New Anti-HIV Agent Prevents Virus From Entering Cell

BARCELONA, Spain—A new anti-HIV agent from Roche and Trimeris, Inc has a unique mode of action that suggests it will be active in HIV infections that have developed resistance to other antiretroviral agents and can be combined with other agents without substantially increasing toxicity.

The agent, enfuvirtide (Fuzeon, formerly known as T-20), is the first of a new class of drugs known as fusion inhibitors. Unlike existing anti-HIV drugs that work inside the cell to prevent viral replication, enfuvirtide is designed to block HIV from entering T cells by preventing membrane fusion (see Figure).

Data at 24 weeks from two large, international phase III trials presented at the XIV International AIDS Conference showed that patients on enfuvirtide combination regimens were twice as likely to achieve undetectable HIV levels as those on combinations that lacked enfuvirtide. Based on these data, Roche and Trimeris have submitted a new drug application to the FDA for approval to market Fuzeon for use in HIV infection in combination with other antiretroviral agents.

The sponsors have requested priority review status for Fuzeon, which, if granted, would require the FDA to complete its review within 6 months (early 2003).

The two companies have also completed a phase I/II study of a second-generation fusion inhibitor T-1249. The results showed that the agent was well tolerated and exhibited antiviral activity in HIV patients.

TORO 1 and 2

Both TORO 1 (T-20 vs Optimized Regimen Only) and TORO 2 were randomized, open-label trials that enrolled patients at 112 centers worldwide. Patients were treatment experienced and/or had documented resistance to each of the three classes of currently available antiretroviral agents. Patients were required to have a plasma HIV-RNA level of more than 5,000 copies/mL.

At entry, an optimized background regimen (consisting of three to five drugs, including up to two newly approved or investigational drugs if appropriate) was chosen for each patient based on treatment history and antiretroviral resistance testing. After selection of the regimen, patients were randomized 2:1 to receive either the background regimen plus enfuvirtide or the background regimen alone. Enfuvirtide was administered as one 90-mg subcutaneous self-injection twice daily.

TORO 1, conducted in North America and Brazil, enrolled 491 patients who had previously been treated with an average of 12 antiretroviral agents. Among the patients receiving enfuvirtide combination therapy, 37% had undetectable levels of HIV (less than 400 copies/mL) at 24 weeks, compared with 16% of those who received no enfuvirtide (P < .0001), according to lead investigator Jacob P. Lalezari, MD, director, Quest Clinical Research, San Francisco, and assistant clinical professor of medicine, UCSF/Mount Zion Hospital.

In 20% of patients on enfuvirtide, viral load was reduced to less than 50 copies/mL, compared with only 7% of those who received combination therapy alone (P = .0002).

The primary efficacy endpoint for the study—the mean difference in the magnitude of decrease in HIV viral load between the two groups—was 0.934 log10 copies/mL (P < .0001). Those who received enfuvirtide as part of their combination regimen achieved a reduction in HIV levels of 1.697 log10 copies/mL, compared with 0.763 log10 copies/mL for the controls. Furthermore, 52% of patients receiving enfuvirtide had a 1.0 log10 copies/mL or greater reduction in HIV levels vs 29% of those who did not receive enfuvirtide in their combination therapy (P < .0001).

The enfuvirtide patients had a mean CD4+ cell increase of 76 cells/mm³, compared with 32 cells/mm3 for controls (P < .0001).

At 24 weeks, the incidence of grade 3-4 laboratory abnormalities and clinical adverse events was similar in both arms. While most patients on enfuvirtide experienced injection site reactions, only 3% of patients discontinued the drug as a consequence of those reactions.

European Study

Findings from TORO 2, conducted in Europe and Australia, were consistent with those from TORO 1. In TORO 2, which enrolled 504 patients who had been treated with an average of 11 antiretro-virals, 28% of patients on enfuvirtide had undetectable HIV levels at 24 weeks vs 14% of controls (P < .0001). Among the enfuvirtide patients, 12% had viral load reduced to less than 50 copies/mL vs 5% of controls (P = .0099), said lead investigator Dr. Bonaventura Clotet, head of the HIV Section, Hospital Germans Trias i Pujol, Barcelona, Spain.

The mean difference in the magnitude of decrease in HIV between the two arms at 24 weeks was 0.78 log10 copies/mL (P < .0001) (1.43 for enfuvirtide vs 0.65 for controls). The mean CD4+ cell increase was 65 cells/mm3 for enfuvirtide and 38 cells/mm3 for controls (P = .023).

Patient Acceptance

A poster presented at the Barcelona meeting reported results of a survey of 639 patients in the two phase III TORO studies about the impact of subcutaneous delivery of enfuvirtide on their daily activities. The survey showed that subcutaneous delivery was well accepted by a majority of patients after the first 8 weeks of treatment.

"Our challenge in HIV treatment is not only to develop novel agents for treatment-experienced patients but also to identify therapies that can be tolerated over the long term," said TORO 1 investigator Cal Cohen, MD, research director, Community Research Initiative, Brookline, Massachusetts. "We are pleased that preliminary feedback from patients in these trials reveals that after 2 months of treatment, the majority of patients were able to manage subcutaneous delivery of the agent with little impact on their daily lives."

Difficult to Manufacture

According to Roche and Trimeris, enfuvirtide, a peptide drug consisting of 36 amino acids, is one the most challenging molecules ever to be chemically manufactured on a large scale. Production requires 106 manufacturing steps, about 10 times more than that of a protease inhibitor, the companies said. Roche’s Colorado plant has been working virtually nonstop to keep pace with the clinical development program.