Fusion inhibitors are a new class of anti-HIV therapy that targets the
earliest part of HIV's lifecycle, its entry into the human cell. Unlike the reverse
transcriptase inhibitors (nucleoside, non-nucleoside, and nucleotide) or protease
inhibitors which attack HIV already inside the cell as it attempts to reproduce itself,
fusion inhibitors prevent HIVs entry in the first place. Since HIV specifically
targets the human CD4 immune cell, blocking fusion could mean greater protection of the
immune system. And by working outside the cell, fusion inhibitors minimize the potential
for side effects associated with anti-HIV therapy.
T-20 is a synthetic, 36 amino acid peptide that mimics a segment of the
HIV gp411 that, with gp120, forms a key portion of the HIV-to-cell binding
complex. gp41 is the "stinger" that penetrates the cell membrane and brings the
virus into contact with the cell membrane in such a way that fusion can occur. Once gp120
latches onto the cell's receptor, it unfolds to expose gp41. T-20 binds to gp41,
preventing it from changing its shape. Without this change of shape, gp41 cannot penetrate
the cell membrane and cannot complete its task of initiating cellular fusion.
TRI-001: Phase I/II safety, efficacy, and PK dose escalation trial
Seventeen HIV-1 infected volunteers (both treatment-naïve and
-experienced) with CD4 counts ³ 100 and a viral load ³ 10,000 (4.0 log 10) copies/ml were randomized to one of
four doses: 3, 10, 30, and 100 mg of T-20 administered intravenously BID. Subjects
discontinued any current antiretroviral medications 15 days before screening and remained
off them through the course of the study. At Day 1, each subject was given a single dose
at the assigned level and then monitored for safety and PK through a two-day washout
period. Then therapy was restarted at the assigned dose and continued for 14 days.
No adverse events were reported. Pharmacokinetic assessment showed a
strict dose-dependent response to T-20. The 100 mg BID dose maintained peak trough plasma
levels of T-20 above 1 mg/ml2 for a 24-hour period.
HIV RNA viral load data3 also showed a dose-dependent response at 10, 30, and
100 mg BID. At day 18, all of those subjects receiving 100 mg BID had viral loads below
the level of detection, with a mean suppression of viral load of 1.5 log10. A
similar dose-dependent response was observed on CD4 counts, which rose a mean of 52 cells
in the 100 mg dose group. In conclusion, T-20 demonstrated potent antiretroviral activity in
vivo and T-20 monotherapy was at least as effective as combination therapy in reducing
viral load over 14 days4.
TRI-003: Phase II safety, efficacy, and PK trial
Seventy-eight HIV-infected individuals with a viral load of > 5,000
copies/ml (3.7 log10) and either on no or a stable ARV regimen were randomized
to one of six dose groups ranging from 12.5 to 200 mg/day. T-20 was administered either by
continuous subcutaneous (SC) infusion or BID SC injection for 28 days. At entry, the mean
viral load was 5.0 log10 copies/ml with a mean CD4 count of 117 cells/mm3.
Seventy-seven of the 78 had prior ARV experience (mean number of prior ARVs = 9) and 98%
were PI-experienced (mean number of prior PIs = 3).
T-20 was well tolerated throughout the study period with only two
subjects withdrawing due to adverse events. No difference in effect was observed between
injection and infusion. The average maximum change from baseline in viral load was -0.3 to
-1.6 log10, with a greater magnitude and durability of response in subjects
with baseline viral load of < 100,000 copies/ml (5.0 log10)5.
T-1249, a synthetically designed proprietary peptide, is the second, newer-generation
fusion inhibitor designed to be effective on HIV that becomes resistant to T-20. Trimeris
announced enrollment for Phase I dose ranging and safety trials on 1 July, 1999.
Pre-clinical data suggest that T-1249 might be dosed only once a day by injection SC and
that will be tested in this trial as well. Similar in design to TRI-001, this trial will
enroll up to 60 HIV-infected individuals at eight clinical sites in the United States and
test three different doses of T-1249 monotherapy over 14 days of therapy6.