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Safety and Antiviral Activity of PA-457, the First-In-Class Maturation Inhibitor, in a 10-Day Monotherapy Study in HIV-1 Infected Patients
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Reported by Jules Levin
ICAC, Wash DC, Dec 17, 2005
George Beatty (UCSF Positive Health Program) reported at the information ICAAC. PA-457 is first in a new class of Maturation Inhibitors. It blocks the last step in gag processing: CA-SP1 cleavage (Li et al Proc Natl Acad Sci USA 2003; 100:13555). It has nanomolar inhibition of HIV-1 replication (IC50 about 5-10 nM); retains activity against drug-resistant isolates. Its orally bioavailable. Metabolism profile is distinct from approved HIV drugs; low probability of drug-drug interactions. Summary: highest dose 200mg reduced VL by average 1 log at day 10. Appeared safe & tolerable. Phase IIb planned for 2006. Higher doses possible.
Multiple dose placebo-controlled studies HIV-negative subjects showed no hepatic or renal toxicity; adverse events were all mild or moderate with no pattern relative to dose. Drug has long half-life (about 60 hours) supporting once daily dosing regimen. Plasma trough concentrations exceed predicted therapeutic levels. Single dose placebo controlled study in HIV-infected subjects showed dose-related reduction in viral load and activity against HIV resistant to major classes of existing drugs.
The primary endpoint of this study was to demonstrate antiviral effect in 10 day monotherapy study at day 11. Secondary endpoints were safety and PK.
The study was rabdomized, double-blind, placebo-controlled multiple dose trial. HIV-1 infected patients no on other therapy. Once daily dosing for 10 days at six major medical centers in USA. Dosing: 25mg, 50mg, 100mg, 200mg or placebo (6 patients per dose, 8 placebos): for 25-100mg cohorts, loading dose given on day 1 of 2x the maintenance dose.
Patients were ART naive or no ARV therapy within 12 weeks of first dose. CD$ >200. HIV RNA 5000-250,000 c/ml.
Baseline age was 36 to 41 yrs. HIV RNA was 4.27 log to 4.93 log. CD4 counts were 319 to 512. There were 1-4 patients in each dose group who had previously received ART. Some patients had NNRTI, PI & NNRTI mutations in most dose groups but none in 200mg group.
PK
PK was dose proportional with 200mg dose reaching approximate trough levels double that of 100mg dose. Steady state was not reached until about day 7 of dosing so day 10 viral load reduction represented change after 3 days of steady state drug level.
VIRAL LOAD REDUCTIONS AT DAY 11
200mg dose achieved average 1 log reduction in viral load (range -0.07 to -1.61 log).
The 100mg dose achieved average reduction of 0.48 log ((range +0.30 to -0.67).
50mg dose only acheived -0.17 average log reduction & 25 mg dose showed little change.
It appeared that immediately after starting dosing viral loads increased a bit before starting to decline and viral load continued to decline for another 1-2 days after day 10.
The strongest predictor of viral load reduction was blood concentrations of drug, except for 1 outlier in 200mg dose. No mutations in CA-SP1 cleavage site were detected at baseline or during study. Prior ARV exposure was not predictive of response. No baseline PI mutations detected in the 100g or 200mg dose groups.
SAFETY
Reported as well tolerated. AEs mild or moderate. One SAE designated possible related to drug: patient with 5-year history of hypertension, poorly controlled, had transient findings of a probable lacunar CVA.
ADVERSE EVENTS
Most complaints were of diarrhea/altered bowel habits: 1-6 patients in each dose group reported this, but 5/8 in placebo arm also reported this. Headaches were also reported.
There were no grade 3-4 lab abnormalities. One grade 2 lab abnormality (triglyceride on day 5in patient with baseline elevation , returned to baseline). Sporadic grade 1 lab abnormalities with no pattern noted. No evidence of hepatic, renal or other organic toxicity.
Phase IIb planned for 2006. Greater response is possible with higher doses.
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