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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: Twitter: Dereklowe

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May 1, 2009

Niacin, No Longer Red-Faced?

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Posted by Derek

One of Merck’s less wonderful recent experiences was the rejection of Cordaptive, which was an attempt to make a niacin combination for the cardiovascular market. Niacin would actually be a pretty good drug to improve lipid profiles if people could stand to take the doses needed. But many people experience a burning, itchy skin flush that’s enough to make them give up on the stuff. And that’s too bad, because it’s the best HDL-raising therapy on the market. It also lowers LDL, VLDL, free fatty acids, and tryglycerides, which is a pretty impressive spectrum. So it’s no wonder that Merck (and others) have tried to find some way to make it more tolerable.

A new paper suggests that everyone has perhaps been looking in the wrong place for that prize. A group at Duke has found that the lipid effects and the cutaneous flushing are mechanistically distinct, way back at the beginning of the process. There might be a new way to separate the two.

Niacin’s target seems to be the G-protein coupled receptor GPR109A – and, unfortunately, that seems to be involved in the flushing response, since both that and the lipid effects disappear if you knock out the receptor in a mouse model. The current model is that activation of the receptor produces the prostaglandin PGD2 (among other things), and that’s what does the skin flush, when it hits its own receptor later on. Merck’s approach to the side effect was the block the PGD2 receptor by adding an antagonist drug for it along with the niacin. But taking out the skin flush at that point means doing it at nearly the last possible step.

The Duke team has looked closely at the signaling of the GPR109A receptor and found that beta-arrestins are involved (they’ve specialized in this area over the last few years). The arrestins are proteins that modify receptor signaling through a variety of mechanisms, not all of which are well understood. Wew’ve known about signaling through the G-proteins for many years (witness the name of the whole class of receptors), but beta-arrestin-driven signaling is a sort of alternate universe. (GPCRs have been developing quite a few alternate universes – the field was never easy to understand, but it’s becoming absolutely baroque).

As it turns out, mice that are deficient in either beta-arrestin 1 or beta-arrestin 2 show the same lipid effects in response to niacin dosing as normal mice. But the mice lacking much of their beta-arrestin 1 protein show a really significant loss of the flushing response, suggesting that it’s mediated through that signaling pathway (as opposed to the “normal” G-protein one). And a known GPR109A ligand that doesn’t seem to cause so much skin flushing (MK-0354) fit the theory perfectly: it caused G-protein signaling, but didn’t bring in beta-arrestin 1.

So the evidence looks pretty good here. This all suggests that screening for compounds that hit the receptor but don’t activate the beta-arrestin pathway would take you right to the pharmacology you want. And I suspect that several labs are going to now put that idea to the test, since beta-arrestin assays are also being looked at in general. . .

Comments (9) + TrackBacks (0) | Category: Biological News | Cardiovascular Disease | Toxicology


1. hell to the chief on May 1, 2009 10:53 AM writes...

"A group at Duke has found that the lipid effects and the cutaneous flushing are mechanistically distinct, way back at the beginning of the process. There might be a new way to separate the two."

Yes, and so did the joint group at Merck and Arena over 2 years ago! Lefkowitz barely gives them a mention though, despite using their clinical candidate to prove his claims!
It's a very cool story though and recognition that there is such a thing as differential GPCR signalling will become increasingly important in the future but nothing is as simple as you may think. If you check the literature on MK-0354, you will find that it lowered free fatty acids in the clinic and was indeed pretty well flush free, but it failed to raise HDL.

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2. Jan on May 1, 2009 4:10 PM writes...

Interesting blog! i am a newbee so please.

Take a look at Karo Bio. Maybe you can comment on what you think the chances are for success.

I am waiting for a publication of the result Eprotirome 2115, could be NEJM in near future.

20 pharma where interested in the beginning, now there are a couple or 5 BP left doing due dilligens on the company and Eprotirome 2115.

Fas3 is planned with partner and FDA before Q2.

