Monday, June 8, 2009

MY Errata: in the Kansas City Star, Online Edition, Tonight. . . .

06.10.09 @ 6:30 AM EDT
Credit Salmon
Salmon found the Federal Register item in question -- July 30, 2009 is the planned FDA Advisory Committee Meeting at which Asenapine will be considered for approval. I now humbly bow before Salmon's superior prowess -- that of parsing FDA back-water publications -- more seriously, I am indebted. Corrections now noted, below, throughout.


Some online desk called "The Consumer Memo", inside the Kansas City Star's constellation(!) of web-columns is running the below item, tonight -- and at least as to Schering-Plough's Saphris (asenapine) -- it appears to be a case of "mistaken (chemical compound, and company) identities" my inability to read the Federal Register, online:
. . . .Cancer drug review

Johnson & Johnson’s experimental cancer treatments and Schering-Plough Corp.’s new antipsychotic drug will be reviewed next month by outside advisers to the U.S. Food and Drug Administration. The FDA’s Oncologic Drugs Advisory Committee will meet July 15 to review J&J’s trabectedin infusion combined with Doxil for relapsed ovarian cancer and Doxil combined with docetaxel for breast cancer, according to a notice posted today on the agency’s Web site. . . .

Presumably, he means to refer to Saphris (Asenapine). I can verify -- and thus will immdediately accept -- that the ODAC is meeting July 15 on J&J's above-candidate. However, the only notices most current notice for an upcoming meeting on antipsychotics is for potential pediatric indications (as Salmon let us know, almost a full week ago!), here, and here. Among them is Lilly's Zyprexa; Astra-Zeneca's Seroquel and Pfizer's Geodon. But no asenapine, at the-below meeting.

Nope, no Schering-Plough's upcoming meeting agenda item exists, is scheduled for July 30, 2009, via the online Federal Register. The below, as I said, however, is on the agenda for June 9-10, 2009:

The committee will discuss safety and efficacy issues for the following new drug applications (NDA): 1) NDA 20-639/S-045 and S-046: Seroquel (quetiapine), AstraZeneca Pharmaceuticals LP, for (a) the acute treatment of schizophrenia in adolescents (13-17 years of age), and (b) the acute treatment of bipolar mania in children (10-12 years of age) and adolescents (13-17 years of age); 2) NDA 20-825/S-032: Geodon (ziprasidone), Pfizer Inc., for the acute treatment of manic or mixed episodes associated with bipolar disorder, with or without psychotic features in children and adolescents ages 10-17 years; and 3) NDA 20-592/S-040 and S-041: Zyprexa (olanzapine), Eli Lilly and Company, for (a) the acute treatment of manic or mixed episodes associated with bipolar I disorder, and (b) the acute treatment of schizophrenia in adolescents. The committee will be asked to vote on whether or not these products have been shown to be effective and acceptably safe for these pediatric indications. . . .

So, I think I Steve Rosen, the author of this "Consumer Memo" column, just simply got his my wires crossed.


Anonymous said...

Well SP announced ~ Feb 20th that the complete response was filed. The review clock on that is 6 months so the decision will come mid- Aug.

I just found the advisory committee announcement for the hearing on asenapine. It was in today's Federal Register and will be held July 30th.

Today's advisory committee hearing was as I predicted, very misleading.

There was quite a lot of talk about increases in blood pressure and heart rate and what the long term risks might be. As expected based on the background documents that you so kindly linked to (your 3rd link) they said the due to the fact that these were short term studies (3 weeks) in small numbers of kids with even the long term safety being only 6 months and not that many kids they couldn't predict what the risk with decades of exposure might be.

In addition they are pushing Zyprexa/olanzapine (brother of asenapine) to be second line therapy ostensibly because of the risk of weight gain and diabetes.

Now if you actually go through the 589 pages of the FDA review which is the 1st PDF document of the third link. You find on page 54 that with Seroquel (another structurally related to asenapine and olanzapine) 1 child with Pulmonary Hypertension and 1 child with Hypertensive Crisis developing respectively on days 84 and 129. Also take a look at page 24 on submission quality and page 85.

For ziprasidone (Geodon) take a look at page 247 ISR# 5259176 5606100, and 4197199.

For olanzapine (Zyprexa) begin looking at page 581 and there are a whole bunch of deaths and pregnancy cases effects from post marketing that are potentially consistent with the same mechanism.

What am I talking about why things that are consistent with the phen-fen like effects (pulmonary arterial hypertension) that I've speculated about previously based on Olanzapine's original review and presentations from Pfizer.

Plus last week Lilly got approval for Cialis to be used for Pulmonary Arterial Hypertension. (Great timing Lilly!)

Now as for Olanzapine (Zyprexa) being promoted as second line therapy due to weight gain I don't buy it and think it's a red herring. Especially as 1 out of every 8 kids had liver damage after 2 weeks of treatment and 1 out of 30 had Zyprexa stopped because of it. (By 3 weeks the study was over) Plus the post marketing reports listed 1 kid who died after 2 years due to hepatic steatosis.

Now all this kind of points to something similar to what you would see after an alcoholic binge but death due to alcoholic cirrhosis (which includes steatosis) takes 1 - 2 decades. Now considering the structural relationship I pointed out previously with Zyprexa's N-formyl metabolite and how it looks like SP's hepatitis drug and how these might be somehow effect aldehyde metabolism which is tied in with alcoholic liver toxicity. I do believe that we have a signal.

Now considering what was said in the online businessweek comment about hepatotoxicity with asenapine. I'd say they're concerned about a lot more than weight gain for Lilly to propose making Zyprexa second line treatment in kids.

I know this isn't the most well written post but hopefully it'll help you follow the dots with me.


Anonymous said...

Clarification. The online businessweek comment was by someone who interviewed with Pfizer while they were developing asenapine and wanted her to work on hepatotoxicity issues with asenapine.

If I recall it was to work on a white paper which would likely be used to diminish any concerns.


Anonymous said...

PPS the higher rate of hepatotox in kids is likely due to the proportionately higher doses being used. As for why hasn't it been so much of a concern in adults so far, maybe because in addition to FDA's usual suppression of any cases that adults tend to not stay on antipsychotics for prolonged periods.

Kids on the other hand will have forced compliance by their parents. Don't worry though maybe SP's and Vertex's hepatitis drugs under development can be used to treat it.


Condor said...

Apparently, FDA's Advisory Committee "green-lighted" the pediatric indication for these three drugs, late today.

Disappointing, to say the least.

Namaste -- and thanks, as ever, Salmon!

Anonymous said...

Oops -- I forgot to embed the link to the "Cautious Green Light" story. . . .

Anonymous said...

Yes it was clear at the meeting from the first vote that this was going to be the outcome.

What I found very interesting is that those advisory committee members who abstained from voting on the issue of if the drugs were acceptably safe were precisely the same AC members who had the most concerns about safety.

Considering all the information that has come out of Senator Grassley's office about how many academic psychiatry departments and key opinion leaders are getting huge amounts of money from the pharmaceutical industry on these drugs and at the same time not reporting personal financial interests. Plus how academicians, FDA reviewers, parents of children etc. who raise safety or efficacy concerns about these drugs are retaliated against by companies. I would speculate that perhaps these AC members may have been afraid to vote no.