Roche and Trimeris announce 24-week results from second pivotal study of HIV fusion inhibitor T-20

11 July 2002. Related: Antiretrovirals.

Roche and Trimeris have announced positive 24-week results from the second pivotal Phase III study of T-20 (TORO 2), just four weeks after reporting similarly positive 24-week results from the first Phase III study of T-20. Together, the results from TORO 2, as well as the results from the first study, TORO 1, will form the basis of the submission to regulatory authorities.

T-20 is the furthest in clinical development in an investigational class of antiretrovirals called fusion inhibitors. Unlike currently approved classes of antiretrovirals that work inside the cell and target viral enzymes involved in the replication of the virus, clinical trials have shown that T-20 inhibits fusion of HIV with host cells before the virus enters the cell and begins its replication process.

The results from the TORO 2 study show that T-20 administered in combination with an optimised antiretroviral treatment regimen provides a significant additional decrease in the amount of virus in the blood as compared to an optimised antiretroviral treatment regimen alone. TORO 2 was conducted in 504 HIV infected patients in Europe and Australia who were treatment-experienced and/or had documented resistance to each of the three classes of currently available anti-HIV drugs.

At baseline, patients had a median HIV RNA level of over 5 log copies/mL (100,000 copies/ml HIV viral load) and extensive prior exposure to multiple anti-HIV drugs. At 24 weeks, patients who received T-20 as part of their combination regimen achieved a mean reduction in HIV levels of 1.43 log copies/mL compared to a mean of 0.65 log copies/mL for those who were randomised to the control arm, calculated in accordance with the study protocol. The primary efficacy endpoint for the study, the difference in the magnitude of decrease in HIV between the two arms at 24 weeks, was 0.78 log copies/mL and was statistically significant (p<0.0001). Roche and Trimeris expect to present these data in detail at scientific conferences in the next several months.

Safety results

Through 24 weeks, as in TORO 1, overall clinical adverse events aside from injection site reactions were similar between T-20 and control groups. Other adverse events (>10%) occurring more frequently in the T-20 group were headache, fever, and asthenia. It was not possible to establish a causal relationship between these other adverse events and T-20. Grade 3 laboratory abnormalities were more frequent in the T-20 group, and Grade 4 laboratory abnormalities were more frequent in the control group. In TORO 2, discontinuation at 24 weeks was 17 percent in the T-20 group and 5 percent in the control group. Patients experiencing virologic failure in the control group could switch to a T-20 regimen and not discontinue the study. While most patients on the T-20 arm experienced injection site reactions, only 3 percent of patients discontinued the study as a consequence.

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. Roche and Trimeris are committed to starting early access programs in the second half of this year when increased drug supply is expected to be available.

Study design

TORO 2 (T-20 vs. Optimized Regimen Only), previously known as T20-302, and TORO 1 (previously known as T20-301) are randomized, open-label trials that enrolled approximately 1,000 patients at 112 centers worldwide. TORO 2 is being conducted in Australia, Belgium, France, Germany, Italy, The Netherlands, Spain, Sweden, Switzerland and the United Kingdom, TORO 1 is being conducted in North America and Brazil. 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 was required to have 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 randomised 2:1 to receive either the regimen in combination with T-20 or the regimen alone. Patients randomised to T-20 receive T-20 administered as one 90 mg subcutaneous self-injection twice-daily.

Source: Roche/Trimeris media release

Comment

Despite the mounting evidence for the utility of this drug patients should be warned that the injection site reactions can become very unpleasant long-term and may result in painful subcutaneous nodules in some patients. The skin becomes more and more indurated and injecting yourself becomes an increasingly painful procedure. This is a major challenge for long-term use of T-20.

Further information on resistance to T-20 in the context of combination therapy is needed in addition to reassurance over concerns that neutralizing antibodies will not compromise efficacy as immune reconstitution on treatment may favour formation of such antibodies. Pegylation of T-20 with less frequent dosing should be explored as a matter of urgency to encourage adherence and longer term utility of this compound.