Antiviral activity and safety of 873140, a novel CCR5 antagonist, during short-term monotherapy in HIV-infected adults.
OBJECTIVE
873140 is a spirodiketopiperazine CCR5 antagonist with prolonged receptor binding and potent antiviral activity in vitro. This study evaluated plasma HIV RNA, safety, and pharmacokinetics following short-term monotherapy in HIV-infected adults.


METHODS
Double-blind, randomized, placebo-controlled multi-center trial.


METHODS
Treatment-naive or experienced HIV-infected subjects with R5-tropic virus, CD4 cell count nadir > 200 x 10 cells/l, viral load > 5000 copies/ml and not receiving antiretroviral therapy for the preceding 12 weeks were enrolled. Forty subjects were randomized to one of four cohorts (200 mg QD, 200 mg BID, 400 mg QD, 600 mg BID) with 10 subjects (eight active, two placebo) in each cohort, and received treatment for 10 days. Serial HIV RNA, pharmacokinetics, and safety evaluations were performed through day 24.


RESULTS
Of the 40 subjects, 21 were treatment-experienced; 35 were male, 20 were non-white, and eight were coinfected with hepatitis C virus. Median baseline HIV RNA ranged from 4.26 log10 to 4.46 log10. 873140 was generally well tolerated with no drug-related discontinuations. The most common adverse events were grade 1 gastrointestinal complaints that generally resolved within 1-3 days on therapy. No clinically significant abnormalities were observed on electrocardiogram or in laboratory parameters. Mean log changes in HIV RNA at nadir, and the percentage of subjects with > 1 log10 decrease were -0.12 (0%) for placebo, -0.46 (17%) for 200 mg once daily, -1.23 (75%) for 200 mg twice daily, -1.03 (63%) for 400 mg once daily, and -1.66 (100%) for 600 mg twice daily. An Emax relationship was observed between the area under the 873140 plasma concentration-time curve and change in HIV RNA.


CONCLUSIONS
873140 demonstrated potent antiretroviral activity and was well tolerated. These results support further evaluation in Phase 2b/3 studies.
Lalezari
Jacob
J
Quest Clinical Research, San Francisco, California, USA.
Thompson
Melanie
M
Kumar
Priny
P
Piliero
Peter
P
Davey
Richard
R
Patterson
Kristine
K
Shachoy-Clark
Anne
A
Adkison
Kimberly
K
Demarest
James
J
Lou
Yu
Y
Berrey
Michelle
M
Piscitelli
Stephen
S
D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001565:Benzoates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D065100:CCR5 Receptor Antagonists; D054659:Diketopiperazines; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D012367:RNA, Viral / Q000097:blood; D013141:Spiro Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D001565:Benzoates; D065100:CCR5 Receptor Antagonists; D054659:Diketopiperazines; D010879:Piperazines; D012367:RNA, Viral; D013141:Spiro Compounds; C499671:aplaviroc