24-week results from phase III study of HIV fusion inhibitor T-20

11 June 2002. Related: Antiretrovirals.

Roche and Trimeris announced 24-week results from the first pivotal phase III study of T-20, the first in clinical development of an investigational class of antiretrovirals called fusion inhibitors.

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 the approval submission for the drug to the US Food and Drug Administration and other regulatory authorities.

TORO 1 (T-20 vs. optimised regimen only)

In the TORO 1 study, T-20 administered in combination with an individualised antiretroviral treatment regimen was shown to provide a significant additional decrease in the amount of virus in the blood as compared to an individualized antiretroviral treatment 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 HIV RNA level of over 5 log10 copies/mL and extensive prior exposure to multiple anti-HIV drugs.

Patients who received T-20 as part of their combination regimen achieved a reduction in HIV levels of 1.697 log10 copies/mL compared to 0.763 log10 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, was 0.934 log10 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.

“These Phase III results demonstrate that T-20 enhanced the activity of combination therapy over 24 weeks,” said William M Burns, Head of Pharmaceuticals, at Roche.

Safety Results

Through 24 weeks, the incidence of grade 3 and 4 laboratory abnormalities and clinical adverse events was similar between the T-20 and control arms. Additionally, 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 three percent of patients discontinued the study as a consequence.

Other adverse events (>10 percent), where the incidence was greater on the T-20 arm than on control, were insomnia, headache, peripheral neuropathy, and dizziness. It was not possible to establish a causal relationship between these other adverse events and T-20.

Study Design

TORO 1, previously known as T20-301, and TORO 2 (previously known as T20-302) are randomised, open-label trials that enrolled approximately 1,000 patients at 112 centres 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 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.

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 over the next several months 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. Additionally, Roche and Trimeris are committed to starting early access programmes in the second half of this year when increased drug supply is expected to be available.

Source: Press release, Roche Laboratories and Trimeris, Inc.

Comment

With the array of new drugs for HIV in early development the duration of necessity of injection with T-20 may not need be considered indefinite but simply ‘until we have suitable oral alternatives to replace it’. Such replacement would be on a case-by-case basis as oral drugs that act similarly to T-drugs may not be feasible. Additionally, patients may wish to replace agents in their regimens that are contributing more to toxicity than T-20 when new alternatives arise.

Encouraging earlier initiation of T-20 may help to diminish the risk of losing current options in what might be called ‘first salvage’ therapy rather than using T-20 against multi-class resistant virus in ‘deep salvage’. Multiple studies in treatment-experienced patients demonstrate the value of commencing 2 new drug classes simultaneously. Appreciation of the extent of cross-resistance with the nucleoside/nucleotide analog class has underlined the need (when feasible) to delay therapy switch until accumulation of several clearly active new agents has been achieved. If we initiate a new regimen now with our last available approved drug class, failing to achieve full suppression would mean T-20 may also then need to be initiated on a sub-optimal backbone. As a result, both remaining classes may be ‘wasted’ rapidly (through resistance development), for only short-term clinical benefits. If the fusion inhibitors are started in persons embarking now on their last approved drug class this is very likely to substantially increase the number of optimal responders at this line of therapy, increasing the chances of maintaining patients’ health until other options arrive.

If physicians are able to impart to patients the potential value to be added by including T-20 in their next regimen, rather than saving T-20 until they are ‘desperate’, the need for more complex and costly (both financially and in terms of toxicity) ‘mega-HAART’ ’deep salvage’ regimens may be averted. ‘Take something a bit more complex now to avoid something really tough next time’.