Inside Story

When Ron Travelletti, 46, began HIV treatment last spring, it wasn’t because he had to: Diagnosed in 1985, this long-term non-progressor had a respectable 330 CD4s and a tame viral load of 19,000. Rather, an HIVer friend had told him about a short-term study in which GSK-873,140(or GSK-140 for short), an experimental GlaxoSmithKline drug, would be tested on HIVers for the first time. Travelletti signed up for the sake of science—and the $1,000 fee: “My partner and I are on disability,” he says, “and it’s pretty tight.” After the requisite 10 days of swallowing the drug, he learned that it had squashed his viral load to a mere 160.

Someday, Travelletti may be able to say he was among the first HIVer guinea pigs for a revolutionary wave of HIV medicines called entry inhibitors (EIs). Essentially, EIs stop HIV before it can get inside the immune system’s CD4 cells, which the virus uses as factories for making more HIV. One EI—the pioneering Fuzeon (T-20)—has been available since 2003, but use has been limited to HIVers who badly need new options and can stand its pain-in-the-ass (sometimes literally)twice-daily needle stick routine.

Happily, most of the coming EIs are plain old pills. And drug companies are hustling to roll them out. “The EI race is on,” says Bob Huff, editor of Gay Men’s Health Crisis’ Treatment Issues, who forecasts that EIs will hit the market in 2007 or 2008. Leading the pack is Pfizer’s UK-427,857 (or just UK-427), which, taken alone in a study of about 80 HIVers, reduced viral load up to 1.6 log (say, from100,000 to about 4,000) after 10 days. Pfizer will test UK-427 in hundreds of HIVers worldwide late this year. Also impressive in a similar trial was Schering-Plough’s SCH-690, which is already enrolling U.S. HIVers on HAART in a phase II, or midsize safety, trial.

Meanwhile, says Glaxo’s Steve Piscitelli, PharmD, “We’ve been quietly sneaking up behind Pfizer” with GSK-140. Pending data from the study Travelletti joined, GSK will begin larger trials by year’s end. Also in the mix are Bristol-Myers Squibb’s BMS-488043, Tanox’s TNX-355and Progenics’ PRO-542. “We may be in a whole new world,” says Huff—one with new options for HIVers with multidrug resistance and without the side effects linked to our current meds. But EIs bring new challenges,too.

Point of Entry

To understand the buzz, here’s a brief HIV refresher course.Normally, the virus hijacks CD4 cells in a three-step, Space Invaders–like process. First, a protein on HIV’s surface called gp120hooks to a pronglike receptor on the CD4 cell. (See “1, 2, 3...Entry!”)Then gp120 hooks to one of two other receptors on a CD4 cell’s surface,called CCR5 or CXCR4. With countless molecular gears and levers whirring, HIV and the CD4 cell move closer, fusing their slippery surfaces until an ever-expanding pore opens up—and HIV slips inside theCD4 cell.

That’s when HIV’s real dirty work begins—and when most HAART drugs start fighting the virus. But by working inside CD4 cells, our current meds also muck up the cells’ energy centers, called mitochondria. And that, many experts believe, is why some current HIV meds can cause or contribute to awful side effects like lipodystrophy and neuropathy. EIs, on the other hand, keep HIV from ever getting inside human cells. BMS-488043, for example, stops HIV’s gp120 from attaching to the CD4 receptor. The Pfizer, GSK and Schering EIs, called CCR5 antagonists, block the CD4 cell’s CCR5 receptor. Yet another candidate, Anormed’s AMD070, blocks the CXCR4 receptor. Fuzeon foils entry’s final step, when HIV and the CD4 cell fuse.

Sparing us side effects is only one of the big hopes for EIs. (We won’t know how often EIs cause more mundane woes like nausea and diarrhea—or even all-new side effects—until they’ve been tested over along period of time). Since different EIs hit the entry process at different stages, researchers believe that they could be taken as a combo and create a whole new anti-HIV strategy outside the cell. Huff explains: “If you can slow down [entry steps 1 or 2], it may not completely block HIV, but it opens up a bigger window for drugs downstream like Fuzeon to work.” Says the AIDS Treatment Activists Coalition’s Nelson Vergel, “I can see humongous synergy among these compounds.”

