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May 19, 2011
Avandia Goes Out
Posted by Derek
So Avandia (rosiglitazone) will be pulled from the market this fall. I've already written a few pieces on that whole market - PPAR ligands - but this still makes a person think. (See this post for the whole list). Starting in the mid-1990s or so, a huge amount of time, effort, and money went into PPAR alpha, gamma, and delta compounds. (In the interests of full disclosure, some of that effort was mine). And a lot of the interest was sparked by the possibilities of rosiglitazone (and its cousin pioglitazone, sold as Actos, which remains on the market). This was the first mechanism that looked to actually target some of the underlying defects in Type II diabetes, although no one was sure quite how. And "Rosi" was the PPAR-gamma ligand that all others were compared to in the labs.
But now it's gone, and the PPAR field is comparatively moribund. Glaxo, SmithKline (before the merger), Merck, Lilly, BMS, Bayer, Kyorin, Ligand - all these companies and many others poured resources into the field, and here's what we're left with: the three earliest PPAR_gamma compounds made it through, and now two of them (troglitazone left early) are gone. So one gamma ligand, one alpha (fenofibrate, the one that everyone started with), and no delta. None of the combinations (and boy, were there a lot of them) every made it, either. Two drugs out of the whole field, and neither of them discovered after the target-based approach kicked in. Yikes. And people still want to know why their prescriptions cost so much.
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1. Dennis on May 19, 2011 12:36 PM writes...
I'm curious, are there any good guesses for the mechanism behind the cardiovascular risks associated with Avandia?
Permalink to Comment2. Boghog on May 19, 2011 1:36 PM writes...
I wonder after this debacle, will anyone have the stomach to pursue this:
PPAR: A Veil Is Lifted, At Last
Permalink to Comment3. johnnyboy on May 19, 2011 1:45 PM writes...
Pfizer, too - if memory serves, active gamma and very active alpha programs (that's from several years ago). All stalled, if memory serves in good part because of adverse effects on other tissues (in animal models). The targets seem to just be too generalized in various organs to not have unexpected and potentially unwanted effects.
Permalink to Comment4. johnnyboy on May 19, 2011 2:02 PM writes...
@1:
Permalink to CommentI'm very far from being knowledgeable in the field, but that hasn't stopped me from talking before... It is known that PPAR-alpha agonists can cause myocardial necrosis (in mice). While it's not sure if this is applicable to humans at clinical doses, it does make me wonder about the sometimes higher incidence of MACE with fenofibrate mentioned by Derek in a previous post. It also makes me wonder about the selectivity of rosiglitazone for the PPAR-gamma receptor. Yes, I'm sure there's good in vitro data showing none or low activity against PPAR-alpha for rosi, but again, how predictive are in vitro selectivity assays to the clinical situation, with millions of people of varied genetic backgrounds taking the drug ?
5. HelicalZz on May 19, 2011 3:21 PM writes...
Well, that is the catch-22 of target based drug discovery isn't it? If you wait until the target is well understood, you will be late to the market. If you design against the target prior to understanding it, the most you are likely to achieve is 'better understanding of the target biology'.
Zz
Permalink to Comment6. Marilyn Mann on May 19, 2011 5:51 PM writes...
@Dennis One of the reasons behind the risk of myocardial infarction with rosiglitazone is that it raises LDL by about 18%. No doubt there are other reasons.
Both pioglitazone and rosiglitazone cause edema and increase the risk of heart failure.
Permalink to Comment7. Mother nature on May 19, 2011 7:20 PM writes...
My take on this was one where the right thing was done at the right time in the right manner. 10 years ago TypeII diabetes landscape had little to work with, the epidemiologic forecast was dim and the financial cost of disease morbidity was building. Avandia provided an alternative to strict dietary discipline and exersize. Fast forward to today and there are better alternatives, combined therapies etc. and it no longer represents a good option. To yank it from the market would have set an entirely new tone for Class action lawyers. As critical as Pharma can be on the FDA, I think the gentle nudging of Avandia out of the marketplace was the perfect solution. This scenario is guaranteed to play out again. Better it be with for a disease with unmet medical need rather than a for a "drug" for "patients" to get longer eyelashes so they too can look like Brook Shields.
Permalink to Comment8. ex-MRK on May 19, 2011 8:48 PM writes...
MK767 might have been pulled sooner, saving considerable $$, if Merck had been competent and realized before stage III that it was causing tumors in rats.
Permalink to Comment9. NHR_GUY on May 19, 2011 9:06 PM writes...
I cut my med-chem teeth in the PPAR field (hence the name NHR_GUY). One of the reasons this area of research was so seductive was because it was so easy to come up with very potent PPAR ligands. Just take a carboxylic acid, slap on an aryl group and a greasy tail and Bob's your uncle. If you got non-selective compounds, you just said that was what you were going for and then rationalized the subsequent pharmacology. My theory on the cardio tox is that by screwing with the PPAR pathway, you were affecting energy homestasis in very energy intensive cells. If you cut off their energy supply by one route, nature in its infinite wisdom offered up a redundant pathway for them which usually meant stealing energy from somewhere else, hence the degenerative tox profiles. This was the case for us with PPAR a in the heart and PPAR d in muscle.
Permalink to CommentBTW, just got a PPAR paper accepted by J Med Chem. Really interesting work.
10. NHR_GUY on May 19, 2011 9:07 PM writes...
P.S. I still think there is an excellent PPAR delta drug (mine :) ) somewhere, its just that Big Pharma doesn't have the stomach for this field anymore
Permalink to Comment11. Ed on May 20, 2011 12:47 AM writes...
Pretty sure that either Roche or Novartis still have some PPAR compounds in the clinic - IIRC I saw a presentation last October at the EFMC conference. Think their "thing" / USP was their selectivity profiles, but have no idea how much of that was just after the fact rationalization.
Permalink to Comment12. petros on May 20, 2011 8:51 AM writes...
And of course rosiglitazone actually originated at Beecham in the 1980s, being identified as a PPAR agonist some time later
Permalink to Comment13. Zippy on May 20, 2011 11:12 AM writes...
PPARs are an example of the risks in doing molecular drug discovery where the basic biology is poorly understood. The working components in the cell based assays were not fully defined or controlled, and the machinery in native tissues was less understood. This class may be the all time leader in compounds that failed in safety.
Permalink to Comment14. soydegales on May 20, 2011 6:18 PM writes...
@Zippy
Could not agree more. On that note, it's going to be interesting to see how the myriad kinase programs being pursued out there pan out. Looks very much like another field where it's now comparatively easy to generate and progress leads ahead of understanding/researching the biology.
Permalink to Comment15. Vader on May 23, 2011 1:31 PM writes...
Any thoughts on whether pioglitazone will stay on the market? I would hate to see it pulled.
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