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New Incyte CCR5 Drug Shows Good Activity: 14 day monotherapy study
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Reported by Jules Levin
4th IAS, 22-25 July, 2007, Sydney, Australia
Potent Antiretroviral Activity of the Once-Daily CCR5 Antagonist INCB009471 Over 14 Days of Monotherapy
C. Cohen, E. DeJesus, A. Mills, G. Pierone, Jr., P. Kumar, P. Ruane, R. Elion, G. Fusco, R. Levy, K. Solomon, C-B Xue, S. Erickson-Viitanen
United States of America
AUTHOR CONCLUSIONS
200 mg once daily for 14 days was well tolerated
--No clinically significant chemistry, hematology, ECG changes observed
Rapid virologic response
--Mean maximal viral load decline -1.81 log on Day 16
16 / 19 demonstrate VL decline > 1.5 log
--16 / 17 remaining R5-tropic had >1.5 log decline
Viral load suppressed beyond dosing interval
--Consistent with prolonged plasma half-life
--Day 28 (two wks post dosing) VL -0.81 log from BL
N = 2 had unmasking of X4-using virus populations
--Preliminary analysis: X4-using virus from pre-existing variants
200 mg once daily warrants longer-term Phase 2b studies in R-5 screened HIV-infected patients
--The safety/activity of other once-daily doses of INCB009471 is under investigation
--Phase 2b studies are planned of one (or more) doses
Background Information: INCB9471
Preclinical studies demonstrate:
--Selective for CCR5 receptor
--90% IC for R5-tropic viruses = 8-10 nM
--Moderate plasma protein binding
free fraction = 16%
--Protein-binding adjusted IC90 = 50-60 nM
--Additive/synergistic in vitro for other ARVs
Single and multiple dose Phase 1 studies demonstrate:
--Rapid absorption
--Long plasma half-life about 60 h;
--Low peak-to-trough ratio
--Predicted Cmin levels with 200 mg QD dosing of about 400 nM
Baseline Characteristics
Patient Population: HIV+ adults; naive or experienced (no antiretroviral treatment for > 3 months)
-- Screening viral load >4.0 log
--14 day dosing period
Mean CD4: 520 in CCR5 arm, 640 in placebo.
Demographics
N enrolled: 23
N completing study: 23
Mean age: 37
% African American: 17%
% Latino: 22%
% Female: 4%
Endpoints
Primary
--mean/median change in viral load; adverse events
Secondary
--% >1 log, >1.5 log, and >2 log decline from baseline
--% <400 and 50 C/ml
Tropism Findings
Tropism determined at:
--Screening, BL (pre-dose), day 7 or 14, day 28 and f/up
N = 2 / 19 on drug showed tropism change
--Both treatment experienced
#1: R5 at Screen, d-1; Dual/Mixed d7 and d28
Preliminary clonal sequencing:
--D/M virus at day -1 at low levels;
#2: R5 at Screen, d-1; Dual/Mixed d14; R5 d28
Preliminary clonal sequencing:
--D/M virus from unidentified ancestral virus
Both pts. show reversion to R5 after d28
--Similar to other CCR5 antagonists as monotherapy
Antiviral Response Rates at Nadir
--Mean Nadir at 16.8 days
--Range: Day 7 ( n=1), Day 14 (n=4), Day 16 (n=6); Day 20
Safety Results
--No serious adverse events
--No discontinuations for any reason
LFT (ALT, AST) changes during study
Cohen reported 1 of 4 patients taking placebo had grade 1 abnormality and 4 of 19 (21%) taking 9471 CCR5 drug with grade 1 abnormality. No patients in either arm with grade 2 abnormalities.
No change to chemistry and hematology parameters
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