icon-folder.gif   Conference Reports for NATAP  
  12th Conference on Retroviruses and Opportunistic Infections (CROI)
Feb 22-25, 2005
Boston, MA
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PA-457, new HIV drug, maturation inhibitor
  Reported by Jules Levin
David Martin from Panacos Pharmaceuticals presented an oral talk at the last day's session at the 12th CROI on "New Drugs" reporting first time data on this new class of drug from a study in patients: "PA-457, the first-in-class maturation inhibitor, exhibits antiviral activity following a single-dose in HIV-1 infected patients".
Martin reported:
This drug has a novel mechanism of action that targets the Gag CA-SP1 cleavage step (explained below).
It's a potent inhibitor of HIV-1 replication.
It retains activity against drug resistant isolates.
Its synergistic when combined with approved drugs, meaning its not antagonistic.
PA-457resistant virus is sensitive to approved drugs.
Its highly active in the SCID-hu Thy/Liv mouse model of HIV infection.
Single & multiple dose studies in unifected volunteers have been completed.
It was safe & well tolerated at all doses studied.
It has a long half-life (i.e. 2-3 days) which results in significant drug accumulation and provides a low peak-to-trough ratio.
Following 10 daily doses of 200 mg, trough plasma concentrations were >15-fold the protein binding adjusted IC90 value.
Previous studies with other potent antiretrovirals have shown antiviral activity after a single oral dose. A single dose of 250 mg produced plasma concentrations that were above the protein binding adjusted IC90 value for up to 7 days. There is a need to establish clinical proof-of-principle for this non-enzyme, non-receptor target.
Previous Single Dose Studies
Viread (tenofovir)
Viread Single Mean Viral load
Dose decrease (day 4)
150mg -0.20 log
300mg -0.33 log
600mg +0.2 log

Reverset Single Mean Viral load
Dose Decrease (day 2)
50mg -0.45 log
100mg -0.42 log
200mg -0.27 log

Martin commented that potent HIV drugs exhibit about 0.2 to 0.4 log reductions in viral load following a single dose, although results are quite variable.
Study design
Randomized, double-blind, placebo-controlled single dose study.
Male, HIV-1 infected patients between 18 & 65 years of age.
No ARV therapy within 4 weeks of first dose.
CD4 >200 & HIV RNA 5,000-250,000 copies/ml.
24 subjects were randomly assigned to placebo, 75 mg, 150 mg, or 250 mg (n=6/group).
HIV RNA: 4.3 log
CD4 count: 516-590
Previous treatment: 1/6 in each dose group
Duration of HIV infection: 3.3 to 7.2 yrs
Age: 33-43 yrs
All doses were safe & well tolerated.
All adverse events were mild to moderate with no severe or serious adverse events reported.
No significant changes in clinical laboratory parameters, vital signs or ECGs reported.
The average response to the two high doses was a reduction of about -0.2 log.
The maximum changes from baseline in viral load: 3/6 patients receiving 150mg dose & 2/6 patients receiving 250mg dose had >0.5 log reduction.0/6 patients receiving 75 mg had >0.5 log reduction. The average reduction for the 75mg dose group was about -0.1 log. The majority of patients (8/12) at the two highest dose groups had a >0.3 log reduction. Reductions of up to 0.73 log were observed.
Martin reported responses for two patients with HIV drug resistance. One patient had mutations M184V & K103N, and their HIV RNA was reduced by 0.53 log. The other patient had mutations K103N, Y181C, & L90M, and their viral load was reduced by -0.73 log. No PA-457 resistant genotypes were observed.
Martin summarized: single oral doses were safe & gave statistically significant reductions in viral load of up to about 0.7 log, similar in magnitude to other potent antiretrovirals. Reductions in viral load were seen in the presence of multiple genotypic changes to 3 of the 4 approved classes of antiretrovirals.
A 10-day, once daily oral dosing viral dynamics study is ongoing & efficacy studies are planned to start later this year.
Here is an explanation of the mechanism of action from the company.
