19th Report from: 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, Friday Feb 4th

T-20 and T-1249: fusion inhibitors

Much attention was paid at this conference to the development of the overall class of entry inhibitors. T-20 is a fusion inhibitor and a type of entry inhibitor. Its the furthest along in development. Sam Hopkins, from Trimeris Inc (the company developing T-20) discussed the hurdles in developing T-20. He reported a 32 week update on T-20 in study T20-205 which follows the 16-week report presented at ICAAC in September '99. Here are selected highlights. T-20 is not expected to have drug interactions with p450 drugs and not cross-resistant with current drugs. From non-clinical models Trimeris detected T-20 rapidly entered lymph system at levels comparable to those in plasma. So plasma levels can be a surrogate for penetration and concentration into lymph tissue, a key target tissue. Antibody formation and its effect on pharmacokinetics and efficacy were a key concern. Although some concerns were raised in early animal studies, Hopkins reported that when looking at chronic administration in clincal use (HIV+ humans) of T-20 did not show deleterious effects with regards to both viral load reduction and pharmacokinetics, and do not appear to cause serious adverse events. Previously, Trimeris was concerned that manufacturing capacity might be a concern in part due to the novel nature of this drug, but Hopkins announced that manufacturing is no longer a concern. Pediatric patients are being dosed. Hopkins said they have seen a clear dose dependent viral load response correlated well with clinical pharmacology data collected to date. Based on initial short-term studies I think about a 1 log viral load reduction could be expected in treatment-naive individuals at the dose used in the 205 study described herein (50 mg bid). But at a higher dose of 100 mg bid the antiviral activity would be expected to be more. Unfortunately, the administration method presents a problem. Using the current formulation, the 100 mg bid dose would require 2 subcutaneous injections twice daily. 

They are seeing a half-life of 6-8 hours. In animals they saw a Tmax of 45 minutes but but humans they're seeing 4-hour Tmax. As well the trough, the Cmin occurs after dose administration rather than after 12 hours. Taken together this suggests a human deposition effect. The decay factors suggest to Hopkins that they could move to a once a day formulation. T20-205 is a single arm open-label study at multi-centers for 71 individuals with extensive experience with antiretrovirals across all classes of drugs for patients who previously received T-20 in trials. Study was intended to look at safety including antibody formation over an extended time. The secondary objective was just to monitor viral load over time. Individuals received subcutaneous injection of 50 mg of T-20 twice daily. Each participant received an individualized regimen based on genotypic testing at baseline and consideration of prior treatment history in consultation with their personal physician. Median number of antivirals was 4 for each person. Median number of prior antiretrovirals was 11. About 1/3 of patients had gone off all antiretrovirals prior to starting this study. Some had been off therapy 3-6 months. Median CD4s were about 89. And VL was just below 100,000 copies, reported at 80,000 copies/ml at ICAAC with 70 CD4s. In order to look at compliance because they were concerned that the type of administration may be difficult for individuals to comply with, they added plasma draws to look at concentration of T-20. After study week 24 concentration levels were well within the therapeutic range and compared well with levels seen in prior human study. Hopkins also said they detected T-20 in all patients at all measured time points. He concluded that compliance was good. 

Hopkins said preliminary data at week 32 support trends seen at week 16. About 1.0-1.5 log suppression is seen at week 32. Median CD4s counts are about 126 showing a gain of about 32 cells. Most comon adverse event seen is local inflammation at the site of injection. So far they've seen no evidence of a systemic antibody response. Although potent antiviral activity hasbeen observed in previous studies I think it should be pointed out that in this study its difficult to sort out antiviral effect of T-20 because patients added T-20 at the same time they they started a new regimen.

At ICAAC Jay Lalezary reported 16-week data-- 60% (33/55) had VL reductions >1 log and/or <400 copies/ml, 36% (20/55) had <400 copies/ml, and 20% had < 50 copies/ml using on-treatment analysis. The ITT analysis was about the same. Individuals with triple class exposure and documented triple class resistance also had similar results. Although the data was not shown Lelazari said there was no difference in outcome between those who took drug holidays and those who did not.

Hopkins described an ongoing salvage study (T20-206) randomized open-label trial. Three T-20 dose regimens are being used. All patients are receiving abacavir+APV+RTV+EFV with or without T-20. This study is ongoing and the first patients are approaching 32 weeks but data is not yet available. 

T-1249 is the second fusion inhibitor in development by Trimeris. It's active against HIV-1 and HIV-2 and SIV. It has a longer half-life in primates so T-1249 may be a once a day or possibly once every other day admninistration. Its AUC is about 2-fold greater than T-20s. Hopkins reported they have seen it to be active in vitro against resistance to T-20.

In poster 500 at Retroviris in vitro synergy was reportedly seen between T-20 and AMD-3100. AMD-3100 is a small molecule inhibitor of HIV-1 attachment to CXCR4 (entry inhibitor). Whether synergy between these two compounds in vitro will translate into clinical benefits will need to be addressed in the context of clinical trials. It will also be of interest to evaluate whether similar interactions are observed using other compounds that act on HIV-1 attachment or entry. The development of additional new types of entry inhibitors would allow testing combinations of entry inhibitors possibly allowing for the creation of entirely new classes of treatments for HIV.