Magic Molecules

Pipeline Report
Dec 01, 2004

Science fiction writer Arthur C. Clarke's Third Law states: "Any sufficiently advanced technology is indistinguishable from magic." Paul Ehrlich, the Nobel Prize-winning pharmaceutical pioneer, used to say, "We must learn to shoot microbes with magic bullets." This year's 25 Most Attention-Getting Investigational Compounds (MAGIC), are all products of advanced technology—"bullets" that may well appear magical some day. But there are no tricks involved. Chosen by pharmaceutical analysts and consultants asked to name the late-stage products that caught their notice (candidates had to be beyond Phase II but not yet launched, and new uses for known products were counted as new), they embody the hopes and hard work of countless people.

Keeping in mind the effort, the uncertainty, the inevitable twists and turns and ups and downs, it might be said that every molecule tells a story. Here then, out of hundreds swimming upstream through the pipeline against all odds, are 25.

Acomplia [rimonabant] from Sanofi-Aventis

The most popular selection in the MAGIC 25, Acomplia (rimonabant) has been dubbed the antimunchie drug because, as a cannabinoid CB1 receptor antagonist, it blocks sites "believed to mediate hunger responses when individuals smoke marijuana," says 2Value analyst Marc Samet, PhD. This mechanism has produced "promising clinical data for two indications—obesity and smoking—both large consumer-friendly spaces," says Mara Goldstein, pharmaceutical analyst for CIBC World Markets. What's more, subjects in a recently reported two-year trial not only lost an average of 19 pounds, their cardiovascular profiles improved. And patients who stayed on the drug tended to maintain their weight loss, while those who went off it gained theirs back. Says David Moskowitz, an analyst with Friedman, Billings, Ramsey:"There may be some nervousness in the wake of fen-phen, but there is clearly a need for a way to reduce weight safely, especially since abdominal fat is an important indicator of cardiovascular risk."

Acomplia is "not an extraordinary breakthrough," in the view of David Goldstein, MD, PhD, formerly with Eli Lilly and now a consultant and a member of the board of the American Society for Clinical Pharmacology and Therapeutics. But it is "a novel mechanism that will add to physicians' arsenals and allow them to try multiple treatments for obesity." Although, he adds, the efficacy of these combinations "has not been tested." He expects "marginally better results from Acomplia compared with other recent products," and thinks it will "probably get off to a hot start—people are hungry for something new." But then "reality will set in: It won't make people thin." Goldstein also foresees three potential problems: "Studies show an increase in infections in year one, possibly involving immune modulator CB2. Cannabinoids are analgesics, so those taking painkillers along with Acomplia may find their effects blunted. Finally, there are hints that Acomplia may be accompanied by an increase in anxiety and depression."

Acomplia may appear formidable, but analysts warn that it is entering a crowded smoking cessation market and is also up against several well-entrenched statins.

A New Drug Application (NDA) for an obesity indication is expected to be filed as early as next year.

Exenatide [synthetic exendin-4] from Amylin Pharmaceuticals/Eli Lilly

Called by analyst Moskowitz "an effective new molecule" for the treatment of Type 2 (noninsulin dependent, adult onset) diabetes, Exenatide was discovered in a protein found in the toxic saliva of the beaded lizard, a close relative of the Gila monster. Exenatide is the first in a new class of drugs called incretin mimetics. A glucagon-like peptide-1 (GLP-1) agonist, it stimulates insulin secretion to improve blood glucose control. But, Moskowitz says, "Unlike insulin, it does so without incurring the risk of hypoglycemia [low blood sugar]." In addition to that, Exenatide appears to promote weight loss—which would in many cases lessen the severity of diabetes—something insulin impedes. Exenatide has been found effective for Type 2 diabetics not taking insulin who have had no success with current oral medications.

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