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Vertex Pharmaceuticals Incorporated Message Board

themicrokid 59 posts  |  Last Activity: Sep 15, 2014 12:54 PM Member since: Jul 10, 2001
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  • Reply to

    speculation

    by thigrlsrk Jun 17, 2014 9:35 AM
    themicrokid themicrokid Jun 17, 2014 10:30 AM Flag

    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.

    Sentiment: Buy

  • Reply to

    Will there be an Isis - Sarepta SMA battle?

    by copphiggins Jun 17, 2014 10:18 AM
    themicrokid themicrokid Jun 17, 2014 11:12 AM Flag

    ISIS with their partnering everything strategy can be in an endless number of battles!

    When Eteplirsen crosses the finish line, there will probably be a place for Sarepta on many battlegrounds.

    Sentiment: Buy

  • themicrokid themicrokid Jun 20, 2014 3:04 PM Flag

    I think these are both strictly applications at this point. To suggest one is clean is ......... I will agree, there is likely some toxicity associated with the ISIS treatment.

    Sentiment: Buy

  • This board makes a lot more sense with _____ named people on ignore!

    I am glad to read that one of those contributed to the Jett Foundation, but I can't cope with reading the endless whining.

    Sentiment: Buy

  • themicrokid themicrokid Jun 21, 2014 9:11 AM Flag

    Look what partnering got Prosensa, a bunch of money, but IF their drug works, they no have a boat anchor data set aroung their neck. Mendell speculated the trial may have failed, not because of the drug, but because of the selection of inexperienced trail sites.

    I would like to see this go faster, but can't be certain a partner would neccesairly speed it up.

    I see no reason Sarepta and the FDA shouldn't both be pressured. The FDA has thrown unessecary monkey wrenches in the works. But it also feels like Sarepta could and should have expanded the trial and manufacturing earlier.

    And it appears some of Muscular Dystrophy groups could be pushing harder to push Eteplirsen across the finish line.

    If there was a certain demand in x months, it justifies a lot higher risk in scaling up the manufacturing process. It's difficult to justify scaleup when you are commiting expensive space, equipment, and inventory that will set idle for an unknown amount of time.

    Sentiment: Buy

  • Reply to

    Think Srpt has a copy of the dna from the

    by thigrlsrk Jun 21, 2014 12:48 AM
    themicrokid themicrokid Jun 23, 2014 10:55 AM Flag

    The 2 approved flu antivirals, shorten the course of the disease by about a day on average. To prove this took a mega amount of testing and statistics to prove out. If something really shorten the course of the disease, proving it out may be simpler.

    Sentiment: Buy

  • Reply to

    Facts the FDA needs to understand

    by usagary1 Jun 23, 2014 10:23 AM
    themicrokid themicrokid Jun 23, 2014 11:09 AM Flag

    I suspect there is not such a tight age bracket as you define. There are really almost major and minor stair steps to the progression. Loss of ambulation is clearly one of those steps. Inability to form Gower's manuveur. There are a bunch probably to do with upper limb activities. Unassisted breathing. Probably if dystrophin is restored well before reaching one of these steps, the step may not be reached or more likely the time to reach the step may be greatly extended.

    Of course this raises the next big question, is there a way to restore muscle in these boys?

    Sentiment: Buy

  • Reply to

    Garabedian's incompetence

    by pasteur420 Jun 23, 2014 5:59 PM
    themicrokid themicrokid Jun 23, 2014 6:08 PM Flag

    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.

    Sentiment: Buy

  • Reply to

    Timing

    by bbqmaster87 Jun 23, 2014 7:36 PM
    themicrokid themicrokid Jun 24, 2014 3:40 AM Flag

    This is their first GMP that will be able to function at mid or large scale. The present Corvallis GMP plant ,ight be able to provide weekly doses for maybe 20 to 30 boys at 30 mg/kg. When I saw it a decade or so ago, it was rather squeezed in.

