Maturation inhibitor shows anti-HIV activity in single dose pilot study

A phase I trial of PA-457, the first of a new class of antiviral drugs, demonstrated that single, oral doses show dose-related antiviral activity, and were safe and well tolerated. PA-457 retained activity in two patients with extensive resistance mutations.

PA-457 is the first of a new class of drugs called maturation inhibitors, which block the conversion of the HIV-1 capsid precursor CA-SP1 (p25) to mature capsid protein (p24) resulting in the release of non-infectious virus particles. It has been shown to potently inhibit the HIV-1 replication, including strains resistant to currently prescribed drugs and is highly active in the SCID mouse model.

This American-German, double-blind, placebo-controlled study assessed the antiviral response and pharmacokinetics of PA-457 following a single, oral dose. 24 HIV positive patients with CD4 counts >200 cells/mm³ and plasma viral load of 5,000 to 250,000 copies/mL were divided into 4 groups of 6 people and each group was given a different single, oral dose: placebo, or 75 mg, 150 mg, or 250 mg of PA-457.

Data from 16 patients (4 in each group) were available for report at CROI. All doses were safe and well tolerated with no drug related adverse events. There were reductions in mean viral load in all three groups compared to the placebo group which was sustained for more than 10 days in the higher dose groups.

Median maximum viral load reduction for each treatment group showed a dose-dependent relationship of –0.17 log, –0.27 log, –0.45 log and –0.51 log in the placebo, 75mg, 150mg and 250mg groups respectively (p < 0.05).

Preexisting mutations in one patient with 210W, 103N, 181C, 77I, and 90M in the 250mg group produced a –0.73 log reduction. Another subject with 184V, 103N, 10I, and 77I in the 150mg group had a –0.53 log reduction.

Martin D, Jacobson J, Schurmann D et al. PA-457, the first-in-class maturation inhibitor, exhibits antiviral activity following a single oral dose in HIV-1-infected patients. 12th CROI, Boston, 2005.
Abstract 159.