T-20: The Next Big Gun?
The hot new drug of the moment is T-20 (Pentafuside), a "fusion inhibitor" that offers a glimpse of the next frontier of anti-HIV therapy. T-20 is a leading member of a new class of drugs. It blocks HIV entry into cells by interfering with gp41, a protein on the outside surface of HIV that is part of the molecular key used to open cell doorways. The excitement began in November, when Nature Medicine published impressive results from a two-week test of the drug. Researchers at the University of Alabama at Birmingham (UAB) studied the effect of the drug in 16 trial participants. Four out of four patients receiving the highest dose (two 100 mg doses per day) had their viral load drop to below 500 copies within 10 to 14 days.

Based on these results, T-20 appears as effective as the most potent protease inhibitors on the market. That's good news for people failing existing regimens. Since T-20 has a different target than existing drugs, it should also work against resistant strains of HIV. On the other hand, researchers will need to look closely at how resistance to T-20 develops: it appears that only one or two mutations in gp41 are needed for resistance to occur. Further trials will also reveal more about side effects and toxicity, which did not cause significant problems in the initial, short-term study. At press time, no tolerance issues had emerged in the one person who had been taking the drug for upwards of a month.

Trimeris, the small North Carolina-based manufacturer of T-20, has already taken the next step in developing the drug. In December, enrollment was completed for a month-long Phase II trial involving nearly 70 participants around the country. This longer study will allow participants to add the drug to existing regimens, to see whether there are positive interactions between T-20 and other drug cocktails. In addition, the trial will test two methods for taking the drug: self-administered injection and a portable intravenous pump that automatically infuses scheduled doses. T-20 cannot be taken orally, since its protein structure is readily broken down by stomach acids. Planning is also underway for a study of T-20 as salvage therapy.

While it's early to project the cost, it's likely that T-20, a synthetic compound, will come with a hefty pricetag. "Making the compound from scratch makes it expensive," explains UAB lead investigator James Kilby, who adds that it could be up to five years before T-20 reaches Phase III trials. Dosing systems like an infusion pump may add to the cost, although such technology is already widely used by diabetics for administering insulin.

Small clinical trials of T-20 will benefit a handful of participants, but the drug's big payoff is what it promises for the future. "T-20 is unlike Ziagen or Sustiva in that it's not a known category ready to hit the market. It suggests a whole new approach to therapy," says Kilby. In his written commentary on T-20, University of California San Diego treatment expert Doug Richman calls it a heartening "proof of concept" that lays the groundwork for future drug development. Investigation is already underway into other compounds that block other HIV binding sites, and genetic therapies that would induce the body to generate its own T-20-like molecules. Several companies-including Merck, Pharmacia & Upjohn, and newcomer Achillion, headed by former National Cancer Institute researcher Bill Rice-already have other novel compounds in the pipeline. For now, all eyes are on T-20, the promising firstborn of this new generation.

-Emily Bass