice. It used to speculated about the DMD application, the disease would be slowed. Stabilization and improvement weren't in the cards. Some of this is quite likely to the parents and the doctors that provide the support team for these boys. I hope and pray for each of these boys continued stabilization and improvement.
The 120 wk data SUGGEST on a macro level STABILIZATION. It leaves open to speculaiton as to whether the dieasese is truly stabilized or just slowed. Even though Sarepta and the folks at Children's chose the best possibly circumstances to monitor 6MWT, it is still a test that has noise. And as has been noted, the boys gain weight, grow taller, subject to their swings, subject to travel, etc.
It is fairly clear some of the boys, particularly in the placebo delay group appeared to fall
in to an area on their walk distances before the application of Eteplirsen and about 12 weeks after where it would not have been surprising to see them lose ambulation in 6 months to a year based on some data from other 6MWT groups. The more we understand about some of these other data points from other groups, the less comfortable it is to compare these boys to them. My unscientific understanding is these boys are approaching an age where their height increase my appear almost explosive. Some of this and the potentially longer stride may be why some of these boys show improvement. This may be balanced by weight gain, some caused by the steroid treatments. It is interesting to note on a few potentially comparable cases in other data sets there have been stabilization far below the 300 meter area.
Very interesting patent. US 8,779,128 Clearly an extension to the morpholino chemistry havin embodiments with and without peptides, Targets antiviral, antibacterial, and exon skipping applications. Very detailed in the enablement of the chemistry.
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.
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.