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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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March 19, 2013

Affymax In Trouble

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Posted by Derek

Affymax has had a long history, and it's rarely been dull. The company was founded in 1988, back in the very earliest flush of the Combichem era, and in its early years it (along with Pharmacopeia) was what people thought of when they thought of that whole approach. Huge compound libraries produced (as much as possible) by robotics, equally huge screening efforts to deal with all those compounds - this stuff is familiar to us now (all too familiar, in many cases), but it was new then. If you weren't around for it, you'll have to take the word of those who were that it could all be rather exciting and scary at first: what if the answer really was to crank out huge piles of amides, sulfonamides, substituted piperazines, aminotriazines, oligopeptides, and all the other "build-that-compound-count-now!" classes? No one could say for sure that it wasn't. Not yet.

Glaxo bought Affymax back in 1995, about the time they were buying Wellcome, which makes it seem like a long time ago, and perhaps it was. At any rate, they kept the combichem/screening technology and spun a new version of Affymax back out in 2001 to a syndicate of investors. For the past twelve years, that Affymax has been in the drug discovery and development business on its own.

And as this page shows, the story through most of those years has been peginesatide (brand name Omontys, although it was known as Hematide for a while as well). This is synthetic peptide (with some unnatural amino acids in it, and a polyethylene glycol tail) that mimics erythropoetin. What with its cyclic nature (a couple of disulfide bonds), the unnatural residues, and the PEGylation, it's a perfect example of what you often have to do to make an oligopeptide into a drug.

But for quite a while there, no one was sure whether this one was going to be a drug or not. Affymax had partnered with Takeda along the way, and in 2010 the companies announced some disturbing clinical data in kidney patients. While Omontys did seem to help with anemia, it also seemed to have a worse safety profile than Amgen's EPO, the existing competition. The big worry was cardiovascular trouble (which had also been a problem with EPO itself and all the other attempted competition in that field). A period of wranging ensued, with a lot of work on the clinical data and a lot of back-and-forthing with the FDA. In the end, the drug was actually approved one year ago, albeit with a black-box warning about cardiovascular safety.

But over the last year, about 25,000 patients got the drug, and unfortunately, 19 of them had serious anaphylactic reactions to it within the first half hour of exposure. Three patients died as a result, and some others nearly did. That is also exactly what one worries about with a synthetic peptide derivative: it's close enough to the real protein to do its job, but it's different enough to set off the occasional immune response, and the immune system can be very serious business indeed. Allergic responses had been noted in the clinical trials, but I think that if you'd taken bets last March, people would have picked the cardiovascular effects as the likely nemesis, not anaphylaxis. But that's not how it's worked out.

Takeda and Affymax voluntarily recalled the drug last month. And that looked like it might be all for the company, because this has been their main chance for some years now. Sure enough, the announcement has come that most of the employees are being let go. And it includes this language, which is the financial correlate of Cheyne-Stokes breathing:

The company also announced that it will retain a bank to evaluate strategic alternatives for the organization, including the sale of the company or its assets, or a corporate merger. The company is considering all possible alternatives, including further restructuring activities, wind-down of operations or even bankruptcy proceedings.

I'm sorry to hear it. Drug development is very hard indeed.

Comments (11) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Drug Development | Drug Industry History | Toxicology


COMMENTS

1. John Tucker on March 19, 2013 9:20 AM writes...

I'm not an immunology expert, but my understanding is that the Omonty's reactions are considered anaphylactoid rather than anaphylactic, as they occurred on the first exposure to drug. A classical anaphylactic response requires prior exposure so that a pre-primed IGE response is possible. Anaphylactoid responses result from chemical agents that disrupt mast cell membranes, thus releasing histamine via a chemically mediated rather than immunoglobulin mediated pathway.

Naively, the answer to this problem seems to be associated with the question "what is in the formulation of Omontys that can disrupt mast cell membranes?" One possible answer is polysorbate, which has been associated with rare cases of anaphylactoid reactions in other contexts.

http://www.ncbi.nlm.nih.gov/pubmed/16400901

Should be interesting to see what the outcome of the investigation turns out to be, assuming AFFY survives long enough to complete it.