I am a small shareholder, and i would be glad if you or someone with this knowlidge and can do some comment.

I know that the results show that Eprotirome combined with statin doesnt increase hdl but lower ldl. and with low does of statin.

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3. Paul S on May 1, 2009 7:41 PM writes...

For what it's worth, I'm a regular niacin user. And I've found that if you can tough it through the first few flushes, a tolerance builds to them and they become much less troublesome.

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4. Muruga on May 2, 2009 1:49 AM writes...

It looks like that Niacin works through both GPR109A-dependent and independent pathways to bring down the global lipid profile. Hence, even if we identify a ligand, which selectively modulates GPR109A signalling without any activation on beta-arrestin 1 pathways, it may not be efffective clinically in terms of lipid modification. The failure of MK-0354 is, indeed, a clear example. So, the discovery of a drug that has an effective lipid-modifying benefit without causing flusing is a challenging task.

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5. Frank on May 2, 2009 8:44 AM writes...

I agree with 'Hail to the chief'

This JBC paper from Arena/Merck is what really nails down this approach. They use receptor internalization/ERK activation as the marker rather than arrestin. Making the leap to arrestin- is certainly not a work of genius at this point- and is essentialy the most obvious direction to anyone schooled in the GPCR field.

This GPR109A story is really the one solid piece of evidence for biased agonism/functional selectivity/arrestin-selective signalling (what ever you want to call it).

I would caution that many of the other examples of arrestin selective signalling do not hold up when you leave overexpression/cell culture paradigms (or do not even hold up if you perform rigorous pharmacology).

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6. lynn on May 2, 2009 5:08 PM writes...

I take niacin and remain flush-free if I take a baby aspirin (which I do anyway) 30-45 minutes before. It's what my doctor recommended, it works and it doesn't take a big drug discovery effort :-), And the flushing can be pretty darn awful. However, the science is interesting.

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7. Bored on May 7, 2009 9:19 PM writes...

I've experienced the "niacin flush." It was hellish. Forget waterboarding, give the prisoners in Gitmo a good healthy dose of the stuff, and I bet they'll spill the beans. Is vitamin overdose torture? :)

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8. MedResearcher64 on May 8, 2009 9:18 AM writes...

Actually, I do not understand the continuing hoopla surrounding HDL raising as a CV target. It is true that evidence from retrospective and prospective epidemiologic studies suggests that higher serum levels of HDL are independently associated with a lower incidence of heart attack and stroke. However, It has never been rigorously proven that a therapeutic agent that has as its sole effect, therapeutic raising of serum HDL in persons with low serum HDL, reduces the incidence of heart attack and stroke. Epidemiologic studies, even when prospective, simply cannot prove causality. HDL may be only a marker for something else that is actually causal. Proving cause will take randomized intervention studies in persons with low baseline serum HDL.

Niacin is an agent that both lowers serum LDL and raises serum HDL. Its effect on serum C-reactive protein has not been documented. Moreover, intervention studies using niacin cannot address this question, because of its multiple therapeutic effects on the lipid profile. The benefits of therapeutically reducing serum LDL are well-known. Any niacin benefit could easily be attributed to LDL lowering.

To understand the effect of therapeutically raising serum HDL, one must study a purpose-made agent such as Pfizer’s torcetrapib that only raises serum HDL. In fact, torcetrapib treatment of persons with low HDL increased mortality. The whole story is made more complex by the fact that HDL raising therapy is often conceived of as add-on treatment to approved LDL lowering treatment.

Branded niacin therapy with improved tolerability, even if it “works” in outcomes studies (and it must, to be approved!) and has no side effects from the anti-flushing agent, will probably be reserved for those who do not tolerate statins. Now, that's a niche market.

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9. nicholson on November 2, 2010 7:30 AM writes...

Inhibiting COX enzymes before dosing nicotinic acid (lyn)to eliminate the flushing reflex has to be an enormous clue.

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