When the FDA approved Fuzeon in March, there was jubilation not only by Trimeris Inc. and F. Hoffmann-La Roche Ltd., but among AIDS fighters around the world.

Fuzeon (enfuvirtide), a first-in-class fusion inhibitor for HIV-1, won approval in the fast-track lane for use in combination with other antiretrovirals in treatment-experienced patients. It's a new weapon.

Working outside the cell to block the virus from entering, Fuzeon also proved active against the crafty mutated versions of the virus resistant to existing drugs. Nobody went so far as to call Fuzeon the final answer, and sales turned out to be not quite what investors expected - about $18.3 million through Sept. 30 - but peak estimates ranged from $250 million to $500 million, and hopes were high.

The problems with Fuzeon are fairly simple: It must be reconstituted with sterile water and drawn into a syringe before it's injected, and it must be given twice a day. Site reactions where the shot enters the skin sometimes include bumps, but the real difficulty is frequency (and inconvenience) of administration, as well as price.

"It comes to about $20,000 a year," noted Aarti Raja, analyst with Decision Resources. "The way it's made calls for that price. It's a pretty difficult compound to synthesize and involves 10-plus steps."

Trimeris and Roche are working on some of the issues, and the next-generation HIV blocker that seemed to hold promise was T-1249. Last week, that promise fizzled. The companies said they would stop development of the drug, still in its early stages, while the search goes on for a compound with a more convenient delivery profile.

Wall Street reacted with less shock than some might have expected, but still punishing Trimeris' shares by 14.5 percent at day's end. The stock closed at $17.31, after sinking to a new 52-week low of $16.60. Maybe investors were somewhat prepared, since Trimeris warned the market in October it would be testing T-1249 as a twice-daily injection (like Fuzeon), rather than less often as some had forecast.

"It definitely wasn't the magic bullet," Raja told BioWorld Financial Watch, adding that Fuzeon "was great because it was the first in a new class in seven years." But "when things started looking bad" for Fuzeon, observers might have expected the picture to darken for T-1249, she said.

"They kept coming out with all the data," Raja added, which lent some optimism. Final results from the Phase I/II trial with T-1249 were reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy four months ago.

At the same time as the shelving of T-1249, Roche and Trimeris extended their research partnership for three years to keep the quest for fusion inhibitors going, with an aim of finding products that might be given weekly or even monthly. Trimeris said it was redirecting resources and realigned its work force - moves that translated into a staff reduction of about 25 percent (25 to 30 people), leaving the firm with 100 employees.

Setting aside T-1249, Trimeris said it expects to designate another clinical candidate next year, but that one likely would not enter Phase I trials until at least 2005, possibly later. Bad news. The better news is that Trimeris expects to spend less on staff costs, and Fuzeon sales could build to allow for profitability as early as 2004.

Trimeris has about two years' worth of cash, reporting $110.8 million as of Sept. 30, with a burn rate estimated at $4 million per month. Some analysts are estimating Fuzeon sales of about $15 million per quarter, which - if that level remains steady - would leave Trimeris with a net burn of only $2.5 million per month next year, or $30 million for the whole year. And that's before Trimeris gets cash from sales outside the U.S., or potential milestone payments.

Research is under way to make Fuzeon dosing easier and boost those sales. Results from pharmacokinetic studies in once-daily dosing are expected to see publication shortly. Alternative methods of preparation are being explored, too.

Meanwhile, whither the next generation of HIV blockers? One method to reduce frequency of dosing Roche is known for, pegylation - in which one or more chains of polyethylene glycol are attached to a molecule, providing a protective barrier that slows elimination of the drug - hasn't worked with HIV. But the companies might try modifying its peptides chemically or combining them with stable carriers such as albumin or immunoglobulin.

"This class is definitely one that will be quite welcome, in terms of entry inhibitors," said Raja. "It's a good idea, if they can come up with a simpler way of delivering it." Raja is putting together a report on the HIV treatment landscape, expected to be available in April or May.

"Everyone's waiting for the next big breakthrough, and that hasn't happened," she said. "I don't know how much it's going to change in the next two or three years. We need drugs from new classes if things are going to change."

Among entry inhibitors, Progenics Inc. has a compound that "seems to be moving along," she said. That compound is PRO 542, in multidose Phase II studies due to finish in the first half of next year. The fusion protein is a monoclonal antibody that blocks the initial attachment of HIV to the cell and has been shown to be synergistic with Fuzeon.

"CCR5 antagonists would be a whole new way" to fight the disease, Raja said, and Pfizer Inc. is developing one that "seems to be ahead of the others."

Pfizer's Phase II drug is UK-427,857, which binds to the CCR5 receptor on the surface of human white cells, blocking the virus from entering the cell and starting its replication. The compound likely would be prescribed in combination with standard therapies.

Vaccines would be ideal, but Raja called that area "another bleak picture right now," given VaxGen Inc.'s recent but not unexpected Phase III failure of an experimental vaccine in a study in Thailand. An earlier Phase III trial conducted in North America, Puerto Rico, the Netherlands and Canada also failed to hit its primary endpoint - statistically significant reduction of HIV infection within the study population as a whole.

Other efforts are under way, but "in the next five years it's hard to say [what will happen], because there's not much data on them," since the drugs are either in preclinical stages or earlier, Raja said. "There's a lot of work to be done."