Even if one tried, it would be difficult to make up a stranger story, stranger than the true story: the one that leads to this moment, in the "Further Asenapine Chronicles" -- now awaiting word from the FDA's PDUC meeting -- on Saphris/Asenapine, this evening [click thumbnails of pages, at right to enlarge]:
. . . .Take a look beginning at page 963 of the asenapine PDAC background package. The OCP reviewer begins to lay out structure activity relationships and why similar toxicities may be occurring with a wide variety of drugs ( i.e. the 3D structures may allow binding to the same binding sites.)
On page 967 he looks at the antihelminic mectins (Merck and SP animal drugs) and you can see he's postulating that the effects on bones seen with the animals studies of the various antipsychotics described elsewhere in the reviews may be related to these drugs causing bone chips in the knees of race horses.Since these drugs are also given to farmed salmon(!) this raises the possibility of these being toxins in the human food chain. [Ed. Note: Click at right -- to enlarge the image of Page 969 -- Agent Orange; Dioxin. . . .]
There's actually an article related to this in the December 2008 issue of of Drug Safety as well as another article in that issue by Dr. Zornberg the FDA team leader on asenapine that basically outlines all the OCP reviewer's concerns.
Coincidence(s)?
-- Salmon
July 30, 2009 12:36 PM. . . .
Wow. Keep it comin'. . . we still are awaiting word from the Hilton on Colesville Road, in Silver Springs, Maryland.
7 comments:
I'm not sure that the figure is greatest example but the point seems to be is they all seem to have structural commonality with bisphenol A.
I'm not sure that the figure is greatest example but the point seems to be is they all seem to have structural commonality with bisphenol A.
Well -- now it is up to the full Commission -- PDAC votes in favor.
Namaste
The PDAC meeting has ended.
Like the last few meetings on AC member wanted a third question of given that they've voted on if a drug is "acceptably safe" or not she wants to then vote on safe relative to the efficacy. To me the idea of safe has to by it's nature include a intellectual balance with efficacy. Because you can't vote on rates of AEs and safety is a judgement on rates of AEs, severity of AEs etc. as compared to the efficacy and the alterative of not treating.
Then it did come out that the AC members are abstaining on voting regarding safety is they vote no on efficacy. To me this is absurd because the way it's reported and used the abstentions are basically ignored.
Here are the tallies:
Schizophrenia
Efficatious Safe Balance
Yes 10 10 9
No 2 0 1
Abstain 0 2 2
BPI
Efficatious Safe Balance
Yes 12 12 12
No 0 0 0
Abstain 0 0 0
The way the questions are worded they only vote on safety for the 3 - 6 weeks of the studies. Even though it will likely be approved later for long term and Dr. Laughren indicated long term use will be implied by the labeling since no one would ever switch to another drug and standard is long term use.
Based on the standards used in the meeting today thalidomide would have been approved.
You know how SP spins the financial well their presentations today were the same. There was a discussion about suicides and SP acknowledged that they were comparing 6 week placebo rates to 1 year drug rates and then ASSUMED rates were stable (bad assumption) since we know suicide is most likely to occur early with drug treatments in depression etc.
As for efficacy NO mention at all that the baseline disease severity was not comparable in study 004.
No mention at all of the concerns of PAH long term.
No mention at all regarding the possibility that efficacy in bipolar might be related to disease severity (see page 759 - 764 and especially the graph on page 761). Although there was discussion how the placebo response rate in schizophrenia has been going up over the past 20 years (likely because they're studying less severely ill people.)
They did seem concerned about long term safety and kids, but basically said the drug was safer than Zyprexa because it didn't cause as much weight gain. In spite of the fact that it appears the diabetes might be due to a toxic effect on the pancreas and not due to the weight gain.
There was no discussion at all of the dose and time dependent hepatotoxicity (page 385) that appears to be due to a toxic metabolite that's formed on swallowing. Which is probably why the instructions are not to eat or drink for 10 minutes and the real reason for BID dosing and not the half-life of D2 receptor occupancy as they claimed. If BID dosing and efficacy is because of D2 receptor occupancy then why even develop a drug to block serotonin receptors and why were the early studies with low oral doses once daily.
AC members talked about SP coming out with a 2.5 mg dose for children (as distinct from adolescents) yet admitted in practice people dose differently than labeled (which often means pushing the dose).
I can just see little kids (5 - 6 yo) given this because it's sublingual, the doc pushing the dose to the maximum adult dose (10 mg bid), and the kid swallowing the drug once the tablet disintegrates.
Personally I think we're going to be seeing a lot of liver failure in kids.
Since PAH is already being reported with the other atypicals in kids I think this one will also be problematic. We just won't know how bad until someone like Dave Graham (Vioxx) fights FDA management to let the info out.
Look for it in about 5 years.
Salmon
Take a look at slide 34 on page 857 which contains the efficacy data for the 4 schizophrenia studies.
The statistician on the the AC committee voted no on efficacy for schizophrenia because he thought the efficacy for the 5 mg dose in study in 41023 could be due to chance and there were problems such as attrition rates.
Plus for study 41004 (the other 'postive study' (really failed study) you can see where not only is the baseline for the asenapine group high but the placebo response compared to the 3 other studies is week.
I think there's potential isses with both of the 2 so called positive studies.
Salmon
Also take a look at the response in mania vs. disease severity on page 781.
I think you should post both this graph and the schizophrenia efficacy table.
Salmon
Will do so now.
Look for both shortly, with your commentary above, as the text.
Thanks a million for your dedication -- I take you were in the Hilton Hotel Ballroom today.
You are a boon to the less educated -- like me.
Namaste
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