T-20, currently in Phase III clinical trials, is the furthest along in clinical development in the entry fusion inhibitor class. T-1249, a second generation fusion inhibitor being developed by Roche and Trimeris, is in Phase I/II clinical trials. Unlike existing AIDS drugs that work inside the cell and target viral enzymes involved in the replication of the virus, T-20 inhibits fusion of HIV with host cells before the virus enters the cell and begins its replication process.

T-20 has fast track designation from the FDA in the United States for the treatment of HIV-infected individuals. Fast track is granted to facilitate the development and expedite the review of applications for drugs that are intended to treat serious or life-threatening disease and that demonstrate the potential to address an unmet medical need.

24-week results from the first pivotal Phase III study of T-20, the furthest along in clinical development of a new class of antiretrovirals called fusion inhibitors, were released. The results from this first study (TORO 1: T20-301) as well as the results from a second ongoing study (TORO 2: T20-302) will form the basis of a submission to the US Food and Drug Administration and other regulatory authorities.

Study Design

TORO 1 (T-20 vs a HAART regimen only), previously known as study T20-301, and

TORO 2 (previously known as T20-302) are randomized, open-label trials that enrolled approximately 1,000 patients at 112 centers worldwide. TORO 1 is being conducted in North America and Brazil, while TORO 2 is being conducted in Australia, Belgium, France, Germany, Italy, The Netherlands, Spain, Sweden, Switzerland, and the United Kingdom. Patients in the trials were treatment-experienced and/or had documented resistance to each of the three classes of currently-available antiretrovirals. In addition, each patient had a plasma HIV-RNA level of greater than 5,000 copies/mL. Patients are expected to undergo treatment for 48 weeks, with an optional 48-week treatment extension.

At entry, genotypic and phenotypic resistance testing was used to aid in the selection of an antiretroviral regimen, consisting of three to five drugs, including, if appropriate, up to two newly approved or investigational drugs. After selection of the regimen, patients were randomized 2:1 to receive either the regimen in combination with T-20 or the regimen alone. Patients randomized to the T-20 arm receive T-20 administered as one 90 mg subcutaneous self-injection twice-daily.

In the TORO 1 study, T-20 administered in combination with an individualized HAART regimen was shown to provide a significant additional decrease in viral load compared to the HAART regimen alone.

TORO 1 was conducted in 491 HIV-1 infected patients who were treatment-experienced and/or had documented resistance to each of the three classes of currently available antiretrovirals. At baseline, patients had a median viral load of >100,000 (5 log10) copies/mL and extensive prior exposure to multiple anti-HIV drugs.

Results

Patients who received T-20 as part of their combination regimen achieved a reduction in HIV levels of 1.7 log10 copies/mL compared

to 0.8 log10 copies/mL for those who were randomized to the control arm without T-20.  This difference of 0.9 log10 copies/mL in the magnitude of decrease in HIV viral load between the two arms was statistically significant (P<.0001).

Safety Results

Through 24 weeks, the incidence of grade 3 and 4 laboratory abnormalities and clinical adverse events was similar in both the T-20 and control arms. In addition, drug discontinuation at 24 weeks was approximately 10 percent overall and was very similar in both arms. While most patients on the T-20 arm experienced injection-site reactions, only 3 percent of patients discontinued the study as a consequence. Other adverse events, which had a 10 percent higher prevalence in the T-20 arm compared to the control arm, were insomnia, headache, peripheral neuropathy, and dizziness. It was not possible to establish a causal relationship between these other adverse events and T-20.

Early Access to T-20

In November 2001, Roche and Trimeris announced the initiation of the T-20 open-label safety study (T20-305) to provide T-20 to 450 patients around the world. The study is ongoing and is being conducted in Australia, Brazil, Europe, and North America. An expansion of this trial during the second and third quarters of 2002 will continue to make T-20 available prior to approval for patients with advanced HIV disease who are unable to construct a viable antiretroviral regimen with currently approved agents. In addition, Roche and Trimeris plan to expand early-access programs later this year when increased drug supply is expected to be available.

Internet Resources

     Roche: <www.rocheusa.com>

     Trimeris, Inc: <www.trimeris.com>

Dr. Valenti is the Founding Medical Director of the Community Health Network, a community-based medical clinic for HIV/AIDS in Rochester, NY, where he continues to see patients. He is Clinical Associate Professor of Medicine at the University of Rochester School of Medicine and Dentistry and has been involved in HIV care, policy, and program development since 1981.