    Sentiment: Buy

  • Reply to

    Timing

    by bbqmaster87 Jun 23, 2014 7:36 PM
    themicrokid themicrokid Jun 24, 2014 5:54 AM Flag

    They didn't need the last secondary to do the factory deal, but having it gave them more runway. It wouldn't surprise me, if contract manufacturers didn't want money for equipment to go to the large scale manufacturing. I have worked with contract manufacturers in other industries and it is often not the dream you are sold, but closer to a nightmare. Furthermore the basic PMO patents are all expired, what is left is application patents and extensions such as PPMO and PMO-X. It could well be that there could be some trade secrets that may arise in scaling to large scale manufacturing. Easier to protect them, if they are under your roof. And let's not forget the fact there are 26 issued patents assigned to ISIS with "morpholino" in the claims. It seems fairly obvious Eteplirsen will be approved eventually, hopefully mid next year. And there is always some potential for some government stockpiling. Don't count on it, but the lack of any substanital manufacturing capapcity may have held Sarepta back. If you recall there was an issue with the contract manufacturing on one of the government programs a year or so ago. And it to some degree may have been opportunity knocking at the right price. This facility was only closed in late 2013.

    Sentiment: Buy

  • Reply to

    Timing

    by bbqmaster87 Jun 23, 2014 7:36 PM
    themicrokid themicrokid Jun 24, 2014 10:12 AM Flag

    We should toss you in time machine without return instructions.

    Just because the restenosis effort failed, does not suggest anything about exon skipping, We are really talking a different mechanism. We are also talking massively higher doses per patient year.

    The entire management team is different. There is fairly solid data supporting that exon skipping is working.

    And if you recall the DES effort, they made this jump from the PMO with a small successful to the PPMO between trials based on much less evidence.

    Then when that failed they tried dipping arterys for bypassing in solution on almost no proof of concept in another Eastern Europe trial.

    Did you see the tweet: "The amount of energy to refute BS is an order of magnitude greater than to create it"?

    You generate enough of it!

    Sentiment: Buy

  • Link on IV partial schedule

    Think following is Cnetral/Chicago TIme rathere than NY eastern
    selected topic
    6/26
    12:30 Welcome - making sense Pat F
    1:00 Understanding nuances: mutations, modifiers, understanding genetic test results - Stan Nelson
    6/27
    8:30-10:00 Ubderstabding the complexities Clinical Trials - John Porter, Kevin Flanigan, Craig McDonald, Brenda Wong, Elizabeth McNally, Ed Kaye, Nathlie Goemans, Stuart Pelts, Vile Campion
    11:30=11:50 FDA& Rate Dusease thinking differently Marlene Haffner
    12-1 FDA Guidance document
    1:10 -3:00 Pipeline , Anti-firbotic, Cardial Skeltal
    3:20 Exon Skip Sarepta
    3:40 Prosensa
    4:00 Duplixations and exons in early regions - Flannigan
    4:20-5:00 Stop Codon read through
    5:20-6:30 Panels Next Steps after approvals Prosensa Sarepta PTCT Pfizer +
    6/26
    9:00 More updaes from pipeline - alternate proteins, Muscle growrth - anti inflamatory
    2:00 early approaches
    2:40 MRI outcome measures
    3:00 enhancing exon skipping Carrie Micelie - work probaly inconjunction with Sarepta based on California grant

    Sentiment: Buy

  • themicrokid themicrokid Jun 26, 2014 12:22 PM Flag

    Sorry, underweather and my touch typing skills somewhat lacking sometimes I get right, sometimes get wrong. Often only glance to see if any relation to my intent

    Sentiment: Buy

  • themicrokid themicrokid Jun 26, 2014 5:14 PM Flag

    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.

