At the 8th Annual Retrovirus Conference held recently, researchers reported encouraging results in early studies of an entirely new class of anti-HIV drug called fusion inhibitors. If these promising results hold up in subsequent studies, patients and physicians will have a new weapon for the treatment of HIV infection. Fusion inhibitors are different from currently available anti-HIV drugs. These new agents are the first drugs that can block the HIV virus from entering or fusing with host cells. Fusion inhibitors belong to a broader category of new drugs called entry inhibitors, of which there are three types: fusion inhibitors, attachment inhibitors, and co-receptor inhibitors. Of these three types of entry inhibitors, fusion inhibitors are the furthest along in development.

Two fusion inhibitors currently in clinical trials are T-20 and T-1249. T-20 is closest to being approved by the FDA. Both entry inhibitors are being developed in collaboration with Trimeris, Inc. and Hoffman La Roche.

Studies of T-20

The promising results of studies so far have raised optimism that fusion inhibitors may offer a new strategy for combating HIV. Ralph DiMasi, MD, Director of Biometrics at Trimeris, commented on results of the first trial that evaluated the addition of T-20 to a standard antiretroviral regimen. He said that in 71 patients who had been exposed to prior HIV therapy with nucleoside reverse transcriptase inhibitors and at least one protease inhibitor, T-20 showed an additive effect to that of a background regimen of abacavir (Ziagen™), amprenavir (Agenerase™), low-dose ritonavir (Norvir®), and efavirenz (Sustiva™). In addition to being effective, the regimen was well tolerated. This bodes well for a positive outcome in two Phase III clinical trials of T-20 being conducted by Trimeris, which include patients more heavily exposed to prior antiretroviral treatment, he commented.

More than a year ago, Dr. DiMasi presented 16-week data from the ongoing study in which three different doses of T-20 were compared. The highest dose (100 mg), given by subcutaneous injection twice daily, had the greatest effect on viral load. Thirty-two week data from the same study, presented more recently, showed that T-20 continues to exert an additive effect to background anti-HIV therapy in suppressing viral load and also shows that T-20 achieved a substantial increase in CD4 cell count (a marker of cellular immunity).

Because results of this trial were so impressive, and because T-20 was well tolerated, Trimeris decided to allow these 71 patients to continue using T-20 beyond the 48-week trial.

Studies in Children

Studies are also being conducted in children with HIV infection. In one such study, children aged 3 to 12 years were given T-20 for up to 12 weeks, and the drug caused rapid suppression of HIV levels. The company plans to continue to test the drug in children and hopes to gain FDA approval for both adult and pediatric use.

Most of the side effects associated with T-20 in clinical trials were mild and moderate. The most frequent side effects reported were injection site reaction, headache, nausea, fever, increased energy levels, asthenia, diarrhea, and dizziness. However, besides injection site reaction, it has not been proved that such effects are caused by the treatment.

Additional Phase II and III studies of T-20 are planned. Because T-20 has a unique target among anti-HIV drugs, it is not expected that this drug will have cross-resistance with older drugs like protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs).

New agents such as T-20 and T-1249 are especially important for patients with advanced disease who have failed on treatment with currently available anti-HIV drugs. According to David Ho, MD, Director, Aaron Diamond Center for AIDS Research, New York City, developing drugs that attack the virus in new ways is a pressing need. "As many as 40% of HIV/AIDS patients have failed multiple treatment regimens or have developed resistance to existing options. While AIDS-related deaths have declined nationwide, the number of people living with HIV continues to grow. Fusion inhibitors may very well be the first new class of anti-HIV drugs since the introduction of protease inhibitors in 1995," he said.

T-1249, another fusion inhibitor developed by the same companies, is also in clinical trials, but less information is available. Preliminary studies suggest that T- 1249 is effective against T-20 resistant strains of HIV. In addition, the dosing may be qd as opposed to bid. Based on preliminary data, T-1249 is 2 to 100 times more active in vitro than T-20 and is currently in Phase I/II clinical trials.

Both T-20 and T-1249 have been designated as fast-track agents by the FDA for treatment of persons with HIV infection. This designation guarantees that studies of these drugs will be expedited. This means that if results are positive, they will receive FDA approval faster than most drugs.