Panacos Pharmaceuticals Inc provides results of a recently completed phase 1 clinical trial of its lead HIV drug candidate, PA-457, at the XV International AIDS Conference in Bangkok, Thailand. PA-457 is the first in a new class of antiretrovirals called Maturation Inhibitors directed against a novel viral target recently discovered by Panacos scientists, a company release says.
Because PA-457 has a different target than approved HIV drugs, it retains activity against virus isolates resistant to currently available treatments including reverse transcriptase inhibitors and protease inhibitors. The increasing prevalence of these drug resistant HIV strains is a major problem for the treatment of HIV infection, driving the demand for the development of novel drugs like PA-457.
In a presentation titled: "The In Vitro and In Vivo Disposition of PA-457, a Novel Inhibitor of HIV-1 Maturation", Dr. David E Martin, Panacos' VP, Drug Development, describes the Phase 1 results. The safety and pharmacokinetics of PA-457 were examined in uninfected, healthy male volunteers following a single oral dose of 25 mg, 50 mg, 100 mg or 250 mg in a dose escalation protocol. At each dose level, six subjects received PA-457 and two additional individuals received placebo.
PA-457 was well tolerated at all doses, with good oral bioavailability and favourable pharmacokinetics. All doses produced mean circulating plasma levels which exceeded the target therapeutic concentration, and at doses of 50 mg or greater PA-457 levels continued to exceed the target concentration 24 hours after administration. These results suggest that PA-457 will be suitable for once daily oral dosing.
Dr. Martin said, "Based on the promising results of the first clinical study, Panacos has now advanced PA-457 into a multiple dose phase 1 study to examine the safety and pharmacokinetics of the compound administered once daily to uninfected, healthy volunteers for 10 days. We anticipate moving PA-457 into phase 2 testing in HIV-infected patients later this year." In the same presentation, Dr. Martin summarizes results of pre-clinical studies that suggest PA-457 is unlikely to exhibit drug-drug interactions when used in combination therapy with approved HIV drugs.
In a related presentation, Dr. Carl Wild, Panacos' CSO, describes a recent study that elucidates PA-457's viral target. The drug candidate specifically blocks a late step in processing of the HIV Gag protein, namely conversion of the capsid precursor to mature capsid protein. Following PA-457 treatment, virus particles released from HIV-infected cells are non-infectious and virus replication is terminated. The Panacos presentation provides new data from a collaboration with scientists at the National Cancer Institute (Frederick, MD), revealing specific amino acids in Gag that are implicated in PA-457's activity.
Dr. Graham Allaway, chief operating officer at Panacos makes a third presentation on PA-457 describing how the drug potently inhibits HIV replication both in vitro and in an animal model of HIV infection. In cell culture studies, PA-457 shows activity against drug-resistant HIV strains that is comparable to that against wild type virus, strongly supporting the compound's potential value for treating strains of the virus that are resistant to approved drugs. Dr. Allaway also describes the results of a collaborative study with scientists from the Gladstone Institute (San Francisco, CA), demonstrating that PA-457 is a potent inhibitor of HIV replication following oral administration in the SCID-hu mouse model of HIV infection. In this study, PA-457 exhibited similar potency to the approved HIV drug EPIVIR (lamivudine or 3TC).
In a fourth Panacos presentation, Dr. Wild describes the Panacos proprietary high-throughput assay system for discovery of small molecule inhibitors of HIV fusion. Compared to peptide and protein-based inhibitors, orally bioavailable fusion inhibitors would offer considerable advantages for the treatment of HIV infection, including viral strains resistant to currently approved drugs. Panacos has successfully identified several novel families of small molecule inhibitors that are currently undergoing optimization to develop a clinical candidate.
On June 2, 2004, Panacos Pharmaceuticals entered into a definitive merger agreement with V.I. Technologies Inc, a biotechnology company dedicated to developing novel anti-infective technologies. The transaction is expected to close in the third quarter of 2004 and is subject to the approval by shareholders of both companies and other customary closing conditions.
Panacos Pharmaceuticals is engaged in the discovery and development of small molecule, orally available drugs for the treatment of HIV and other major human viral diseases. The Company's proprietary discovery technologies focus on novel targets in the virus life cycle, including virus fusion and virus maturation, the first and last steps of viral infection.