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PA-457, New HIV Drug; & Research for new Fusion Inhibitors
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"Panacos Pharmaceuticals Presents Phase 1 Clinical Data on First-in-Class HIV-1 Maturation Inhibitor, PA-457, at XV International AIDS Conference, Bangkok, Thailand"
PRESS RELEASE DISTRIBUTED BY Panacos Pharmaceuticals & emailed to you for your information. There were 4 abstract on PA-457 & their search for small molecule fusion inhibitors, and all 4 are included in this report at the bottom of the report.
Additional Panacos Presentations Include Data on PA-457's Molecular
Target and the Discovery of Novel HIV Fusion Inhibitors
GAITHERSBURG, Md., July 14 /PRNewswire/ -- Panacos Pharmaceuticals, Inc. today 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. 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.
SEE ABSTRACTS AT END OF PRESS RELEASE
In a presentation titled: "The In Vitro and In Vivo Disposition of PA-457, a Novel Inhibitor of HIV-1 Maturation" (Presentation #WePeA5644), 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 favorable 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' Chief Science Officer, 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 (Presentation #WeOrA1276).
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 (Presentation #WePeA5643). 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(R) (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 (Presentation #WePeA5650).
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.
For more information on Panacos Pharmaceuticals, please visit http://www.panacos.com, or email: info@panacos.com.
SOURCE Panacos Pharmaceuticals, Inc
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In vitro and in vivo disposition of PA-457, a novel inhibitor of HIV-1 maturation
D E Martin1, P Smith2, C T Wild1, G P Allaway1
1Panacos Pharmaceuticals, Gaithersburg, United States; 2School of Pharmacy, University of North Carolina, Chapel Hill, United States
abstract WePeA5644
Background: PA-457 is the first in a new class of antiretrovirals called Maturation Inhibitors (MI). PA-457 blocks a late step in HIV-1 Gag processing that results 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. This report describes ADME studies designed to assess PA-457's development potential.
Methods: PA-457 was tested in a variety of in vitro test systems to characterize the metabolic profile of the compound. PA-457 was administered orally (PO) and intravenously (IV) to mice, rats, marmosets, and dogs to characterize its in vivo disposition.
Results: Studies with microsomes from mouse, rat, marmoset, dog, and human liver indicated that only liver microsomes from the rat caused significant metabolism. Inhibition of cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) was evaluated. The IC50 for inhibition for all isoforms was >100 µM except for CYP2C9 which was ~10 µM. Studies with human UGTs indicated that 1A3 was primarily responsible for glucuronidation of PA-457. PA-457 exhibited weak to moderate inhibition of 1A1, 1A3, 1A4, 1A8, 1A10, and 2B7. Following IV and PO administration the oral bioavailability was greatest in marmosets (~60%) and lowest in the dog (~10%). The half-life was longest in marmosets (~14 hrs).
Conclusions: PA-457 appears to undergo glucuronidation mediated primarily by 1A3. It does not inhibit the cytochrome P450 system but exhibits weak inhibition of glucuronidation by a subset of UGT isoforms. These data suggest that PA-457 will not exhibit significant drug-drug interactions when used in combination with other HIV drugs. PA-457 exhibits good oral bioavailability and a long half-life in rats and marmosets with moderate oral bioavailability in mice and dogs. These properties strongly support the further development of PA-457 for the treatment of HIV-1 infection.
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Selection for and characterization of HIV-1 isolates resistant to the maturation inhibitor PA-457
K Salzwedel1, R Goila-Gaur2, F Li1, A Castillo1, N R Kilgore1, M Reddick1, C Matallana1, D Zoumplis1, D E Martin1, G P Allaway1, E O Freed2, C T Wild1
1Panacos Pharmaceuticals, Gaithersburg, MD, United States; 2National Cancer Institute, Frederick, MD, United States
abstract WeOrA1276
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 that results 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 viral protease enzyme that is responsible for Gag processing. PA-457-resistant virus isolates were used to map the determinants of the compound's activity.
Methods: PA-457-resistant virus isolates were selected by continuous culture in the presence of increasing concentrations of compound. Genotyping of resistant virus and preparation of molecular clones with resistance-conferring mutations were carried out using standard methods. PA-457 resistance was characterized using cell-based activity assays and in vitro analysis of Gag processing.
Results: In vitro selection generated PA-457-resistant virus. Genotypic analysis of these isolates revealed two independent patterns of resistance-conferring mutations. Consistent with our MOA studies these mutations map to residues flanking the Gag CA-SP1 cleavage site. An A to V change at either the first or third residues at the N-terminus of SP1 (A1V or A3V) resulted in a resistant phenotype. While these changes resulted in a decrease in sensitivity to PA-457, these viruses remained sensitive to all classes of approved HIV drugs.
