It's natural, so it's marketable

The right chemistry

By JOE SCHWARCZ

Seaweed is prized in some cultures for its supposed medicinal qualities. While there is little evidence for any therapeutic effect, the green stuff may turn out to be the remedy needed to restore an ailing Canadian pharmaceutical company to good health.

Bellus Health has been in the financial doldrums since 2007 when it announced that the long-awaited results from its trial of the anti-Alzheimer's drug tramiprosate, (proposed trade name "Alzhamed") were disappointing.

This had been the company's flagship product. It was to generate billions of profits once approved by the Food and Drug Administration in the U.S. But the chance of approval vanished when the company's large-scale, well-designed study showed that Alzheimer's patients benefited no more from tramiprosate than they did from a placebo.

It now seemed that the $250 million dollars and 15 years the company had invested in tramiprosate research were down the drain, along with investors' money. Could anything be done to salvage the drug? Given that the active ingredient is purported to occur naturally in a type of seaweed - perhaps. Although there had been insufficient evidence to persuade the FDA to approve Alzhamed as a prescription medication, it could still make it to market as a "natural health product," a category much more loosely regulated than prescription drugs. So Alzhamed was reinvented as Vivimind, and the advertising machinery went into high gear promoting it as "memory protection" for healthy people. Aging baby boomers who were beginning to fear that names didn't roll off their tongues with the usual ease were ideal targets.

To be sure, there is some clever science behind tramiprosate. The drug was designed to hinder the formation of "amyloid plaque," deposits in the brain that are the hallmark of Alzheimer's disease.

These deposits gum up the brain's machinery by interfering with the transmission of signals between nerve cells, a process that is fundamental to thinking and memory. How can this be prevented, researchers wondered? Logically, the first step was to determine the chemical composition of such plaque, a step successfully taken.

The fundamental reaction involved in plaque formation links two naturally occurring soluble substances to form an insoluble aggregate.

Beta amyloid peptide, a molecule consisting of a short chain of amino acids, is one of the culprits. It causes neurological mischief when it reacts with certain complex carbohydrates known as glycosaminoglycans, or GAGs. The pharmaceutical challenge, then, is to prevent the peptide from forging a union with the GAGs. This requires identification of the particular feature of their molecules that allows these substances to react. Once that is clarified, a drug that incorporates this feature can be designed to serve as a surrogate partner for one of the substances involved in plaque formation. Of course, the key condition is that the new union must not yield any insoluble substance that can interfere with nerve cell activity.

Back in the 1990s researchers, particularly at Neurochem, (eventually to become Bellus Health), began to explore model compounds they hoped would preferentially bind to beta amyloid peptide and prevent it from reacting with GAGs. Chemists synthesized a number of molecules they believed had the required features, eventually honing in on a rather simple one known as homotaurine. It was soluble, it crossed the blood brain barrier, and it tied up beta amyloid peptide, nipping plaque formation in the bud.

Homotaurine was rechristened "tramiprosate" and investigation into its possible use as an anti-Alzheimer's drug began.

As with most drugs, initial studies involved mice, in this case animals that had been bred to be especially predisposed to Alzheimer's disease.

They fared very well, showing reductions in plaque formation without significant side effects. Neither did rats nor dogs exposed to higher doses suffer side effects except for a few instances of diarrhea. Next step was to test the safety of tramiprosate in healthy human subjects.

Aside from rare cases of nausea, there were no problems. With the safety of the drug now established, the time had come to test its efficacy in humans.

Fifty-eight patients with mild to moderate Alzheimer's disease were enrolled in a three-year study. Analysis of their cerebrospinal fluid showed a reduction in beta amyloid protein with drug use, and tests measuring cognitive ability also suggested modest improvement. Although one would hardly call the results spectacular, they were encouraging enough to mount a Phase III trial, critical for FDA approval, in which over 1,000 Alzheimer's patients across North America would be treated with tramiprosate for two and a half years. Bellus Health eagerly awaited the results. Alas, they showed insufficient improvement with tramiprosate to gain FDA approval. Shares plunged.

Then someone at Bellus had a bright idea. Since company researchers claimed they had found homotaurine to be present in some sort of seaweed, it qualified as a "natural health product," even though the company's version was arrived at through chemical synthesis. True, this meant Vivimind could not be marketed as a treatment for Alzheimer's and that claims on its behalf had to be quite sedate.

"Sustains brain cell health," or "protects the brain structure associated with memory and learning," were vague enough to pass muster. These claims were buttressed by a brain scan study of subjects taking tramiprosate that was spun into a claim of "scientifically proven to help protect memory function." The study had not shown any improvement in memory, but had shown reduced shrinkage of the hippocampus, an area of the brain linked with memory.

So, can this failed prescription Alzheimer's drug reduce memory loss in healthy people as Bellus proposes? It has never been tested for that, so we will have to wait and see. Certainly a degree of skepticism is warranted.

However, given North America's current passion for all things "natural," there is a good chance for market success.

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Bellus Health

Nootropics
BLTC Research
Superhapiness?
Utopian Surgery?
The Good Drug Guide
The Abolitionist Project
The Hedonistic Imperative
The Reproductive Revolution
Critique of Huxley's Brave New World
Alzheimer's Disease: resources/hotlinks
Tramiprosate (Alzhamed, Vivimind): synthesis

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