Monday, October 27, 2008

Salmon's Continuing Asenapine Chronicles -- Next Installment -- Why DID Pfizer Bail Out?

The first installment of "The Asenapine Chronicles, by Salmon" may be found under the link in that title -- and Salmon is, as ever, spot-on, again. Consider the vast sums invested -- almost a quarter of a billion dollars -- that Pfizer apparently abandoned, and simply walked on (detailed below).

Now, a cynical critic of big pharma might also observe that a company with a certain amount of "pliability" on moral, ethical and legal dimensions might -- just might -- be, in part, banking on the fact that nary a single putative-long-term asenapine patient (being mentally-ill to begin with) will be a particularly capable or believable witness in any ensuing litigation about drug safety or efficacy -- if, in fact, it turns out to be unsafe, or unsound.

To such a company, what would matter most, would be how much Medicare/Medicaid (and the patch-work quilt of private health-plans) would be willing to reimburse for such a regimen -- even if it is ultimately found to be unsafe -- years after approval. But that, thus far, is merely a hypothetical scenario, as the candidate has not cleared FDA or EU authorities. Nor, I think, given Salmon's analysis -- is it ever likely to so clear.

. . . .Some other thoughts on Pfizer's actions.

Pfizer dropped out of codeveloping asenapaine in late November 2006. As I've mentioned before Organon's announcement of an accepted filing at Thanksgiving 2007 means that the NDA had to be submitted by early Oct 2007 at the latest or nearly 10 months after Pfizer dropped out of the deal. Since it takes about 9 months do analyses, write reports and to put together the documents for the submission. (even accounting for another couple of months so that both indications could be submitted simultaneously. This means that Pfizer dropped out after the Phase III studies were completed. Since there were 2 indications and both were submitted, and since the Phase II studies are presumably positive (otherwise the drug wouldn't have gone forward) asenapine likely showed efficacy in at least 1 phase III study for each indication which in combo with a positive phase II study is usually sufficient for approval, even if one phase III study was negative.

N.B. there have been published abstracts from meetings regarding study results.

Also Pfizer paid $100 million up front and presumably some other milestone payment (total, if filed, was supposed to be ~$300 million.) Let's assume a second $100 million milestone payment was made for a total of $200 million. In addition to this Pfizer likely conducted and paid for the US studies (assume 1 US study per indication per FDA's usual requirements) with 3 or possibly 4 arms: placebo, active control and 1 or 2 dosages. If there's 150 - 200 subjects per arm in a standard 6 week schizophrenia study and a standard 4 week bipolar study Plus a safety study at $7500/subject that's another $15 million at least. So Pfizer likely dumped at least $225 million into this drug and then walked away after all the work was done. Even if this drug doesn't work very well it still might mean several hundred million in sales per year anyway, which I don't think even Pfizer would walk away from as every penny adds to the bottom line.

To me the total evidence available in press releases points to Pfizer dropping the drug because of a safety signal.

-- Salmon

October 26, 2008 7:01 PM

Indeed -- we shall see.


Anonymous said...

I checked some of AZ, Org, and SP press releases and there were 4 acute schizophrenia studies (2 reported as positive and 1 as failed (i.e. neither asenapine nor the active control olanzapine, (Zyprexa), worked), thus the other study was negative (i.e. the active control worked but asenapine didn't). In addition there were 2 positive bipolar studies, and based on the reported results they appear robust in bipolar at least.

So even if the efficacy of asenapine in schizophrenia was so-so or even insufficient for approval, the reported evidence for bipolar appears adequate for approval. So it's puzzling why at least one indication wasn't approved or at least approvable.

However remember that at about the same time FDA changed their policy so as to no longer have approvable letters, only approval and nonapproval. This would make the real reasons for nonapproval more opaque.

Plus the acute schizophrenia study reported in the press release this week appears to be the same study reported at the APA meeting May 8th. Yet both the May and recent SP press releases said the safety results would be released later, (hmmmm).

Besides lack of efficacy, or clinical safety issues, there could be manufacturing issues or animal toxicology issues that might hold up approval. But these more typically result in approvable letters and not simply nothing.

Prior to negotiations for PDUFA IV pharma was making a lot of noise to get approvals right at the end of the PDUFA review period and no more approvable letters.

Also during the negotiations for PDUFA IV PhRMA was pushing to get the FDA to shorten the review clock to 8 months. This wouldn't fly but in a draft of PDUFA IV the as outlined in the bills for Food Drug and Administration Act of 2007, they did get that labeling negotiations would begin 60 days before the PDUFA due date if it was to be approved or approvable. Yet in the final version of PDUFA IV as outlined in the FDAAA 2007 this isn't specified but instead it refers you to a MOU. (Nice way to hide what's really going on.)

