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Monday, September 25, 2006

The Predictive Powers

To set the stage for the analysis of Medivations Cargo Cult I would like to talk about the predictive powers of science. It is important to know when someone has a disease. We have used science to predict the paths our health can take. This provides us with a measuring stick when we try and alter the outcomes of disease in our favor.

What is the path of Alzheimers? We know that it occurs later in life. Kids don't get Alzheimers. Pfizer and Eisai have a drug called Aricept (donezipil) that showed some effectiveness in delaying the onset of Alzheimer's. From Derek Lowes' blog, In The Pipeline: Aricept is a cholinesterase inhibitor, part of the first wave of compounds that were brought in as Alzheimer's therapies. Inhibiting cholinesterase increases the amount of a key neurotransmitter (acetylcholine) that hangs around in the synapse, which should, in theory, lead to stronger signaling between neurons.

Medivations drug Dimebon began as an antihistamine but was later reported to bind to cholinesterase. As I've discussed before in the Cargo Cult Scientist, biotech companies will associate binding with inhibiting a protein function and curing a disease. But does it really bind specifically to cholinesterase? Medivation claims that it binds to two validated Alzheimers targets, cholinesterase and NMDA. We also need to know how well it inhibits the enzyme and how does that effect the onset of Alzheimers?

Ultimately, we are only interested in the onset of Alzheiimers. Aricept is currently sold for this very purpose. Now we have a positive control to compare Dimebon. According to Derek Lowe, "We don't understand neurotransmission well enough to be sure that we're doing much good just by turning up synaptic signaling. To add to the problem, the relevant cholinergic neurons are among those being damaged by Alzheimer's itself, so the drug's therapeutic target is slowly disappearing. That's why the cholinesterase inhibitors are recommended for very early stages of Alzheimer's, and are considered useless for late stages of the disease."

It is hard to evaluate the recent success of the phase II trials of Dimebon. Cargo Cult Science does not report data. They report their interpretations of the data they select from the research. The methods employed in this trial were to have doctors give opinions or psuedoscientific Alzheimers measurements. The real science has yet to be done in understandinig the human brain. What breaks down? Why do some people get the disease and others not? Many questions remain to be answered. What Medivation has done has been to jump into a muddy pond (along with Pfizer) only to emerge from time to time to tell us how crystal clear everything is below the surface. Why should we question them?

Science is an abstract concept. When assessing the work of scientific pursuits you must admit that you are partly judging the science and partly judging the scientists. You must, in this case, discuss the motivations of the people reporting the work. You must also discuss the way the data is coming in. Dimebon binds to two AD targets. While the additional binding target may look like a bonus, it tells us that the molecule is not target specific. We may wish to see the data including the negative controls, the methods of measurements and so on. When it comes to the phase two trial we will want to know what the doses were. Who did the analysis? This abstract concept of science must begin with soft questions such as these. Then we move on to the real methods of understanding.

Aricept answers one of these first "soft questions". Again, Derek Lowe:

Pfizer went out as early as possible, out to before patients had even shown signs of Alzheimer's at all. It appears that Aricept therapy helped slow the onset of the disease, among those who developed it at all. Problem is, the effect wasn't large, and after three years any benefit had completely disappeared. The placebo-treated Alzheimer's patients were in the same shape as the ones who had been getting Aricept all along.

You wouldn't know all this from a quick look at most of the popular press, though, which went with New Breakthrough headlines like "Drug is First to Delay Onslaught of Alzheimer's." (Science, on the other hand, went with "Study Questions Efficacy of Popular Alzheimer's Treatments", which is more like it.) I'm in the same camp, and it's the same one as the editorial from the issue of the New England Journal of Medicine where the study appeared. Aricept, the journal said, "may offer some benefit, but any such benefit is quite limited and apparently transient" Try turning that into something that'll make you sit past the commercial break. . .

Pfizer has even tested their drug in people without Alzheimers and found that it increases memory function. Derek Lowe reported way back in 2002 that they ran a study that demonstrated a slight improvement in memory when people used their cholinesterase. So what does all this mean for the future of Medivation? There is already a cholinesterase on the market. It's effect has been questioned in the big time journals. But the investors are the ones who have to be impressed. This airplane does not have to land in order for the staff at Medivation to have a good run, make some money before they move on to the next "project".

That's enough for one day. We have gone over some of the background of Dimebon. We have touched on the sociology of biotechnology professionals. They have taken an antihistamine and reinvented it as a cholinestase inhibitor class drug. (they are also testing this drug for Huntington disease!) We have looked into a similar drug that is on the market. Using the predictive powers of science we can assume that Dimebon will show a slight improvement due to some creative work in the clinical trial department at Medivation. We here at the Cargo Cult Scientist do not believe that any airplanes from the cholinesterase airlines have yet arrived. Aricept tells us something. The history of Dimebon tells us something. Let's see what is next.

1 comment:

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