The hype surrounding Pfizer's first-in-class entry inhibitor, the CCR5 antagonist maraviroc (Selzentry), created an air of
disappointment when the drug did well but was not a spectacular success. Schering-Plough's new CCR5 antagonist, vicriviroc, will have to differentiate itself from the Pfizer rival to break into the same combination therapies. But the greatest obstacle
for both drugs is a class problem. Patients must undergo what Eash calls a "cumbersome" test to see if they are infected with
the CCR5 or CXCR4 virus, a variant against which CCR5s are ineffective. The battle for share of the CCR5 market may come down
to dosing and convenience. InCyte's INCB9471 has a long half-life and a different binding site on the chemokine receptor CCR5 and can be expected to compete for CCR5
market share. PRO 140, a monoclonal antibody further back up the pipeline with Progenics, attacks the CCR5 receptor with yet another mechanism.
HIV is a clever and persistent virus that learns to beat back many therapies. Manufacturers keep pipelines stocked with new
protease and integrase inhibitors as back-up therapies. Increasingly, according to Eash, they aim new drugs at expected resistance
problems. Merck, for example, has begun to test drugs such as MK-2048 and others in its preclinical integrase inhibitor research program against viral strains resistant to raltegravir, a recently approved Merck integrase inhibitor expected to launch next year.
Fighting Side Effects
Weight Loss: Fen Phen Redux
Old pharma hands will be forgiven if they see lorcaserin as a new, safer version of the "fen" in Fen Phen. The serotonin inhibitor fenfluramine (like its replacement, dexfenfluramine)
was famously taken off the market when it turned out it reacted with serotonin 2B receptors on heart valves, resulting in
damage to the valves. Arena hopes that lorcaserin, a serotonin 2C receptor agonist, is specific for receptors in the brain.
"They want to see if they can get a good weight-loss effect without side effects or heart-valve lesions," says F. Xavier Pi-Sunyer,
MD, professor of medicine at Columbia University College of Physicians and Surgeons and director of the New York Obesity Center.
In an early 12-week trial, the lorcaserin patients lost an average of eight pounds, according to F. Xavier Pi-Sunyer, MD,
professor of medicine at Columbia University College of Physicians and Surgeons and director of the New York Obesity Center,
who expressed optimism about the efficacy and safety of the drug.
Qnexa resurrects the "phen" in Fen Phen. The drug combines phentermine with topiramate, an anticonvulsant that Johnson & Johnson
markets as Topamax. Topiramate was proven to cause weight loss in clinical trials for obesity, but patients disliked it. "People
got peripheral neuropathy in their hands and feet—even painful neuropathy," said Robert Eckel, MD, professor of medicine,
division of endocrinology, metabolism, and diabetes, at the University of Colorado.
One physician, who declined to be named, speculated that by adding phentermine and sharply reducing dosages, developers could
eliminate the topiramate side effects. Pi-Sunyer, however, who said trials patients lost 25 pounds in 24 weeks, expressed
concern about other side effects, including memory loss.
The basic strategy of combining antidepressants with CNS drugs does not always go smoothly, Pi-Sunyer says. Contrave, which combines buproprion, an antidepressant, with naltrexone, an opioid receptor antagonist, had no adverse effects besides
fatigue and insomnia. However, patients lost less than eight pounds in 24 weeks. Excalia, a combination of bupropion and zonisamide, an antiepileptic, produced more than 9 percent weight loss. But 37 percent of
patients dropped out of the trial, complaining of nausea and other side effects.