FDA regs indicate that going beyond the PDUFA due date can only be done if there is an agreement with the sponsor. Plus extensions to the due date are not to be done for major amendments (such as more data), and manufacturing issues etc. are now supposed to be taken care of by early communications during the review cycle so FDA can give an answer one way or the other at 10 months.

It is now over 1 year since filing. SP had to have known at least 5 months ago (around May when they first reported on this new long term efficacy study) if they were going to get an approval or approvable, and they could infer a nonapproval even before they would hear officially. They then would have had to make an agreement with FDA to extend the review clock. Another interesting clue is Fred Hassan’s rant on the front page of the Wall Street Journal on June 30th, saying he doesn't know how to get something past the FDA. Which is shortly after when he should have known what the results of the review were.

So we should have then heard news about approval at around the time of the 2nd Qtr report or shortly thereafter. But instead we only heard more bad news about Vytorin, i.e. Cancer. If they thought it was never going to be an approval SP would have withdrawn the application quietly and we would never hear anything. However the fact that they're still reporting positive studies and that they're long term suggests that there's an agreement with FDA to extend the review for some reason, and that these new studies will provide some additional safety information. (Even though regulations don't allow this.) All this suggests to me that Fred himself is withholding material information that would have sent the stock price even lower than it did go, and it may even suggest FDA involvement.

However even if the new data is a 6 month study it doesn't mean that people are on the drug for 6 months. (In the labeling for positive studies for other antipsychotic drugs for the same indication the average length of time on the drug until relapse was ~ 50 days and even though this was statistically different from placebo it was only about a week longer, which is so small it may not be clinically significant.

As you can see based on the way the new FDAAA 2007 law is set up, companies will know the results of whether a drug is to be approved or not 2 months before the public. This gives a lot of room for insider trading or other manipulations, including collusion with FDA officials. I followed this law closely and if you know how the process works it's virtually everything that Pharma could possibly want but you really need to know the process to know how to have written this law, which would require a lot of input from Pharma (i.e. Pharma virtually writing the law.)

That leads me to another interesting observation. The FDAAA 2007 is known as the Kennedy - Enzi bill. It just so happens that Ted Kennedy's son runs a consulting firm for Pharma called the Marwood Group. I've really got to wonder what sort of expertise Ted Kennedy Jr. has that he could be a consultant to Pharma (in addition to investors). ( Also Sen Kennedy has just been reported to be actively working on health care and expanded access and we know that this will help Pharma, especially those extremely profitable antipsychotics whose off label use and indications have been expanding and expanding. Just look at Seroquel XR (quetiapine) and all the new indications under study. Not to be partisan let's not forget Bush and his interest in expanded mental health screening programs for children.

Now the same day as Fred’s rant on the front page of the WSJ (June 30th), Janet Woodcock’s (the head of the center for drugs) Public Calendar shows she had a meeting with Ted Jr. of the Marwood group, ( Boy are there a lot of coincidences. As a speaker I have to wonder what clients would have been invited, and what would have she said that could be so interesting to Pharma and investors, and who would have paid for her travel expenses to NYC? Remember Congress has been looking into inappropriate meetings and communications between Sr. FDA officials and Pharma. Even if FDA paid is it really appropriate for the head of the FDA’s drug division to have a private meeting and discussion with investors and Pharma consultants that the rest of the investing public doesn’t have access to?

There's a lot more interesting stuff both on the limitations of efficacy as well as likely toxicities for asenapine and similar drugs that can be inferred by examining the literature and summary basis of approvals that aren't generally appreciated. This would be standard practice for any company to do. Plus Organon has been working on structures similar to asenapine since the 1960's. So they would know a great deal about toxicities. You've also got to ask yourself if they've been working on these structures since the 1960's why have so few come to market and why have they taken so long and why do they keep working on them.

It’s too bad you only post on SP, they’re not the only company whose drugs I follow.


Anonymous said...

I thought this Bloomberg article was also relevant....FDA is going through a huge hiring bender to get on track to meet PDUFA IV standard review times.

Also, in regards to your thoughts on Asenapine's supposed efficacy. I think it has a great market opportunity for not only treating Bipolar disorder's depressive side, but also as an augmentor for treatment-resistant depression. Currently, the go-to drug in these categories is Seroquel, but its sedation and weight-gain limit its compliance. Asenapine could fill that void due to its lower side-effect profile.

At least on paper, this really looks to be a serious contender. However, so did Geodon when it first came out, so we'll just have to wait and see.