Short‐Term Safety and Antiretroviral Activity of T‐1249, a Second‐Generation Fusion Inhibitor of HIV

Abstract

T-1249 is a 39-aa synthetic peptide that inhibits fusion of human immunodeficiency virus (HIV) to the host target cell. A 14-day open-label, phase 1/2 dose-escalation monotherapy study of the safety and antiretroviral activity of T-1249 was performed on 115 HIV-1-infected adults. At baseline, the majority of the patients had advanced HIV disease (baseline median CD4(+) cell count, 57 cells/microL) and had extensive pretreatment (i.e., pre-T-1249) experience with antiretroviral medications (median, 11 antiretroviral drugs). Patients received T-1249 monotherapy by subcutaneous injection, for 14 days, at doses ranging from 6.25 to 192 mg/day. T-1249 was generally well tolerated, and no dose-limiting toxicity was identified. Injection-site reactions were the most commonly reported adverse event (57%). Dose-dependent decreases in plasma HIV-1 RNA load were observed; the median maximum change from baseline across dose groups ranged from -0.29 log(10) copies/mL (95% confidence interval [CI], -0.43 to -0.05 log(10) copies/mL) for the lowest dose to -1.96 log(10) copies/mL (95% CI, -2.02 to -1.37 copies/mL) for the highest dose. These results indicate that T-1249 is a potent new therapeutic agent for HIV-1 infection.

Tropism-independent protection of macaques against vaginal transmission of three SHIVs by the HIV-1 fusion inhibitor T-1249

“…Moreover, our in vitro studies show that T-1249 has substantial breadth of activity across the HIV-1 genetic subtypes, again independently of coreceptor tropism. These properties combine to make T-1249 a promising microbicide candidate, a view supported by its extensive safety record and antiviral potency when delivered systemically to HIV-1-infected humans (by s.c. injection) during clinical trials (7,8).…”

“…One such compound is the fusion inhibitory peptide, T-1249, a second-generation derivative of the licensed antiretroviral drug enfuvirtide (T-20). T-1249 was evaluated clinically for its potential as a therapy to treat established HIV-1 infection and was shown to have a strong antiviral effect, with viral load reductions approaching 2.0 logs after once-or twice-daily s.c. injections delivering 150-200 mg per day (7,8). Moreover, the safety profile for T-1249 was excellent, with only injection-site reactions being a significant concern, something that would not apply to a topically administered formulation.…”

Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency

“…Further analysis of the antiviral potency of C34-Chol is shown in Table 4, where the antiviral activity of C34-Chol is compared, in two separate experiments, with underivatized C34, and with T20 and the second-generation FI T1249 (32,50), which is active against most enfuvirtide-resistant strains (23). Comparison of the IC 90 values, a stringent measure of antiviral potency, across a panel of HIV primary isolates from multiple subtypes shows that, depending on the strain tested, C34-Chol is 25-to 100-fold more potent than C34, 50-to 400-fold more potent than enfuvirtide, and 15-to 300-fold more potent than T1249.…”

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

“…Although there were no differences in the amount of virion-associated envelope glycoprotein, recipient isolates were on average threefold more infectious (P = 0.0001), replicated to 1.4-fold higher titers (P = 0.004), were released from infected cells 4.2-fold more efficiently (P < 0.00001), and were significantly more resistant to type I IFNs than the corresponding donor isolates. Remarkably, transmitted viruses exhibited 7.8-fold higher IFNα2 (P < 0.00001) and 39-fold higher IFNβ (P < 0.00001) half-maximal inhibitory concentrations (IC 50 ) than did donor isolates, and their odds of replicating in CD4 + T cells at the highest IFNα2 and IFNβ doses were 35-fold (P < 0.00001) and 250-fold (P < 0.00001) greater, respectively. Interestingly, pretreatment of CD4 + T cells with IFNβ, but not IFNα2, selected donor plasma isolates that exhibited a transmitted virus-like phenotype, and such viruses were also detected in the donor genital tract.…”