Pipeline - Pharmaceutical Executive

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Pipeline
Rays of Light


Pharmaceutical Executive


The new generation is based on a cell-mediated model pioneered by Merck's MRKAd5. It carries HIV genes in an adenovirus vector, triggering the immune system to mount a T-cell attack—and, ideally, killing HIV-infected host cells. The NIH's Virology Research Center (VCR) took the Merck model and made it a one-two punch, adding a DNA vaccine as a primer to the adenovirus booster in hopes of achieving stronger, longer protection. Both show promise, with HIV-specific T-cell responses in at least half of all recipients. Merck has fully enrolled its Phase II trials worldwide, while VCR's Phase II is nearly full. Results are due in 2008.

Critics say that most people in the developing world have been exposed to the adenovirus, raising concerns that their immune system will neutralize the vaccine along with its vector. But according to VCR head Gary Nabel, MD, "The vaccines are designed with adenovirus doses high enough to overwhelm immunity."

"If both the concept and the design work, it's a home run," says IAVI's Koff. "But if only one aspect succeeds, it's just a single." In that case, Koff adds, next up at bat will be four second-generation candidates that use the same set of HIV genes but an alternative vector.

But a home run is a relative term in HIV vaccine development. "Most of us have a very high level of skepticism around these vaccines," says John Lebbos, MD, therapeutic director of infectious diseases at Decisions Resources. "The consensus is that we need a two-pronged approach to stimulate both a cell-mediated and a neutralizing-antibody response."

IAVI's Nabel agrees. "ALVA/ AIDSVAX taught us that the antibody approach is a lot more complicated than we ever thought," he says, "so we've moved the pendulum back to basic research." While the T-cell approach holds hope, its benefits are more modest. And if it fails to pan out, what looks like a pipeline full of promises will be little more than a pipe dream. –WALTER ARMSTRONG

MK-0518 Merck

TARGET INDICATION HIV
DEVELOPMENT Phase III
LAUNCH DATE 2008
PEAK ANNUAL SALES: $450 million


Sylvia Eash, Decision Resources
Merck is set to redeem its hard-to-fathom failure to produce a single anti-HIV drug since the pandemic started 25 years ago. MK-0518 is the leader of a pack of breakthrough compounds called integrase inhibitors, and word on both the street and the Street is "blockbuster."

Merck spent a decade in the lab defining its target—the integrase enzyme that enables HIV to cut and paste its genetic material into the DNA of the human T-cell—and screening compounds to short-circuit this critical function. With MK-0518, its researchers hit the bull's eye: The small molecule puts the brakes on viral replication faster than the most potent meds on the market. Plus, it looks clean on the toxicity front because the integrase enzyme it disables is so specific.

"MK-0518 is one of the most exciting stories in HIV drug development," says Sylvia Eash, an analyst at Decision Resources. "It shows impressive potency and no serious side effects so far, and if the long-term data fulfill its promise, it's likely to be a major advance."


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