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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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November 19, 2010

Merck's CETP Compound: Still Alive, But The Big Fun Awaits

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Posted by Derek

Four years after the torcetrapib disaster, Merck has released some new clinical trial data on their own CETP inhibitor, anacetrapib. It's doing what it's supposed to, when added to a statin regimen: decrease LDL even more, and strongly raise HDL.

So that's good news. . .but it would actually be quite surprising if these numbers hadn't come out that way. Pfizer's compound had already proven the CETP mechanism; their compound did the same thing at this stage of the game. The problems came later, and how. And that's where the worrying kicks in.

As far as I know, no one is still quite sure why torcetrapib actually raised the death rate slightly in its phase III treatment group. One possible mechanism was elevated blood pressure (part of a general off-target effect on the adrenals) and Merck saw no sign of that. But no matter what, we're going to have to wait for a big Phase III trial, measuring real-world cardiovascular outcomes, to know if this drug is going to fly, and we're not going to see that until 2015 at the earliest. Well, unless there's unexpected bad news at the interim - that, we'll see.

I hope it doesn't happen. If the whole LDL-bad HDL-good hypothesis is correct, you'd think that a CETP inhibitor would show a strong beneficial effect. This compound is either going to help a lot of people, or it's going to tell us something really significant that we didn't know about human lipid handling (and/or CETP). Problem is, telling us something new is almost certainly going to be the same as telling us something bad. It's still going to be a long road in this area, and good luck to everyone involved. . .

Comments (17) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology


COMMENTS

1. mad on November 19, 2010 11:12 AM writes...

Elevated blood pressure? If this is their best guess for incresed COD then the really dont know whats goin on...

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2. anchor on November 19, 2010 11:22 AM writes...


Waiting until 2015 is a long time and lot of things can go wrong for any drug on a clinical trial. Longer the trial drags on more bad information about the drug also begin to surface... Not sure if this is a good news or not for Merck.

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3. Rock on November 19, 2010 11:36 AM writes...

In simplistic terms, here is my issue with using CETP for raising HDL: HDL is considered "good cholesterol" since the lipoprotein takes cholesterol from tissues and returns it to the liver through VLDL and LDL. CETP blocks that transfer, hence cholesterol builds up in HDL particles resulting in higher HDL levels. That is, the same number of HDL particles loaded with more cholesterol, not more particles capable of removing more cholesterol from tissues. I view HDL as pay-loaders, taking cholesterol from vessel walls, then dumping it into the 'dump trucks' VLDL and LDL which in turn empty into the liver in a continuous cycle. If you block the ability of the pay-loaders from dumping their cholesterol into VLDL, yes you will have more cholesterol in HDL particles, but they will be unable to perform their main protective function. There is some evidence in animals and humans to the contrary, but this is the reason CETP had been controversial years ago as to whether you want to block it, or activate it. I am still not convinced which would be best.

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4. LipidHead on November 19, 2010 12:41 PM writes...

I kind of agree with Rock here - if one simply had more HDL particles of all sizes or better yet, little particles that were very "hungry", then that would clearly be anti-atherogenic. But by making little HDL's swell up to big HDL's, that I'm not so sure about. HDL is serving a function and is not an end in itself. Having said that, what do we know about populations studies with different CETP functions? I am a little familiar with hepatic lipase which to me is somehow similar in function to CETP and people who have very weak heaptic lipase function have high HDL but not better outcomes and possibly worse. One also has to keep in mind the function of the statin because all these processes are ideally coupled together to make a really good working machine. It will be interesting. My guess is that it will at best show a very modest benefit and much less than the numbers would predict. I hope not though, I am looking forward to taking these drugs as I get older!

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5. mad chemist on November 19, 2010 4:08 PM writes...

One of my former supervisors bragged to me about how low his cholesterol levels were from his last blood test. I snapped back "That's because it's all stuck to your arteries!".

I'm not sure where exactly that rather callous response was born in my organic solvent-rotted brain, but sometimes have wondered if it has some strange relevance. What disturbs me most is the statistical tendency for MI victims to present with very low cholesterol levels. The cholesterol theory never really impressed me that much....I know really old people with significantly-elevated cholesterol that never had any thrombotic events.

