In the U.S., AIDS may not seem to be the urgent problem it once was. Powerful drugs introduced since 1996 have slashed the annual death rate in the U.S. from nearly 50,000 in 1995 to 16,000 in 2004. But the picture is still grim. New cases of infection continue unabated, at about 44,000 per year, with more Americans than ever -- more than 1 million -- infected with HIV. Around the world the epidemic is growing, with more than 40 million people carrying the virus. What's more, HIV increasingly outwits today's drugs even as side effects take a toll.
That's why an urgent need for new treatments remains -- especially those that tackle the virus in new ways. Now an experimental drug is showing promise. In late September researchers from Panacos Pharmaceuticals Inc. (PANC ) in Watertown, Mass., are scheduled to present results of a clinical trial showing that their drug, dubbed PA-457, can dramatically reduce levels of the virus. "This is quite exciting because of the novel mechanism of action," says Dr. Daniel R. Kuritzkes, director of AIDS research at Brigham & Women's Hospital and professor at Harvard Medical School.
There is still a long road ahead. While the drug appeared safe and effective in a so-called Phase II trial, it was given to only 33 people for 10 days. Proving that PA-457 can be taken safely for years "is the next hurdle," says Carl T. Wild, Panacos' chief science officer. Even if all goes well, doing a larger Phase III trial and getting Food & Drug Administration approval will take several more years. But so far there are no signs of trouble. "There are a series of 'ifs,' but if it pans out, this could be substantial," says Needham & Co. analyst Clay Wilson. Needham predicts that if the drug gets approved, sales could easily top $500 million per year.
Even if PA-457 stumbles, it opens the door to a new attack on HIV. All but one of the 28 approved drugs fight the virus in one of two ways. After HIV gets into a cell, it hijacks the cell's machinery to copy itself. One class of drugs, called reverse transcriptase inhibitors, block the enzyme the virus uses to do this. The second type of drug, the protease inhibitors, act later. An HIV gene called gag contains instructions to make a big protein that becomes part of the new viruses. For the viruses to become infectious, this protein must be cut into several pieces. Protease inhibitors block the enzyme that cuts the protein.
Panacos' experimental medicine offers a new tack. The original compound, found in a variety of tree barks, was discovered nearly 10 years ago by Kuo-Hsuing Lee at the University of North Carolina as part of an effort to test thousands of natural substances for anti-HIV or anti-cancer effects. Then it was tweaked to make it more potent. In 2003 scientists at Panacos, with the help of Dr. Eric Freed at the National Cancer Institute, figured out how it works: It prevents the gag protein from being cut in one key spot. New viruses still get released from infected cells, but they're harmless. "The drug hits the same step as the protease inhibitors, but by a quite different mechanism," says Freed. Because it bollixes up the last step, called maturation, in the virus' life cycle, it's called a "maturation inhibitor."
Since it works in this new way, Panacos' drug is effective against HIV strains that have acquired resistance to protease inhibitors, a growing problem in AIDS treatment. In the test tube, using PA-457 and a protease inhibitor together is far more effective than either drug alone. The next step: testing PA-457 in combination with other antivirals. "It's too early to say if this will be the next widespread drug, but everything looks about as good as it could at this point," says Freed. The AIDS battle is still raging. Now doctors may get a new weapon for their arsenal.
By John Carey in Washington