Proof of Concept of Antiretroviral Activity of AMD11070 (an Orally Administered CXCR4 Entry Inhibitor): Results of the First Dosing Cohort A Studied in ACTG Protocol A5210
Michael Saag*1, S Rosenkranz2, S Becker3, K Klingman4, B Kallungal5, A Zadzilka6, E Coakley7, E Acosta1, G Calandra3, V Johnson1, and NIAID AIDS Clinical Trials Group, Bethesda, MD USA
1Univ of Alabama at Birmingham, US; 2Harvard Univ, Statistical and Data Analysis Ctr, Boston, MA, US; 3AnorMED Inc, Langley, Canada; 4NIAID, NIH, Bethesda, MD, US; 5ACTG Operations Office, Silver Spring, MD, US; 6Frontier Sci & Tech Res Fndn, Amherst, NY, US; and 7Monogram Biosci, South San Francisco, CA, US
Background: AMD11070 exhibits potent and selective inhibition of HIV-1
replication by binding to the chemokine receptor CXCR4. We conducted a phase
IB/IIA proof-of-concept study to determine the safety and relative antiviral
activity of AMD11070 administered over 10 days to HIV-infected subjects who
harbor X4-tropic virus.
Methods: A5210 is a dose-escalating, open-label study of AMD11070 in subjects with a
plasma HIV RNA >5000 copies/mL who had been off ART for at least 14 days at
study entry. Subjects were screened for the presence of X4 or X4/R5 virus
(luciferase activity >2000 relative luminescence units [rlu]) as measured by
the HIV-1 co-receptor tropism assay. Cohort A examined 6 subjects administered
200 mg by mouth every 12 hours x 20 doses (10 days); subjects could restart ART
after study day 11, based on screening HIV-1 drug-resistance assay results.
Plasma HIV RNA levels and safety labs were obtained over 90 days. Intensive
24-hour pharmacokinetic and a trough level at hours 30 to 38 were obtained at
steady state. As-treated statistical analyses for subjects remaining on study
drug through day 10 were employed.
Results: We enrolled 6 subjects into Cohort A: 1 Caucasian and 5 African Americans of whom 3
were male, mean age 41 years; mean baseline CD4+ T-cell count was
196/mm3 (range 25 to 531). Median baseline log10 plasma
HIV-1 RNA was 4.23 copies/mL. All 6 subjects were dual/mixed X4/R5 at study
entry with median entry log10 rlu 5.33 X4 and 5.73 R5 rlu,
respectively. At day 10, 5 of the 6 subjects were dual/mixed X4/R5 and 1 was
R5. During 10 days of treatment, 3 subjects had a ≥1 log10 rlu
reduction in X4-tropic virus with changes from baseline to day 10 of –3.3,
–1.8, and –1.0 log10 rlu; the remaining 3 subjects had increases
less than 0.05 log10 rlu. No subjects had >1 log10
decline in plasma HIV-1 RNA from baseline at day 10. No grade 3 or worse
toxicities were seen during 10 days of AMD11070 or 7 days after therapy.
Conclusions: AMD11070 was well-tolerated when administered at 200 mg
every 12 hours for 10 days. Reductions of ≥1 log10 rlu in X4
virus were seen in 3 of the 6 subjects after 10 days of treatment, thereby providing
proof of concept that AMD 11070 can selectively inhibit X4-tropic virus in
HIV-1-infected patients. Further studies within the class of CXCR4
inhibitors to determine the optimal agents, dosing, long-term safety, and
efficacy are warranted.