Do we really know yet the cause & effect relationship? Send your opinions....

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6. frequent visitor on November 19, 2010 10:21 PM writes...

What Rock and Lipidhead put forward is very probable scenario to what is actually occurring. I know little about the actual distribution of these compounds, but from what Rock and Lipidhead say implies that the HDL particles should be expressed more by CETP; may not be.

It would seem to me that this function should be measured through an enumeration-type assay rather than concentration type, which is what is most common (e.g. any absorbance assay can tell you the amount of bits that absorb, but the not the amount of bits in a particle). I am not familiar with these assays, so if I am way off, please shoot me down. But it makes sense that if 2 drugs fail that get to phase III, the gauge to measure them is somehow off.

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7. Aleck Alexopoulos on November 20, 2010 8:27 AM writes...

The point that Rock makes is right on.
Id like to add another.
The whole HDL/LDL hypothesis is bogus!
Cholesterol is produced and directed to tissues to
repair cell membranes. IF you decrease LDL you're impairing this process leading to leaky membranes and I guess increased cancer risk. Evidence for this are all the large clinical trials with statins which show a modest decrease in CVD risk yet no change in total mortality.
Is this just a fringe "conspiracy theory" opinion?
No, low cholesterol levels have been associated with increased cancer risk. Even mechanisms have been proposed, e.g., the "leaky" membrane hypothesis.
Also, even mainstream medical literature are now voicing their concerns over abuse of statins. Low cholesterol levels lead to decreased lipid rafts in the membrane which can lead to impaired assembly of membrane proteins.

What do you prefer, a modest reduction in CVD (1-2% absolute risk) or proparly functioning cell membranes throughout your body?

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8. ronathan richardson on November 20, 2010 9:14 AM writes...

So if some of the commenters here are correct, and this drug won't help as much as the biomarkers suggest, then cardiovascular drug discovery is going to be flipped on it's head. But my question is, how much will the FDA take into account risk of death/number of heart attacks and serious symptoms vs HDL/LDL biomarkers in reviewing this drug? What if p=0.10 for survival or hospitalizations, but p

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9. Kismet on November 20, 2010 4:31 PM writes...

@Aleck Alexopoulos
Citations?
The cancer association may very well be due to reverse causality. I will taken proven CVD benefits over putative cancer risks.

@mad chemist
cross-sectional analyses are terribly weak evidence, that is why we use prospective epidemiology.
The old, sick and dying tend to have low cholesterol. Guess why? Because many diseases lower cholesterol levels before they develop and because sick people will actually receive lipid lowering therapy.

A prospective study will catch the fact that low cholesterol does not predict those diseases (with few exceptions), a cross-sectional analysis won't.

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10. Kismet on November 20, 2010 4:40 PM writes...

I almost forgot, can anyone tell me where the lies and misconceptions about statins originated? E.g. claims that they do not help women, the young, elderly or reduce all-cause mortality?

The mortality claim is patently false, the others may stem from people misunderstanding subset analysis (or perhaps it is my bad understanding, but I doubt it)

see:
BMJ. 2009 Jun 30;338:b2376. doi: 10.1136/bmj.b2376.
The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials.

Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, de Craen AJ, Knopp RH, Nakamura H, Ridker P, van Domburg R, Deckers JW.

Permalink to Comment

11. Anonymous on November 20, 2010 5:44 PM writes...

Derek,

Here is a recrent news story about a Cell article on Sirt 3:

"IN A major breakthrough a team of US scientists said today that they are a step closer to developing drugs that may arrest the ageing process and extend life span.

Researchers from the University of Wisconsin-Madison said they have uncovered a molecular pathway that is a key determinant in how fast people age.

They said their findings not only help explain the events that contribute to getting old but also provide a basis for devising interventions and drugs that may retard ageing and contribute to better health in old age.

The Daily Express newspaper in Britain said the discovery could pave the way for drugs that help all people to live well beyond 100.

