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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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« And Now A Word. . . | Main | What We Are Pleased to Call State of the Art »

January 23, 2005

A Trial Too Far

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Posted by Derek

So Johnson and Johnson is the latest company to try to broaden their market for a drug and run into cardiovascular side effects. Their Alzheimer's drug Reminyl (galantamine), makes some money, but is hardly a blockbuster. It's a natural product (derived from daffodil bulbs, of all things), and it's a cholinesterase inhibitor, the same mechanism as the two other Alzheimer's drugs on the market. None of them are gigantic sellers, because they don't do all that much for people, especially once they have serious symptoms. But if you could show beneficial effects in the pre-Alzheimer's population, then the potential number of patient could be much larger. I should, in fairness, point out that the potential benefits to the patients could be larger, too: earlier treatment before the disease has had more time to do irreversible damage.

Cholinesterase inhibition is a pretty crude tool to help Alzheimer's, but it's all that we have at the moment. The idea is the turn up the volume of neuronal signals that use acetylcholine as a transmitter molecule, by inhibiting the enzyme that would break it down and sweep it out of the synapse. I don't see an obvious connection between this mechanism and the cardiovascular effects that showed up in J&J's trial.

This is another illustration of the same thing that's bringing down the COX-2 inhibitors. The larger the population that takes your drug, and the more clinical trials you run, the better your chance of finding the side effects. All drugs have side effects, and if you turn over enough rocks you'll see them. But without expanding the patient population, you won't be helping all the people you could help, and you won't be making all the money you could make. It's like walking through a minefield. It's what we do for a living over here. What a business!

Comments (7) + TrackBacks (0) | Category: Alzheimer's Disease | Toxicology


1. David Govett on January 23, 2005 9:27 PM writes...

I realize there is demand from desperate people, but time and again it seems promising drugs have intolerable side effects in clinical trials. Perhaps our understanding of human physiology is too primitive for the development of efficacious drugs. Shouldn't there be more emphasis on modeling the entirety of human physiology, so as to be able to predict deleterious side-effects?

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2. Bill Kargo on January 24, 2005 1:17 AM writes...

"The idea is to turn up the volume of neuronal signals that use acetylcholine as a transmitter molecule, by inhibiting the enzyme that would break it down and sweep it out of the synapse." I think early stages of AD are characterized by a more-or-less selective reduction in the number/functioning of cells in a brain area called the Nucleus Basalis of Meynert. Large cells in the NBM are the main supply of acetylcholine (Ach) to the cerebral cortex and hippocampus. If NBM cells are experimentally lesioned (e.g. in animal models), there are clear behavioral deficits, e.g. in memory formation, memory retrieval, and attention, and the (downstream) cortical plasticity associated with new learning is blocked. Thus, if a small population of NBM cells is still functional, AchE inhibitors should amplify Ach levels in the cortex and hippocampus in response to the discharge of these remaining NBM cells. The enhanced levels should improve attention and cognitive functioning in early AD, when the receptive brain areas are still 'healthy'. A biq question though is whether higher Ach levels will also prevent or delay later stages of AD, which are characterized by more widespread anatomical changes (i.e. plaques, tangles and degeneration in other brain areas). Some people believe that there may be a connection between the loss of plasticity (e.g. the synaptic or cellular events enabled by the presence of Ach) and the progression of AD, but I don't think it's very clear at all. It may be that NBM cells are more sensitive, for some reason, and die off first and other more resistant brain areas follow suit. I think it's pretty clear that raising Ach levels does not stop the ultimate progression of AD (I don't even know if AchE inhibitors delay it), but they should improve cognitive functioning in early AD and therefore improve quality of life at least for a brief period. I just don't know if these potential, short improvements outweigh the cardiovascular risks (Is there any equation out there to determine such a thing?). Oh, by the way, it looks like some companies are developing drugs for ADHD that also increase Ach levels in the cortex (e.g. H3 receptor antagonists and modafinil). Maybe J&J should further broaden the market for their AchE inhibitor by testing it on an ADHD population. This seems to be the norm for neuro-pharmacologics (re-usability), but might not be such a bad thing.

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3. Derek Lowe on January 24, 2005 10:35 AM writes...