    Sentiment: Buy

  • Reply to

    6 Min walk test

    by jamesworfolk Jun 26, 2014 4:48 PM
    themicrokid themicrokid Jun 26, 2014 9:25 PM Flag

    1) I have no concerns the 144 wk 6 MWT results won't be good.
    2) I do have concerns that there could be boys in jeopardy, especially in the placebo cross over. Two or three of those boys approached 300 meters most likely prior to cross over. Boys under 315 or 325 meters typically have less than a year left of ambulation. These boys will be at over 2 years from start of treatment. And recall it takes close to 24 weeks to build enough dystrophin to be effective. These boys are probably growing taller and heavier. This also works against them. They have already defied natural history.
    3) I do have a concern the market may misinterpret the 6MWT results.
    4) I don't think anything other than an unexpected safety issue puts the NDA filing in jeopardy.
    5) RNA released some data as far out as 177 weeks. A couple boys in that trial tapered off. Some of those boys were youger and had higher bedinning 6MWT scores so were less likely to lose ambulation.

    I just added to my position.

    Sentiment: Buy

  • themicrokid themicrokid Jun 26, 2014 9:31 PM Flag

    I was going from memory of the UK trial and even in the 50 mg/kg group at 12 wks, I thought there was some slight, but inconsistent increase in dystrophin. Whereas at 24 wks, we had pretty consistent increase in dydtrophin.

    If I understand the Drisa is a longer half life and that may be why they are seeing fasted dystrophin production.

    But with all the differences in methodology and the general lack of dystrophin data from Prosensa, it becomes confusing and makes one wonder, if they are really producing dystrophin as rapidly as claimed.

    just my thoughts.

    Sentiment: Buy

  • Reply to

    6 Min walk test

    by jamesworfolk Jun 26, 2014 4:48 PM
    themicrokid themicrokid Jun 27, 2014 11:12 AM Flag

    it is very unclear what happened after 177 weeks and there my have been months of delay before the 177 wk reporting. even if no longer on drug their curvves would be interesting as dystrophin is a fiarly long half life gene

    Sentiment: Buy

  • Reply to

    Considering

    by thigrlsrk Jun 28, 2014 11:15 PM
    themicrokid themicrokid Jun 29, 2014 6:51 PM Flag

    Sarepta didn't have the rights to the Wilton work till well after University of Leiden filed the patent licensed to Prosensa. The question that is largely left and being fought over is whether there was prior art invalidating much of the Leiden patent. And the answer is probably including some published by the inventor, who now claims it wasn't sufficient to enable to one skilled in the art or some such. Prosensa/ Univeristy of Leiden is primairly trying to destroy various pieces of prior art and claim because they didn't have human cell data or weren't in the general knowledge of practioners of the art they shouldn't be counted.

    Sentiment: Buy

  • Reply to

    Considering

    by thigrlsrk Jun 28, 2014 11:15 PM
    themicrokid themicrokid Jun 29, 2014 11:09 PM Flag

    Avi Biopharma should have fired Leslie Hudson for screwing up the IP space in DMD. He was convinced he owned the space. And possibly he should have. The Kole patents on alternate splicing should really have been prior art to any exon skipping. But the folks at Leiden ignored them. As they ignored lots of other things in the IP arena and toxicity in the clinical arena. To determine freedom to operate in reality can take and insane amount of litigation. And much is more about the procedure, dotting the i, and crossing the t's than about science and what is invented.

    It is really a stretch to imagine that a drug that is toxic at over 6 mg/kg, appears to not create meaningful dystrophin is enabling or meaningful art to a drug that requires 30 mg/kg, creates meaningful dystrophin, and is non toxic.

    But that is the legal systems in this world.

    Be it University of Leiden or Western Australia University, the world of exclusive licensing has allowed universities to essentially reward kids with death sentences. University chancellors were robes, judges who sentence criminals to death penalties were robes. But I have never heard of a judge sentencing a young boy/man to death for having a non transmittal disease.

    But in thinking about it, how is it different than Hitler sentencing people to death for a religous .........

    Sentiment: Buy

  • Reply to

    Considering

    by thigrlsrk Jun 28, 2014 11:15 PM
    themicrokid themicrokid Jun 30, 2014 12:00 AM Flag

    efficacy and lack of toxicity should rule. why subject parents to making a decision unless both products are medically comparable.

    Sentiment: Buy

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