Tag Archives: Additional Salmon’s Asenapine Chronicles Erstwhile Salmon FDA PDAC Phen-Fen Repeat July 31 2009

Salmon’s “Asenapine Chronicles” Weekend Edition, Part II


This time — some thoughts on safety — from Salmon’s review of the FDA’s asenapine PDAC background materials, at pages 791 to 792. Click image at right, to enlarge; then read the comments, below — to fully-understand Salmon’s perspective:

. . . .Notice the last paragraph (of page 792, at right):

Organon (now SP) states that asenapine is unsafe with chronic oral dosing of greater than 4 mg daily due to both cardiovascular and liver toxicities. (Companies never say things like this so you know they’re really concerned.) This is equivalent on average to around 12 mg daily sublingually and the dose for schizophrenia is 10 mg daily and 20mg for bipolar.

Based upon information here and elsewhere in the review both may be due to high exposures to metabolites formed when asenapine goes through the liver immediately after being absorbed. This is why a) they switched to sublingual and b) switched to BID dosing c) a possible reason they didn’t submit long term studies where it may have been feasible and probably especially in bipolar.

SP claims the subjects had NMRB (vasovagal syncope) but on pages 785 – 788 the description of the actual events are not consistent with this.

For the more severe case the ECG shows the patient’s heart stopped. He was given CPR then his heart stopped again and he was given CPR again, but had cardiac arrhythmias. They had to give drugs, a blood type product, and oxygen. He then had a different type of arrhytmia. At a followup visit with a cardiologist he found no problems with the guy’s heart and upon doing a simple test (carotid massage) that would cause him to faint if had NMRB nothing happened.

The cardiologist report says: “This almost certainly has to be classed as a drug induced effect with a serious effect on the conducting system of the heart.”

Now dose and time dependent liver toxicity (organon’s assessment) won’t show up as liver failure for a years unless someone already has some problems. But a 6 year old kid taking 10 mg BID and swallowing it will get the equivalent of a 75 mg oral dose. Will get liver failure much much sooner, and this dose equivalence estimate doesn’t even account for the proportionately larger livers in kids and the likely higher exposure to any toxic metabolite.

Notice that the reviewer also states that he was told not to review the study.

From all the other efficacy studies that they did first with piddly sublingual doses (e.g. 0.1 mg) you know they were scared and didn’t want to go anywhere near the doses they’re asking approval for. That’s why it took so long to develop this drug.

This also the reason why in the AC meeting SP was so keen on teaching people to take the drug properly and not drink for at least 10 minutes which would wash drug into the stomach. . . .

Salmon
August 2, 2009 9:35 PM

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The Continuing “Asenapine Chronicles” — By Salmon — Over The Weekend “Pondering” Edition


We now offer even more on Schering-Plough’s drug candidate, Saphris, or asenapine, from Salmon:

. . . .The background package shows the reviewer asked that the metabolites be properly identified and tested for phen-fen like pharmacology (agonism at the 5HT2B receptor).

The reviewer then disappears and someone else claims the metabolites were adequately identified when they weren’t. It also looks like FDA management refused to even look into the receptor binding of the metabolites and they only talk about the effects of asenapine itself at receptors.

Even a screen of the most important metabolites should have only taken a few days. Identifying and testing all the metabolites could have been done during the past year.

Something similar happened with Phen-Fen. They had tested the metabolites internally and knew it was the metabolites that were toxic but didn’t report the results to the FDA.

Looks like very suspicious to me. . . .

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Every AC meeting I’ve been to FDA sets up questions or issues for the AC to address. In this case they made the AC focus on schizophrenia study 023 and why the 5 mg worked and the 10 mg didn’t. This distracts from the real issues, i.e. hepatotox, cardiac tox, and the higher baseline and low placebo response in study 004.

As expected the clinicians, who don’t know statistics said well if the 5 mg dose works it must work (especially since the 5 mg dose in study 004 works. NOT. Whereas the statistician, the expert, said he didn’t believe the 5 mg dose hadn’t been shown to work in study 023 and they never even discussed 004.

Look at the YMRS quintile graph from page 761 (click to enlarge):

I’ll explain my thoughts and concerns in the comments, below.

Salmon

Added another installment, above, now.