Until we have enough EIs for a combo, we can likely combine EIs with current meds for a broader treatment palette (that’s how they’ll be tested in phase II and III trials). Gegeny imagines a day when everyone starts treatment on EIs alone and uses “protease inhibitors and nukes [NRTIs]”—with their infamous side effects—only “down the road if resistance develops.”

Wait a minute! Resistance to EIs? Sorry to say, the class is vulnerable, due mainly to mutations in HIV’s gp120. (It’s already happened with Fuzeon.) Then there’s…

The 64,000 Question

Pfizer’s, GSK’s and Schering’s EIs are CCR5 antagonists—a promising group. CCR5 receptors aren’t essential to CD4 cells, so drugs blocking them are a seemingly safe bet. But there’s a catch. In early infection,the virus prefers attaching to CCR5 receptors. However, in roughly half of HIVers, as HIV progresses over the years, it is increasingly able to attach to CXCR4 receptors. What isn’t known is whether advanced disease causes the CXCR4 switch or vice versa. The big fear—what Piscitelli calls “the $64,000 question”—is that blocking the CCR5 receptor will drive HIV toward the CXCR4 receptor and hasten disease progression.

The makers of the CCR5 antagonists haven’t spotted such a switch in the test tube or, for the most part, in their early trials. But even though all 66 HIVers on Pfizer’s UK-427 had been screened to ensure that they had only CCR5-using virus, CXCR4-using virus emerged in two of them. They stopped taking the drug: One patient’s virus went back to using CCR5 only, but the other’s virus has continued to use both CCR5 and CXCR4 for nearly a year. Howard Mayer, MD, a Pfizer scientist at the fore of the UK-427 research, says both patients still responded to UK-427 and that the one with the CXCR4-using virus has shown no disease progression. But experts acknowledge that the screening test, which Mayer says is 97 percent sensitive, may miss “lurking” CXCR4, and they worry what that could mean once more HIVers go on the drugs in larger trials.

The drugmakers say that trials will separately track HIVers with the CCR5-using, CXCR4-using and mixed-use virus and watch for treatment failure. Participants will also take standard HIV meds for backup,which the Food and Drug Administration requires. “We’re hopeful [the CCR5 drugs] will also be useful in people with resistance [to current meds],” explains the FDA’s Jeff Murray, who works with drug companies on HIV trials. Yet he worries that up to half of the very folks who most need the CCR5 antagonists—longtime HIVers with heavy drug resistance—may benefit least because their advanced virus now grabs mainly CXCR4 receptors.

Room for All?

These HIV veterans may benefit nonetheless. All three CCR5 candidates target HIV in entirely new places, so trials won’t reject anyone because of heavy resistance to current drugs. Better still: HIVers coinfected with hepatitis B or C won’t be excluded unless they have skyrocketing liver enzymes. Coinfected patients constitute at least one third of all HIVers; their response to new drugs is “something we want to know right away,” says Piscitelli.

The biggest EI-testing debate concerns how soon drugmakers will let their separate agents be combined in multidrug-resistant HIVers, who generally need more than one new med at a time. Makers of CCR5 antagonists say they likely won’t pair up their drugs before their expanded-access programs, which usually don’t launch until well into phase III (final, large-scale) trials. “You don’t study two investigational drugs in early development because you need to learn about your one compound,” says Piscitelli, insisting, “It’s not that we’re not going to share.”

But Vergel says that for emergency cases, he and other

activists want action early in phase III. Huff says, pharmaceutical companies are “afraid that if something goes wrong, the FDA will stop all trials until they figure out [which drug] caused the problem.” Theoretically, earlier collaborative studies may happen, says the FDA’s Murray, adding that the agency is “not opposed at all” to the idea. Vergel stresses that for those who need new options most, “We can’t go on with this stupid sequential monotherapy”—giving people one new drug at a time.

Hype and Hope

Poised for major investigation, EIs are at a crossroads between promise and reality. When it comes to large-scale data, “nothing has blown me away yet,” says Gegeny. “My fingers are crossed.”

Meanwhile, Ron Travelletti got an unexpected EI bonus. On a visit to the trial site to take his GSK-140, he saw that the receptionist was absent. “I asked if they were looking for someone,” he says. “I didn’t want to sit around on disability.”

Five months later, Travelletti reports, “I’ve never been happier with a job.”