The Bay Area Reporter - February 6, 1999
Matthew Sharp, ACT UP/Golden Gate Writers Pool

Fusion inhibitors bring hope to a group of people with AIDS needing more options for treatment, because other choices have failed to bring HIV under control, or have become too difficult to tolerate. With news of increasing deaths in AIDS, this new class of drugs is promising for people who have run out of alternatives and are getting sick again.

The inhibitors work by stopping fusion - or attachment - to the outside of the human T-cell in the beginning phase of the HIV replication life-cycle. Other HIV drugs work at later stages of the life-cycle, combining to bring a powerful determent to replicating virus. Since many people are experiencing drug resistance and are no longer getting any effect from the older drugs, activists have been clamoring for new therapeutic targets to hit the virus. And together with protease inhibitor/nucleoside combinations, adding a drug that hits a different HIV target may weaken the virus further. The new data looks compelling, though not earth-shattering, as a new treatment option.

At the Chicago meeting Trimeris, the company developing T-20 (also known as Pentafuside), presented data on its Phase II clinical in people who had taken most other antiviral drugs. The news was some of the most hopeful of all drugs in the pipeline at the conference, and in this day of protease inhibitor hoopla, it's very encouraging to see a new class of HIV drugs hit the radar screen.

Activists from ACT UP/Golden Gate and Project Inform have been working with the company to bring this new drug to fruition. Two sites in the Bay Area, San Francisco General Hospital and Dr. Jay Lalezari's practice, enrolled patients for this study.

In the study, T-20 was given to 78 people for 28 days. In the higher dose group participants were able to see 90 percent reduction in viral load. All dose groups combined (except the lowest dose) saw an average viral load drop of 0.6 logs, which is not in the range of "highly active" therapies used today. But the result was not bad considering half of the participants had used all three classes of antiviral drugs and 98 percent had used protease inhibitors before. Unfortunately, there was a trend in increased viral load by week four in these patients, which probably means that the drug becomes resistant. Therefore, T-20 will most definitely be best used in combination with other antivirals, and the company plans to continue studying this population.

Lalezari, a lead investigator of the study, stated in a company press release, "The encouraging results from this trial affirm that T-20 continues to hold promise for the growing number of HIV-infected people who are failing currently approved drugs." He added, "There is genuine excitement in the medical community for T-20 because it is the only drug in Phase II clinical trials which works by an entirely novel mechanism of action."

Initially, there was hope that the drug might be useful as a monotherapy, but like all the previous classes of drugs, we now know that the best way to prevent resistance is to use more than three drugs in combination. Longterm survivor and AIDS activist Jeff Getty, who has used up many of his therapy options, said, "I'm waiting for compassionate use of T-20 in combination with other drugs so I can buy another year."

In the trial, T-20 was given twice daily by subcutaneous (under the skin) injection or by a pump, which delivers the drug continuously, similar to one used in people with diabetes. People could either stay on their present stable antiviral regimen or take T-20 alone. Local injection site irritation was noted in most of the patients, but fortunately only 3 percent had to discontinue and leave the study because of it. The researchers say the drug appears to be well tolerated, at least in this early phase of study that was designed to look at safety among other parameters.

A surprising result of the study was that the twice-daily injections delivered equal drug in the blood as did the pump, and there was no difference in effectiveness between the two delivery mechanisms. This is good news because the pump could've been a difficult addition to the already burdensome regimen people with AIDS must endure. Trimeris does not plan to pursue further studies using the pump given this information.

AID$ research

Trimeris has another fusion inhibitor in development that is showing effectiveness against T-20-resistant strains in the test tube, another positive step in fusion inhibitor development. Other companies are working on at least three other fusion inhibitors, but they are only in Phase I studies. Clearly there is new interest in this class of drugs because of their novel mechanism of action. Plus, pharmaceutical companies need new interest in HIV drug development, especially in this new era, since the market has become flush with other drugs.

The caveat to this encouraging news is that there is concern that the small bio-technical companies developing these drugs will not have the money to take them through expensive clinical trials. T-20 is difficult and expensive to make and there is stiff competition among the pharmaceutical companies, so the drug will most likely be expensive. As Getty observed, "The FDA makes it so expensive for a company to develop drugs and these huge companies, who have already cornered the market, will end up buying the rights for fusion inhibitors. The result will be less competition and higher prices for the gouging companies. HMOs will be reluctant to pay. Is that helping people with AIDS?"

Given that problem, it is too early to tell if the newer fusion inhibitors will definitively work, but it is truly exciting to see them in the pipeline, and hopefully this flurry of excitement will generate development of more new compounds for people in late stage HIV disease.

ACTion UPdate:

Two studies are currently enrolling patients in San Francisco using cyclosporine to treat immune activation in HIV-positive people, both on individuals who are and who are not on antiviral therapy. One study is at San Francisco General Hospital (ACTG 334, please call 476-4082, x360) the other study is at a private research center, Virx (please call Debbie Hildebrandt at 474-4440).

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