 |
|
|
| |
873140, A Novel CCR5 Antagonist:
|
| |
| |
Antiviral Activity and Safety During Short-Term Monotherapy in HIV-Infected Adults
Reported by Jules Levin
This is the GSK new CCR5 inhibitor and 10-day monotherapy data in HIV+ treatment-naives and experienced was presented at ICAAC (October 2004).
The drug is potent & novel in its binding, potential combination with other entry inhibitors will be considered. It has prolonged receptor binding and so far the safety profile looks good.
Jay Lalezari reported study results in the late breaker oral session at ICAAC. The study was a randomized, placebo-controlled trial with 40 patients (8active/2 placebo per dose cohort) and 4 treatment arms.
Doses were administered for 10 days with moderate fat (30%) meal:
200mg once daily, 200 mg twice daily, 400 mg once daily, and 600 mg twice daily. Serial sampling was performed for HIV RNA, PK, receptor occupancy, and safety on treatment and for 14 days post-dosing.
Both treatment naïve and experienced patients were enrolled. Experienced patients had no ARV treatment for the preceding 12 weeks and could have failed up to 2 previous HAART regimens. Plasma HIV RNA was >5000 c/ml and stable over previous 30-90 days. CD4 nadir was >200 cells. The Virologic Phenosense HIV Entry assay was used to try to identify whether patients had R5 or X4 virus upon study entry. This assay has a limit of 10%, ie if a patient has less than 10% of their viruses as X4 the assay won't pick it up.
BASELINE CHARACTERISTICS. Average age 34-49 yrs. 4 females. 19 patients were treatment-naïve. 8 patients were HCV+. Average CD4 count was 297-404. HIV RNA was 4.2-4.7 log copies/ml. There were 20 whites, 16 african-americans, and 4 latinos in the study.
MEDIAN VIRAL LOAD REDUCTIONS
Median viral load change from baseline at nadir:
Placebo: -0.09 log (n=9)
200 qd: -0.51 log (n=7)
200 mf bid: -1.20 log (n=8)
400 mg qd: -1.02 log (n=8)
600 mg bid: -1.49 log (n=8)
% Subjects with 1 log drop at Nadir
placebo: 0%
200 qd: 16.7% (1/7)
200 bid: 75% (6/8)
400 qd: 62% (5/8)
600 bid: 100% (8/8)
VIRAL TROPISM MONITORING
Tropism and IC50 was evaluated at screening & days 1, 5, 10, and 24. Investigators reported minimal variation was observed in fold change in IC50 versus control virus during the study. It appears that in vitro resistance to this CCr5 inhibitor is hard to develop. One subject in the study at the 200 mg qd dose had R5-tropic virus on day 1, dual/mixed-tropic virus on day 10, and R5-tropic virus on day 24. Investigators report that preliminary analysis demonstrated dual tropic virus was pre-existing on day 1 but below assay detection limit.
CIRCULATING LYMPHOCYTE CCR5 OCCUPANCY
Median receptor occupancy on day 10 was >97% across all doses. Substantial and prolonged receptor occupancy was observed for several days post-dosing. Higher doses tended to result in longer duration of occupancy after discontinuation of dosing, but there was no correlation after 10 days of dosing between occupancy and antiviral activity.
SAFETY
There was 1 withdrawal (unrelated to drug); no SAEs; no grade 4 clinical AEs; no clinically significant abnormalities on EKG; most common AE: loose stools, diarrhea, abdominal pain, nausea, flatulence which generally resolved on drug within 3 days. Other adverse events included headache, dizziness, fatigue. Several patients on placebo & drug reported CNS side effects.
Phase IIb clinical trials are being planned.
|
| |
|
|
|
|
|
