Background:  PA-457 is the first in a new class of antiretrovirals called maturation inhibitors that specifically block the conversion of the HIV-1 capsid precursor, CA-SP1 (p25) to mature capsid protein (p24), resulting in defective core condensation and the release of non-infectious virus particles. PA-457 potently inhibits HIV-1 replication including strains resistant to approved drugs and is highly active in the SCID mouse model of HIV-1 infection. PA-457 was well tolerated in single and multiple dose phase 1 studies in healthy subjects with pharmacokinetic parameters that suggest once-daily oral dosing. This study assessed the antiviral response and pharmacokinetics of PA-457 following single oral doses in HIV-1-infected patients.

Methods:  In this double blind, placebo-controlled study, a single oral dose of PA-457 was administered to 4 groups (placebo, 75, 150, or 250 mg) of 6 HIV-positive patients/group with CD4 counts ≥ 200 and plasma viral load of 5000 to 250,000 copies/mL. Patients were antiretroviral naοve or at least 4 weeks without other antiretrovirals. HIV RNA and plasma concentrations were measured over a 20-day period. 

Results:  Data from 16 patients are currently available (4/dose group). All doses of PA-457 were safe and well tolerated with no treatment emergent drug-related adverse experiences reported. All 3 dose groups exhibited reductions in mean viral load compared with placebo that was sustained for more than 10 days in the higher dose groups (see the figure). The maximum viral load reduction for each patient was determined and the median of this value for each treatment group was compared, revealing a dose-dependent relationship (p < 0.05):  placebo  –0.17 log; 75 mg –0.27 log; 150 mg –0.45 log; 250 mg –0.51 log. Genotyping revealed preexisting drug-resistance mutations in 2 subjects:  subject 101 (250 mg) had 210W, 103N, 181C, 77I, and 90M, while subject 103 (150 mg) had 184V, 103N, 10I, and 77I. Subject 101 had a –0.73 and 103 had a –0.53 log₁₀ reduction.

HIV-RNA group means (change from baseline) ♦ = placebo, ■ = 75 mg, ▲ = 150 mg, X = 250 mg.

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Conclusions:  Single, oral doses of PA-457 demonstrated dose-related antiviral activity and were safe and well tolerated in HIV-infected patients. PA-457 retained activity in 2 patients with extensive resistance mutations. Although longer duration studies are needed to fully establish the potency of this new compound, these initial data support further development of PA-457 as a potential new treatment option for HIV infection.

Keywords: PA-457; Viral Dynamics; Pharmacokinetics