February 8, 2001
T-20 is the first member of a new class of antiretroviral rugs called fusion inhibitors. For over two years now, there has been a lot of excitement about this drug. T-20 binds to gp41, when this molecule is exposed after gp120 binds to the last domain of CD4 in the surface of the cell. T-20 is a 39 aa peptide. Because of this, it has to be given as an injection (if it were given orally it would be digested). Two years ago, in a short clinical trial, Michael Saag demonstrated good activity of T-20 in patients with multi-drug resistance. He also demonstrated that if given as a single drug, resistance appears rather quickly.
Lalezari presented the first major study of this drug for the treatment of drug resistance. This was a dose-finding study. T-20 was administered subcutaneously in three different doses of 50mg BID, 75mg BID, 100mg BID and placebo. The study was not powered to make comparisons between the arms. The study enrolled 71 patients who had drug resistance but they had to be naive to NNRTIs. All patients received a combination of abacavir, amprenavir, ritonavir, and efavirenz with or without T-20. Each arm had approximately 15 to 20 patients, with the median viral load at baseline 4.2 logs. By week 16, 18 patients had discontinued the study, ten of them because of local reactions (most likely related to T-20) and another eight patients with systemic problems, most likely related to the other drugs in the combination. Using the most conservative analysis (intent-to-treat) by week 16, 48% of the patients had a viral load of less than 50 and 71% less than 400 in the T-20 arms compared to 37% and 58% in the control arm.
These are pretty good numbers in rescue treatment, but it is important to note that all patients were naive to efavirenz. The results are not as impressive as the rescue of similar patients with Kaletra and efavirenz, but direct comparisons between both studies are not fair and should be avoided. Probably a combination of T-20 with Kaletra would be very potent in this setting.
T-20 arms had 0.5 log lower HIV RNA levels than non T-20 arms. CD4 count went up as expected.
T-20 was relatively well tolerated. Local reactions were frequent at the site of injection, but otherwise it does not look like it has many other side effects.
What is the future of this drug? This is the big question that I am sure everybody at Trimeris (the company developing this drug) is asking. Although T-20 looks potent, the fact that it has to be injected complicates its administration. In the future, it will probably be used only in the setting of bad resistance, which in turn makes the responses not look as they would look if they were facing naive patients.
We will need a large randomized trial to see what role this drug will have in the management of multi-drug resistant HIV. There is a group of patients who will definitely benefit from this drug. Subcutaneous injections complicate administration, but do not make it impossible (there are, after all, many insulin-dependent diabetics in this world). Oral fusion inhibitors would be a big advance, but it will be a few years before they are on pharmacy shelves. Trimeris is also developing a new peptide called T-1249, which also inhibits HIV fusion. They are now starting phase I trials for this drug.
Maybe these drugs do not have the ideal formulation, but we desperately need treatment options for patients with multi-drug resistance. T-20 will probably be the first of these drugs to receive approval.
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