I think that cholinergic treatments for AD are merely stopgaps, and probably not very good ones. I spend some time ten or fifteen years ago in a group looking for selective m1 agonists, which was a fool's errand, and then several more years making selective m2 antagonists. That at least had a more interesting idea behind it, but I don't think it ever resulting in any clinical success (I left before the story ended.)

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4. Daniel Newby on January 24, 2005 2:05 PM writes...

"Shouldn't there be more emphasis on modeling the entirety of human physiology, so as to be able to predict deleterious side-effects?"

It takes a lot of computer time to calculate how a single protein behaves in isolation. Modeling trillions of complex chemical interactions with meaningful accuracy is pretty much impossible.

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5. David Govett on January 24, 2005 3:13 PM writes...

@Daniel Newby
I realize the impossibility of predicting every possible interaction in every human cell, that's why it's called a model. However, from the research and clinical trials I've seen--I work as a translator of Japanese biotech documents--no metasystemic modeling is used. Computer grids like that used by SETI@home would allow complex, albeit slow systemic modeling.

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6. michael on January 24, 2005 5:37 PM writes...

I'm on the other side of the fence from David Govet. I don't think the Government should try to coddle me. Doing so means the government decides what an acceptable risk is. Since we all have different risk thresholds, there isn't any way that the government can effectively dictate what level of risk is "reasonable."

The reality is that drugs have side effects. The mass polio immunizations when I was a kid more than likely killed some kids. On the other hand, most of us benefited by not catching polio.

In my perfect world, the FDA's role would be solely one of data gathering and reporting. Want to know what the chance of having a heart attack when you take a medication? Go to the FDA's website and look it up. If that number got so high that people figured it wasn't worth taking the medication (the cure is worse than the disease) they'll stop taking it and it'll disappear from the market. This idea that the government should protect me from side effects has a stifling effect that I'm not at all convinced is for the good. There'll never be perfect drugs and the FDA shouldn't pretend that it can find them by witholding its imprimatur. Just give people the facts and let them make up their own mind as to what's "acceptable."

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7. Jeet on January 25, 2005 1:03 PM writes...

Or a trial not allowed.

This (from biospace) is terrible. Now, I'm all for patent protection in the industry as there are a number of factors than make drug development very reliant on IP. And, of course, it isn't clear what TKT is infringing on.

Still, in an industry that is PR challenged to say the least, this is terrible.

Genzyme Corporation (GENZ) Files Suit Against Transkaryotic Therapies, Inc. (TKT) (TKTX) For Glucocerebrosidase Patent Infringement; Sues To Halt TKT Gaucher Trial

CAMBRIDGE, Mass., Jan. 24 /PRNewswire-FirstCall/ -- Transkaryotic Therapies, Inc. (Nasdaq: TKTX - News) today announced that Genzyme Corporation has filed suit against TKT in the District Court of Tel-Aviv-Jaffa but not yet formerly served process on TKT. The suit claims that TKT's Phase I/II clinical trial evaluating its investigational Gene-Activated® glucocerebrosidase (GA-GCB) for the treatment of Gaucher disease infringes one or more claims of Israeli Patent No. 100,715. In addition, Genzyme filed a motion for preliminary injunction, including a request for an ex parte hearing and relief on the merits, to immediately seize and destroy all GA-GCB being used to treat patients in TKT's ongoing clinical trial and to prevent the company from submitting data generated from the clinical trial to regulatory agencies. The judge has already rejected Genzyme's request for ex parte relief.

"We believe Genzyme's efforts to try and disrupt our ongoing clinical development of GA-GCB are an improper attempt to extend its monopoly in the area of Gaucher disease," said Kerry A. Flynn, Vice President of Intellectual Property and Licensing at TKT. "We do not believe we infringe any valid claim or that there is a reasonable likelihood that this unprecedented tactic will interrupt our clinical trial. We intend to honor our commitment to continue treating our Gaucher patients with GA-GCB."

TKT is conducting an open-label Phase I/II study to evaluate the safety and clinical activity of GA-GCB. The study enrolled twelve patients with Type I Gaucher disease from several countries. TKT expects to report top-line data from this study in the second half of 2005.

Gaucher disease is the most common of the inherited lysosomal storage diseases and is caused by a deficiency of the enzyme glucocerebrosidase. As a result of this deficiency, certain lipids accumulate in specific cells of the liver, spleen, and bone marrow causing significant clinical symptoms in the patient, including enlargement of the liver and spleen, hematologic abnormalities, and bone disease.

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