Safety, Pharmacokinetics, and Antiviral Activity of T-20 as a Single Agent in Heavily Pre-treated Patients
J Lalezari, J Eron and others

Report from Jules Levin

Joe Eron reported on this 2nd study of T-20 in HIV infected individuals. A previous report discussing data from the first study and a pictorial on how fusion inhibitors work is available on this web site (click here to read the article). Fusion inhibitors are a new class of drugs. Therefore, individuals with resistance to the other 3 classes of drugs should be fully sensitive to T-20. In this study, T-20 displayed potent antiviral activity at the highest dose used (100 mg BID administered by subcutaneous injection (see below). The previous study only explored administration by infusion from a pump. Very importantly, this study indicates that T-20 does not have to be administered by a continuous infusion from a pump. This is a very important development. It is hoped that T-20 will be a helpful component of therapy for individuals with resistance to other antiretroviral drugs.

Eron said T-20 is not expected to be cross-resistant with other therapies. As a fusion inhibitor, T-20 prevents HIV from fusing with a CD4 cell. It attaches itself to the receptor on HIV which binds to the CD4 cell and prevents the receptor from attaching itself to the CD4 receptor. Eron presented results from study TRI-003 which was a multicenter, randomized, phase 2 dose ranging trial. 78 patients were randomized to 6 regimens (13 per dose group).The drug was delivered in two ways. One was a continuous subcutaneous infusion (CSI) daily using a pump like that used to deliver insulin to diabetics at 4 doses: 12.5 mg, 25 mg, 50 mg, 100 mg. For the first time this study also administered T-20 with twice daily subcutaneous injections (SCI)of either 50 mg or 100 mg. This was a 28 day study. There was no limitation on treatment experience. Patients had to be either off their current therapy for at least two weeks or on a stable regimen for greater than 6 weeks. They could not have any opportunistic infections and their viral load must have been greater than 5,000 copies/ml.

Three patients withdrew before starting the study and 5 discontinued during the study. Three discontinued voluntarily due to having mechanical problems with the pump. They had trouble with the pump "in this form" alarming and also patients developed small subcutaneous nodules. So, a third of the way through the trial they allowed participants to switch from the subcutaneous infusion to the injections, and 14 patients (37%) chose to do that. Two patients dicontinued due to adverse events.

The baseline characteristics were similar for all the arms

Median Viral Load 5.02 log (100,000 copies/ml)
Median CD4 96

59% remained on stable antiretroviral therapy for study and 41% chose to be off any other therapy. The patients in the study had extensive prior treatment experience. Only 1 patient in the study was treatment naïve. The average number of prior antiretrovirals per person was 9, 98% had protease inhibitor experience. The median number of failed PIs was 3, and 41% had experience with all approved PIs. 46% had prior experience with all three classes of antiretroviral drugs.

Preliminary Safety Results. There were mild to moderate injection site reactions consisting of little bumps which occurred more with use of the pump. Two patients (3%) had an abscess at the injection site. As mentioned before there were 2 discontinuations: 1 patient (100 mg CSI) due to Grade 2 pain at the infusion site; 1 patient taking 100 mg by subcutaneous injection experienced a Grade 2 disseminated rash. Eron said T-20 was well tolerated for the 28 days as there were no Grade 3 or 4 adverse reactions.

Pharmacokinetics. Eron said they were pleased by the pharmackinetics or the plasma levels of drug. They measured blood levels at steady state on day 14 and found a dose response. The people receiving a daily dose of100 mg by infusion had a similar trough to those receiving 50 mg BID by subcutaneous injection. But, individuals taking 100 mg BID had the highest blood levels and a higher trough. Although, Eron said there was a good deal of variability in blood levels for the 100 mg BID group. There was a consistent and constant blood level of T-20 through the 12 hour dose period for the 50 and 100 mg bid dose group. Trimeris researchers suggested it was almost as if there is a skin depot where the drug slowly enters the blood over the dosing period. Eron said the subcutaneous injection provided 12 hour trough well above the average in vitro IC90 of clinical isolates.

HIV-RNA Reduction. The group receiving 100 mg BID bu subcutaneous injection had the highest median nadir viral load reduction (Intent-To-Treat) of about 1.5 log. For the 50 mg BID it was about 1.2 log and for the 100 mg by continuous infusion group it was almost 1 log. Median nadir represents the greatest viral load reduction achieved during the 28 days, because the viral load started rebounding back up after reaching the nadir. The mean (Intent-To-Treat) viral load reduction was about 1.5 log for the 100 mg BID subcutaneous group which was achieved about 1 week after starting T-20. By day 28 the viral load reduction was back up close to baseline. Bear in mind 41% were receiving T-20 monotherapy and the other 59% were also failing the regimen they started the study with- the median baseline viral load was 100,000 copies/ml. The middle 3 doses had much lower mean viral load reductions (about 0.05 log).

In the abstract in the Conference program the authors said the magnitude and durability of viral load suppression was greater in patients with baseline viral load less than 100,000 copies/ml. Trimeris Inc. , the compant developing this drug, is planning follow-up studies. It appears as if the company is pacing a high priority on exploring T-20's use in salvage therapy. I expect it will be studied in combination with new PIs being developed which may not be cross-resistant with currently available protease inhibitors. These include ABT-378, BMS-232632 from Bristol Myers-Squibb, and tipranavir being developed by Upjohn and Pharmacia. ABT-378 is the furthest along in development (click here to see the report on ABT-378 at Retrovirus). A study of ABT-378 for individuals failing 1 protease inhibitor started in Fall '98. Preliminary results should be available soon. Bristol Myers is preparing to launch trials soon for their PI. Hopefully, salvage studies will be on a fast track.