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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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August 9, 2004

Fast, Cheap, and Sometimes Even Good

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Posted by Derek

The New York Times has a good article this week on a trend in clinical trials that's been developing for several years - small intensive trials in humans, run before giving the go-ahead for the real thing.

It makes a lot of sense, but only when you can use it to ask (and answer) the right questions. That's where technologies like functional NMR imaging or PET scans come in, because they allow you access to in vivo data that's otherwise unobtainable. Take, for example, the studies mentioned in the Times article, where they look at glucose uptake in a solid tumor. That's a reasonable proxy for its metabolic activity, as you'd guess, and it'll give you a quick read on whether your targeted cytotoxic compound is having the effect you want.

What you'd do, normally, is dose the compound for days or weeks, then use NMR or another imaging technique to see if the tumor has changed size. That's clearly a more convincing answer, but it takes a more convincing amount of time and money to get it. And if your compound isn't having an effect on a fast marker like the tumor's metabolic rate, it's probably not going to have any effect after you dose it for two months, either. You're better off trying something else.

But if your new cancer therapy is, say, a compound that interferes with cell division, then you're not going to have that clear an answer through that glucose uptake technique. Same problem if the cancer you're treating is a more diffuse one like leukemia, because there's not such a clear tissue to image. (There are other approaches to each of those problems, naturally, but I just wanted to emphasize that each clinical trial is its own set of new problems, even inside the same general therapeutic area.)

And even when you get to the traditional large-scale trials, there's a huge need for surrogate markers that can show progress against slow-moving diseases. Glycosylated hemoglobin as a measure of efficacy in diabetes is a good validated example. It still takes quite a while to establish (weeks or months of dosing), but that's like lightning compared to the progress of diabetes complications themselves. You can do a quick assay in this field - the oral glucose tolerance test - but the improvement in that assay isn't so quick to come on.

The CNS diseases are a real clinical challenge, which is why their trials are so brutally expensive. There are hardly any markers at all for most of them. Everyone would love to have a short-term noninvasive readout for Alzheimer's, but despite years of effort, no one has quite made it. (And that's despite the definition of "short-term" in Alzheimer's is rather permissive.) Similarly, it would be good to be able to get a faster readout on depression, whose therapies are notorious slow starters.

There's a bigger problem, though, looming over some of the generally accepted markers - what effect do they really have on long-term mortality and morbidity? Glycosylated hemoglobin has been pretty well correlated in diabetes over the long term, so that one's pretty safe. But the question is worth asking, for example, about HDL and LDL levels. Yes, things do line up well, up to a point. But does long-term administration of statin drugs, say, help as much as we'd like to hope it does over, say, twenty years? The jury's still out on that one.

Comments (5) + TrackBacks (0) | Category: Clinical Trials


1. Clark on August 10, 2004 9:11 AM writes...

Quick note on HDL, LDL and Statins. Just FYI there is some good, but not yet conclusive, data that says statins effect on heart attack incidence is much more heavily related to its anti-inflamation effects than its LDL lowering effects. (e.g. an interesting article by some Japanese researchers who found the amount of atherosclerosis slowing was highly correlated to the change in CRP after statin initiation, but minimally correlated to change in LDL after statin initiation). Just a case in point that surrogate markers are very tricky things - even when they are 'accepted' science.

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2. Chris on August 11, 2004 10:58 AM writes...

Glycosylated hemoglobin? I think you mean *glycated* hemoglobin, hemoglobin A1c. Glycosylation is a different, enzymatic process which occurs during protein synthesis which adds sugar chains to asparagine (N-linked) or serine or threonine (O-linked) residues.

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3. Chris on August 11, 2004 11:03 AM writes...

From the JCBN/NC-IUB Newsletter 1984 [1]
Several authors are improperly using the terms 'glucosylated (or glycosylated) hemoglobin', 'protein glucosylation (or glycosylation)', etc. to refer to the products of nonenzymic reactions between glucose or other sugars and free amino groups of proteins. The compounds so formed are not glycosides, however, but result from the formation of a Schiff's base followed by an Amadori rearrangement. For example, the product of the reaction between glucose and hemoglobin is not glucosylated hemoglobin but an amino linked 1-deoxyfructose derivative of hemoglobin. We suggest the term 'glycation' for any reaction that links a sugar to a protein, whether it is catalysed by an enzyme or not. Thus glycation includes glycosylation as a special case. The product of glycation is a glycated protein, or, in the particular case of the reaction with hemoglobin, glycated hemoglobin.

1. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN), and Nomenclature Commission of IUB (NC-IUB),.Newsletter 1984, Arch. Biochem. Biophys., 1984, 229, 237-245; Biochem. Internat., 1984, 8, following p 202; Biochem. J., 1984, 217, I-IV; Biosci. Rep., 1984, 4, 177-180; Chem. Internat., 1984(3), 24-25; Eur. J. Biochem., 1984, 138, 5-7; Hoppe-Seyler's Z. Physiol. Chem., 1984, 365, I-IV; Trends Biochem. Sci., 1984, 9, various issues.

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4. Derek Lowe on August 11, 2004 3:23 PM writes...

Yep, HbA1c is what I'm referring to. You're right that I really should call it "glycated" - I and my fellow drug discovery people are some of the ones who have fallen into the casual usage of "glycosylated." I did carbohydrate-based chemistry during my PhD, so I'm sensitive to the difference.

In my defense, though, I note that a Google search for "glycated hemoglobin" pulls up about 11,600 documents, while a search for "glycosylated hemoglobin" has more than twice that number. So the error is widespread.

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5. Brent M Krupp on August 11, 2004 8:53 PM writes...

Regarding glycosylated vs. glycated, I'd add that pretty much everyone at my medical school and most of the doctors I worked with as an intern said "glycosylated". A few endocrinologists (i.e. diabetes docs) and anal retentives would say "glycated" and take some delight in correcting people. Being one of the latter, I'd do it too. This was 5+ years ago, but I suspect not much has changed.

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