Conclusions: These results support and extend previous observations that PA-457 is a specific inhibitor of CA-SP1 cleavage, with no activity against other Gag processing events. Characterizing the determinants of PA-457 activity is the first step in defining the molecular target for this novel HIV maturation inhibitor.
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The first-in-class maturation inhibitor, PA-457, is a potent inhibitor of HIV replication both in vitro and in vivo
G P Allaway1, J Bare2, N R Kilgore1, M Reddick1, D E Martin1, C T Wild1, C A Stoddart2. 1Panacos Pharmaceuticals, Gaithersburg, MD, United States; 2Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, CA, United States
Abstract WePeA5643
Background: PA-457 is the lead drug candidate in a new class of antiretrovirals termed maturation inhibitors. It has been shown that PA-457 blocks virus replication by disrupting conversion of the capsid (CA) precursor, p25 to mature CA protein, p24. This block to CA processing results in defective core condensation and the release of non-infectious virus particles. PA-457's mechanism of action is distinct from that of protease inhibitors in that it appears to target the Gag precursor protein rather than the viral protease. PA-457's anti-HIV activity both in vitro and in the SCID-hu Thy/Liv mouse model was examined.
Methods: In vitro activity against a panel of wild-type (WT) and drug resistant virus isolates was determined in cell-based assays employing either HIV-permissive cell lines or PHA-stimulated PBMC targets. In vivo studies in the SCID-hu Thy/Liv mouse were carried out over a 21 day period and used an orally bioavailable salt form of PA-457, and the HIV-1 molecular clone NL4-3.
Results: PA-457 proved to be a potent in vitro inhibitor of HIV replication with a mean IC50 value of ~10 nM against a panel of WT virus isolates, and retained similar activity against HIV strains resistant to approved drugs. Oral administration of the PA-457 salt to NL4-3-infected SCID-hu mice reduced Thy/Liv implant viral load in a dose-dependent manner, causing reductions of 2.1 log10 (mean of 3.9 log10 versus 6.0 log10 copies HIV-1 RNA per 106 cells for untreated mice), 0.9 log10, and 0.3 log10 (not significant) at 100, 30, and 10 mg/kg/day, respectively.
Conclusions: These results establish PA-457 as a potent inhibitor of HIV replication both in vitro and in vivo. The in vitro results demonstrate the compound's broad range of activity against clinically relevant HIV-1 isolates. The potent activity observed in the SCID-hu Thy/Liv mouse system establishes a proof-of-principle for this new class of compounds and supports further development of this novel inhibitor.
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Novel small molecule inhibitors of HIV-1 fusion
K Salzwedel, K Crisafi, T Jackson, A Castillo, N R Kilgore, M Reddick, G P Allaway, C T Wild. Panacos Pharmaceuticals, Gaithersburg, MD, United States
Background: Fusion inhibitors are a promising new class of HIV therapeutics that act by blocking conformational changes in the HIV envelope glycoprotein (Env) that drive fusion of the viral and cellular membranes during virus entry. Proof of concept for this therapeutic approach is provided by the recently approved inhibitor, T-20 (Fuzeon), a peptide-based drug that must be injected twice daily and is expensive to manufacture. The identification of orally available small molecule fusion inhibitors would provide new therapeutic options for HIV/AIDS. Here we describe the identification and characterization of novel small molecule inhibitors of HIV fusion.
Methods: We used a previously described high-throughput fusion inhibitor assay to screen diverse libraries of drug-like small molecules. Our approach identifies compounds that block conformational changes within the HIV Env protein that are critical for virus entry. Hits from the primary screen were confirmed in functional assays measuring inhibition of gp41-mediated membrane fusion, virus entry, and virus replication. The effects of these compounds on exposure of conformational epitopes within gp120/gp41 were studied by flow cytometry.
Results: We identified two structurally distinct families of drug-like small molecules that inhibit HIV-1 fusion and virus entry with low micromolar potency. Mechanism of action studies suggest that these compounds bind to HIV Env and specifically block receptor-induced conformational changes. As a result, the Env protein is unable to form a critical gp41 six-helix bundle structure that is required for fusion.
Conclusions: The compounds identified in this study are promising starting points for the development of more potent small molecule HIV fusion inhibitors. Optimization of these compounds may lead to attractive alternatives to peptide-based fusion inhibitors.
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