"We’re getting closer and closer to a good understanding of how caloric restriction works," said Tomas A Prolla, a UW-Madison professor of genetics and a senior author of the new study, in a press release. "This study is the first direct proof for a mechanism underlying the anti-ageing effects we observe under caloric restriction."

[ I thought there was a big story on Sirt 3 last year as well. Anyway, more below]

http://www.theaustralian.com.au/news/breaking-news/us-scientists-move-step-closer-to-developing-drugs-that-arrest-the-aging-process/story-fn3dxity-1225956574684

Permalink to Comment

12. Anonymous on November 21, 2010 12:10 AM writes...

I have serious doubts about the cholesterol hypothesis, and question whether it has any real bearing on vascular disease, at least outside of various hereditary disorders associated with extremely high levels (which is no doubt where the whole concept originated). Statins may be beneficial, but likely due to their other effects, not cholesterol level modification. And as mentioned by others above, I have severe reservations about this new class of drugs based on their mechanism of action. FWIW, this is coming from a board certified internist.

Permalink to Comment

13. Aleck Alexopoulos on November 21, 2010 2:16 PM writes...

Some examples of changes in total mortality reported from Statin clinical trials:

Trial prevention Absolute
Risk
4S secondary -3.3%
WOSCOPS prim/sec -0.9%
>7mmol/l
EXCEL primary +0.3%
CARE -0.78%
AFCAPS +0.09%

Usually the studies that present the largest decreases in CVD risk and statistiacally significant decrease in total mortality are those related to patients with pre-existing disease or very high levels of cholesterol or diabetic patients.

I think that the safest conclusion is that statins do not change overall mortality except
in those with pre-existing CVD (e.g., 4S trial).

What bothers me as an "outside observer" (I'm a biomedical engineer) is how much statins are trumpeted and marketed compared to the actual clinical trial results.

Even in journal papers the results are presented in a biased manner. For example the reduction in CVD risk is presented in relative terms, e.g., relative risk and described is "significant" or "astounding" or such. The increase in deaths due to other causes which is equal in terms of absolute risk is presented as "minimal" or "insignificant".
Common guys!
Either both are significant or both are insignificant. Bottom line is that total mortality hardly changes at all.

I predict (i'm optimistic...) that in the future statins will only be given to those with a true risk (unrelated to lipid status) probably determined by plaque vulnerability.
Also that statins will be provided in a targeted manner maybe part of a multi-drug therapy.

As for the effect of low-cholesterol on lipid raft formation and membrane protein assembly
here is a review paper.

"Cholesterol-lowering therapy and cell membranes. Stable plaque at the expense of unstable membranes?"
Glyn Wainwright, Luca Mascitelli, Mark R. Goldstein
Arch Med Sci 2009; 5, 3: 289-295

I think its a good (and courageous) paper but I doubt it will receive many citations....

Permalink to Comment

14. Morten G on November 21, 2010 3:59 PM writes...

For the Sirt3 story at least include a link to the real article: http://download.cell.com/images/edimages/Cell/cell5364.pdf

It is a very good paper but it'll probably be tricky to design a drug that activates Sirt3 or IDH2. Good structural information available for Sirt3 though.

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15. MTK on November 22, 2010 7:32 AM writes...

Aleck,

You seemingly do not know what "significance" means in a statistical study.

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16. Kismet on November 22, 2010 10:23 AM writes...

What are your selection criteria? Why only so few studies?(could it be confirmation bias?)

From the op. cit. meta-analysis of *primary-prevention* trials 5 showed significant (or borderline significant) reductions in mortality netting a significant overall effect:

WOSCOPS*
AFCAPS/
TexCAPS
PROSPER
ALLHAT-LLT
ASCOT-LLA*
HPS
CARDS*
ASPEN
MEGA*
JUPITER*

Please address the differences in methodology or direct us to a critical review.

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17. Nick K on November 18, 2011 4:06 PM writes...

17 immobilier: Si l'immobilier est ta "plus grande passion", qu'est-ce que tu fais ici, alors? Ici, c'est un blog sur l'industrie pharmaceutique. Vas-t'en!

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