Permalink to Comment

2. Virgil on March 19, 2013 9:48 AM writes...

Another one for the books - Neurosearch A/S in Copenhagen appears to be shutting down & selling off.

https://newsclient.omxgroup.com/cdsPublic/viewDisclosure.action?disclosureId=546741&lang=en

Permalink to Comment

3. Nplate on March 19, 2013 10:37 AM writes...

Let's not forget that AFFY also developed the active peptide in Romiplostim, which has revolutionized the treatment of ITP. Amgen fused that peptide to Fc and gets all the credit for developing the drug, including a Prix Galien award. While it may be true that the peptide was not destined to be a drug on its own, the drug would not have happened without AFFY. The pharmaceutical industry sorely needs this kind of innovation.

Permalink to Comment

4. Electrochemist on March 19, 2013 11:07 AM writes...

@#1, John Tucker: From the Omontys label: Inactive ingredients in single use vials and single use pre-filled syringes: sorbitol, sodium phosphate monobasic (dihydrate), sodium phosphate dibasic, polysorbate 20, and sodium hydroxide in Water for
Injection.

Permalink to Comment

5. NJBiologist on March 19, 2013 12:08 PM writes...

@#1, John Tucker: Good questions all, but I'd also keep an eye open for the possibility of direct agonist effects at Fc[epsilon]R.

Permalink to Comment

6. John Tucker on March 19, 2013 1:00 PM writes...

NJBiologist, please elaborate.

Permalink to Comment

7. anon on March 19, 2013 1:48 PM writes...

The spin off from Glaxo was after the merger with SmithKline. The primary reason for divesting, very simply, was that the ownership was not worth the return.

Glaxo'a purchase of Affymax, at the time, was a very expensive hot-technology of the moment aquisition. You'd think they'd have learned, and then there was Sirtris. But of course management had changed at least twice and there is little organizational memory. And folks wonder what has gone wrong in the Pharma industry?

Permalink to Comment

8. NJBiologist on March 19, 2013 3:22 PM writes...

@6, John Tucker: Fc[e]R is known as a *protein* receptor, degranulating mast cells in response to IgE crosslinked through antigen. But I bet someone who screened enough peptides could find one that activated Fc[e]R.

Permalink to Comment

9. Current GSKer on March 19, 2013 4:06 PM writes...

@7, anon

With respect to the return on the Affymax purchase in 1995,rumor has it GW made it money back and then some when Affymetrix was sold. Still doesn't justify the Sirtris boondoggle.

Permalink to Comment

10. AC on March 20, 2013 6:52 AM writes...

Indeed, drug development is very hard and unpredictable as well.

I worked on the discovery of this as a chemist many year ago. I was very happy when the wonderful science turned into an approved drug. The news in last few days turned out to be very depressing.

Permalink to Comment

11. exGlaxoid on March 28, 2013 8:48 AM writes...

Had GSK sold the Affymetrix stock at its peak, it would had made a good return, despite losing money on Affymax. But they held on to it until the price went down quite a bit, so they about broke even instead. But the Affymax part continued to burn money for several years after the purchase, and that helped lower the return.

The automation used to make the libraries was very cleaver, no argument there, but the quality of the final product libraries was fairly poor. While mass spec could find a peak for most desired products, there was often a very uneven amount of each material, such that when screening "36,000 compounds", you might have really been screening a few hundred or thousand, which is still useful, but not nearly as good as advertised. The LC-MS's of the "mixtures of 36" compounds each were not 36 even peaks, but rather a few large peaks, and many more than 30 smaller ones. Plus the screening of individual beads, which was part of the plan, was never nearly as successful as hoped for, only in a few rare cases did anything come of that.

Given the number of chemists and other employees at Affymax during that time, and the money spent, I suspect that you could have likely made 500,000 to 1,000,000 discrete, pure, compounds in a vial, with the same resources that were used to make "Millions" of them in pools, mixtures, and beads, most of which were never tested adequately. That is the missed opportunity that I see, as those compounds would still be available for screening and testing, unlike the pools.

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