PA-457 and Maturation Inhibitors
PA-457 (3-O-(3',3'-dimethylsuccinyl) betulinic acid, DSB) is the first in a new class of antiretrovirals that block HIV-1 replication by disrupting virus maturation. Specifically, PA-457 inhibits a late step in the Gag processing cascade, namely the release of the capsid protein (CA or p24) from the capsid precursor (p25 or CA-SP1). As a result, PA-457 causes defective core condensation and the release of non-infectious virus particles from HIV-1 infected cells, thus blocking the spread of the infection to new cells. Due to its novel mechanism of action, PA-457 exhibits potent antiviral activity against HIV-1 strains resistant to all currently approved classes of antiretrovirals as well as wild- type virus. Furthermore, PA-457's anti-HIV activity is synergistic with approved HIV drugs.
PA-457 was found to have potent in vivo efficacy in the SCID-mouse model of HIV infection, following oral administration over a three week period. In vivo metabolism studies showed that the drug is not oxidatively metabolized, but is glucuronidated. Additional studies found that PA-457 does not inhibit or induce the enzymes responsible for metabolism of approved HIV drugs, suggesting that drug-drug interactions are unlikely to occur if this compound is used in combination therapy.
Panacos has completed single dose (Phase 1a) and multiple dose (Phase 1b) clinical studies of PA-457 in uninfected volunteers. The drug was well tolerated in these studies, with a half-life of ∼2.5-3 days. Plasma concentrations of the drug exceeded the target trough concentration that is predicted to be sufficient for a significant antiviral effect in HIV-1 infected patients.. These Phase I studies demonstrate that a once-daily oral dosing regimen should be effective for PA-457The Phase 1b study is the subject of a poster presentation at CROI (Poster #551, presented Wednesday 1.30-3.30 pm in Session 96: "New Antiretroviral Agents: New Classes").
Panacos recently completed a proof-of-principle Phase I/II clinical trial of PA-457. In that study, the drug was administered as a single oral dose to HIV-infected patients who were not on other therapy, in order to determine the pharmacokinetics and antiviral effect of the compound. Several different dose levels were tested in addition to placebo and the viral load was measured before and at intervals after treatment in each patient. A significant reduction in viral load, of up to approximately 0.7 log10, was seen in patients receiving the higher dose levels. The Phase I/II study is the subject of an oral presentation at CROI (Presentation #159, presented Friday 10.45 am in Session 37: "Antiretroviral Therapy: New Agents, New Combinations, and Virologic Responses").
In December 2004, the Company initiated a Phase IIa study of PA-457. The study, being performed at several sites in the U.S., is designed to demonstrate the antiviral potency of the drug following once-daily oral dosing for 10 days in HIV-infected patients who are not on other antiretroviral therapy. Results of the Phase 2a clinical trial are expected in Q2, 2005. During the second half of 2005, Panacos intends to initiate Phase 2b studies of PA-457 designed to pave the way for pivotal Phase 3 studies.
The US Food and Drug Administration has granted Fast Track designation for PA-457. Based on the drug's profile, PA-457 may have a role throughout the HIV treatment spectrum. PA-457 has potential as a second-line therapy for patients failing first line regimens, and will likely also have utility in third-line and salvage regimens. PA-457 could also have a role in first-line therapy based on once daily dosing and a favorable toxicity profile. The potential value of the drug in these different indications will become clearer as we move into and through late stage development.
• PA-457 is the first-in-class HIV Maturation Inhibitor
• Small molecule, once daily oral dosing
• Potent activity against HIV resistant to currently available drugs
• Targets capsid-SP1 cleavage: New target for HIV drug discovery discovered by Panacos scientists
• Synergy with approved drugs; distinct metabolism with low potential for drug-drug interactions
• Phase I studies of single dose and 10 daily doses in uninfected volunteers completed: High oral bioavailability, long half life and trough plasma concentrations exceeding therapeutic target
• Phase I/II single dose study in HIV-infected patients completed: Proof-of-concept established with up to ∼0.7 log10 reduction in viral load from baseline in patients at higher dose levels and mean viral load significantly reduced compared to placebo
• Well tolerated with no significant clinical toxicities identified to date
• FDA Fast Track status granted
• Potential utility throughout HIV treatment spectrum from first line to salvage
NDA filing goal: 2007