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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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In the Pipeline

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April 4, 2008

Another Cholesterol Medication Goes Down (Or Does It)?

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Posted by Derek

This is turning into Cardiovascular Week around the blog, I have to say, and not in a good way. The latest news is the failure of a drug candidate from Takeda, TAK-475 (lapaquistat). They were in the lead in the field of squalene synthase inhibitors for cholesterol lowering (many other companies have taken a crack at this target, and dropped out along the way)., and their compound once had hopes of being a pretty big deal.

Not any more. In retrospect, the bell sounded late last year, when the company had to stop dosing at their highest level. Elevated transaminase levels were being seen in the treatment groups as the dose went up, which is a sure sign of trouble, as in liver damage trouble. Some investors seem to have held out hope for the compound to show enough efficacy at the lower doses, but Takeda has announced that the safety/efficacy ratio doesn’t justify taking the drug forward.

Liver enzymes are definitely one of those things you worry about when you go into man. There are all sorts of assays that are supposed to give you a read on that problem beforehand, and it’s safe to assume that Takeda ran them. But you’re never sure until you hit humans. Animals can react very differently to some compounds, although that can go either way. But if you set off liver enzyme trouble in rats or dogs your compound is probably dead, no matter how it might act in humans. You won’t get the chance to find out, most of the time.

The alternative is to use human liver tissue, but cultured human liver cells rapidly lose their native abilities and become untrustworthy as a model for the real world. Human liver slices are another alternative, but those are rather hard to come by, as you can well imagine, and the data from them have a reputation for being hard to interpret and hard to reproduce. No, for now, there’s no way to really know what will happen in humans without, well, using humans.

The big question that always gets asked in these failures is whether this is a compound-specific effect, a compound class effect, or a mechanistic effect. Most of the time it’s one of the first two. There are particular compounds, and particular structural series, that are known to be Bad News for liver enzymes. There will be some lingering doubt, though, because there’s plenty of squalene synthase activity in the liver, and it’s not impossible that any compound that hits it could cause the same trouble.

There are a number of other inhibitors out there – interestingly enough, they may have other uses besides lowering cholesterol. For some time, it’s been thought that such compounds might be useful antibiotics, since many bacteria need cholesterol synthesis pathways to survive. And there’s a recent report in Science putting this to the test in a particularly relevant system, particularly virulent strains of Staphylococcus aureus.

The “aureus” part of the name refers to the yellow hue that many strains of the bug exhibit, which seems to be correlated with how nasty they are as an infectious agent. The color comes from staphyloxanthin, a pigment that seems to be used as a defense agent by the bacteria by neutralizing reactive oxygen attacks from a host’s immune system. As the current work shows, the first enzyme in the biosynthetic pathway for staphyloxanthin (known as CrtM) has a lot of structural similarities to human squalene synthase. The authors prepared a number of known squalene synthase inhibitors from the literature, and found that one class of them (the phosphonosulfonates) also inhibit CrtM.

They went further, showing that one of these compounds (a BMS clinical candidate from about ten years ago) actually works quite well as an antibiotic in vitro and in an in vivo mouse model. I'm not sure why this compound didn't go further, but perhaps it (and the others in its class) will have a second life in the antiinfectives world. . .

Comments (8) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Infectious Diseases


COMMENTS

1. Still Scared of Dinosaurs on April 4, 2008 9:25 AM writes...

An important point is that an antiinfective can tolerate a much worse liver profile than a cholesterol lowering agent. It's just that much easier to approve an agent that prohibits alcohol use for 10 days than for the rest of the patient's life. Especially if the patient's life depends on it.

Also, I think we are WAY far away from preclinical tests that will adequately inform us about liver toxicity. The key point - as noted in the original post - is the the benefit/risk ratio. Knowing that an agent tweaks some disease mechanisms positively and some liver mechanisms negatively doesn't get you very far. Knowing whether an MD can manage them in a patient is the issue - and you need patients for that.

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2. DrTapper on April 4, 2008 5:57 PM writes...

So what sorts of assays do people use for predicting liver tox in vitro? I know of CYP inhibition and induction.

Clinical tests are overviewed here:
http://en.wikipedia.org/wiki/Liver_function_tests

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3. Gaudisso on April 4, 2008 9:04 PM writes...

That's two down (ezetimibe and squalene synthase inhibitors) and three to go (CETP inhibitors, microsomal triglyceride transfer protein inhibitors - MTPi, and apolipoprotein B mRNA antisense oligonucleotides). Next up, possibly Roches' CETP inhibitor JTT-503?

I still believe there's a lot of disconnects with the ezetimibe story (its hard to dismiss a drug which lowers LDL-cholesterol and CRP, but failed to positively modify a carotid plaque surrogate endpoint), but I think the market will move on to focus on these next groups of lipid lowering compounds.


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4. Morten on April 5, 2008 4:01 AM writes...

Can't you just buy half a liver in India - like a kidney? Or would that be unethical? ;)

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5. milkshake on April 5, 2008 5:17 AM writes...

The meanest comlication is a sporadic liver tox that is not dose-related, does not appear in animal models and shows up suddenly in 1 out of 300 patients. At such frequency you have a decent chance of not noticing it until phase III.

The you can have never-ending discussion whether the problem is mechanism-based or whether a new series with chaged profile/PK/selectivity might work the next time around.

There was so much money put into p38 projects, by almost every major company - and still no drug came out of it/

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6. Petros on April 6, 2008 1:01 PM writes...

Milkshake mentions the p38 inhibitors. But there is still a stack of these ind evelopment. And while gossip about their liver tox problems is widespread, has anyone actually publicly admitted this to be the key issue in any case (of those that made the clinic)?

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7. price comparison on April 22, 2008 6:51 PM writes...

I certainly hope that not just this particular drug, but any drug that helps lower cholesterol gets out in the market.

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8. Matt on June 15, 2008 5:09 PM writes...

I am strongly against the use of statins to reduce choleterol, It can be done much more safely using magnesium, water, and excersise. I would highly suggest any one worried about this topic to check out this article Magnesium and Walking Will Always be Superior to Lipitor

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