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Recent data on PA-457 Maturation Inhivitor
David. E. Martin, PharmD
Panacos Pharmaceuticals Inc., Gaithersburg, MD.
Background: PA-457 is the first in a new class of antiretrovirals that inhibit HIV replication
by disrupting virus maturation. PA-457 blocks a late step in Gag processing, resulting in
defective core condensation and the release of non-infectious virus particles. Specifically,
PA-457 disrupts the conversion of the capsid precursor, p25 (CA-SP1), to mature CA
protein, p24. PA-457's mechanism of action (MOA) is distinct from that of protease
inhibitors in that it appears to directly target the Gag precursor protein rather than the
protease enzyme that is responsible for Gag processing. This report describes the in vitro
antiviral profile of PA-457 and results from clinical studies in normal, uninfected volunteers
and HIV-1 infected patients.
Methods: We analyzed the activity of PA-457 against a panel of HIV-1 isolates resistant to
NRTIs, NNRTIs or PIs. MOA studies focused on events late in the virus life cycle including
protease function and viral protein processing. PA-457-resistant isolates were generated
by serial passage of virus in the presence of increasing concentrations of compound.
Phase 1 and Phase 2 clinical studies have been conducted to evaluate the safety,
pharmacokinetics and antiretroviral potency of PA-457 and its potential for drug-drug
interactions.
Results: PA-457 retains low nM IC50 against all drug-resistant HIV-1 isolates tested. MOA
studies indicate that PA-457 inhibits virus replication by causing a defect in Gag
processing, specifically the conversion of p25 to p24. As a result of this block, virions
produced in the presence of PA-457 are defective for capsid condensation, exhibiting
spherical electron-dense cores and a second crescent-shaped electron-dense structure
lying just beneath the viral membrane. Furthermore, genotypic analysis of
PA-457-resistant virus indicates that mutations that confer resistance map to residues
flanking the p25 to p24 processing site. Clinically, multiple oral doses up to 200 mg of
PA-457 administered once daily for 14 days were safe and well tolerated. In a 10-day
monotherapy study, PA-457 produced statistically significant reductions from baseline in
HIV RNA of up to 1.78 log10 in the 200 mg QD dose group. These data suggested that
the plateau of the dose response relationship had not been reached. Population
sequencing of the CA-SP1 cleavage site from patients in the highest dose group (i.e.,
200 mg QD) found no mutations known to cause a reduced sensitivity to PA-457.
Drug-drug interaction studies were conducted with PA-457 and atazanavir and ritonavir,
which suggest that PA-457 has a limited potential for clinically relevant interactions.
Conclusions: PA-457 is the first in a new class of drugs called Maturation Inhibitors.
It utilizes a novel mechanism of action to potently inhibit HIV-1 replication of all
drug-resistant HIV-1 isolates tested. Clinical studies suggest that PA-457 has a low
potential for clinically relevant drug-drug interactions. Monotherapy studies with PA-457
have demonstrated potent antiviral responses. Future clinical studies will explore higher
doses to attain the maximum antiviral effect and evaluate the durability of the antiviral
response.
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