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Bungee Jumping with PPAR Drugs

The PPAR family (known in the US as alpha, gamma, and delta, for obscure historical reasons) is one of those biological jungles that keep us all employed. They’re nuclear receptors, and thus they’re involved in up- and down-regulation of hundreds of genes. Like most of the other nuclear receptors, they do that by responding to small molecules, which makes the whole class a unique opportunity for medicinal chemists.
Normally, we can’t do much about gene regulation, because it’s all handled by huge multicomponent protein complexes, terrible and unlikely candidates for intervention with our drug molecules. But when the whole thing is set off by binding of a small ligand, well, that’s all the invitation we need. To pick a well-known class of small ligands, the best-known members of the NR superfamily are the steroid receptors, which should give you some idea of how powerful these things can be.
For their part, the PPARs are all major players in cellular energy balance and fuel use, the handling of fatty acids and other lipids, the generation and remodeling of adipose tissue, and similar things. That lands them squarely in some very important therapeutic areas such as diabetes, obesity, and cardiovascular disease. But more recently, it’s become clear that they’re also involved in things like inflammation and carcinogenesis, which brings in another huge swath of the drug industry. Every large drug company is working on them, for one indication or another. Heck, you could run an entire drug company on nothing but PPAR-related targets, that is, if you weren’t terrified by the insane risk that you were taking.
Problem is, the biology of nuclear receptors is powerfully complex and murky. We know a lot more about them than we did five or ten years ago, but it’s obvious to everyone in the field that we still have very little idea of what we’re doing. Take a look at the three PPARs: there are two diabetes drugs on the market that target PPAR gamma (Avandia and Actos, aka rosiglitazone and pioglitazone), but no one has been able to get anything significantly better or safer than either of those. PPAR alpha is supposed to be the way an old class of lipid lowering drugs (the fibrates) work, but no one’s really sure that they believe that. Several companies have been working on PPAR alpha drugs for a long time now, and nothing’s made it deep into the clinic yet, which isn’t a good sign. And no one really knows what PPAR delta does – it seems to have something to do with lipid levels, and something to do with wound healing, and something to do with colon cancer. The clues are rather widely scattered.
I’ve mentioned that several companies have been working on combination diabetes drugs that would hit both PPAR gamma and alpha. The idea is that they’d do all the glucose lowering of a gamma-targeted drug, and lower lipid levels at the same time – a worthy goal for the typical overweight Type II diabetic patient. But Novo Nordisk, racing along with a compound they licensed from India’s Dr. Reddy’s (the evocatively named ragaglitazar) hit the banana peel when long-term rodent testing showed that the compound was associated with bladder cancer. Then Merck, which had a compound from Japan’s Kyorin in advanced trials, pulled it when another rare cancer showed up in long-term rodent studies. Screeching halt, all over the industry.
Now the FDA has jumped in, with a requirement that any new PPAR drugs go through two-year rodent toxicity testing. That’s an unusual requirement, but (as the two examples above show) it’s something that companies were already doing on their own initiative. Bristol-Meyers Squibb and AstraZeneca have already done theirs, for example, and are plowing on.
The feeling has been: no one really knows what to expect from new PPAR compounds, so you’d better test the waters extensively. The thought of putting a compound on the market that turns out – years later – to be linked to increased risk of something like bladder cancer is enough to give everyone nightmares. I should mention that nothing bad has been seen from the two marketed PPAR gamma compounds I mentioned. But everyone remembers that there was another one, troglitazone, the first to market and the first to be pulled. It showed liver toxicity, but that seems to have been compound-related rather than mechanism-related.
Here’s an article from Forbes on the subject, one of the few outlets that covered this story in any detail. It’s pretty good, although it glosses over a lot of things. For example, the article quotes Ralph DeFronzo of UT-San Antonio saying that the fibrate drugs have been targeting PPAR-alpha for years, so why is the FDA worried about that subtype? What that ignores is that the fibrates are actually very weak drugs at alpha, which is why I mentioned the doubts people have about the whole mechanism. The drugs being developed now are thousands of times more potent. And look at the alpha-gamma combinations: why did all the trouble start only when alpha was added to the mix?
Well, we’ve got plenty of work to do. Unraveling the biological effects of the PPARs is going to take many, many years. And we’re going to have to do it in rodents, in dogs, and in humans, at the very least – all the major species that are tested for toxicity. We already know about some significant differences between the species in the way that these nuclear receptors work. Will these cancer problems be another one? Are humans going to be just fine? Or will we react in even worse ways, given enough time? We just don’t know. Everyone’s holding their breath, waiting to see what comes next. . .

2 comments on “Bungee Jumping with PPAR Drugs”

  1. Is that Dr. Reddy’s of patent-busting fame?

  2. Derek Lowe says:

    Yep, that’s them. Those guys and Ranbaxy have been famous for their patent-breaking skills, but now that India’s easing its way into the rest of the world’s IP framework, they’ve been turning themselves into drug-discovery companies.
    They’ve been quite productive, which makes sense when you consider the number of skilled Indian chemists and biologists out there. . .

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