Proof of activity with AMD11070, an orally bioavailable inhibitor of CXCR4-tropic HIV type 1.
BACKGROUND
The X4 Antagonist Concept Trial investigates the safety and antiviral activity of AMD11070, a potent inhibitor of X4-tropic human immunodeficiency virus (HIV) in vitro in HIV-infected patients harboring X4-tropic virus.


METHODS
Patients enrolled in the study had an X4 virus population 2000 relative luminescence units (rlu; by the Monogram Trofile Assay) and an HIV-1 RNA level 5000 copies/mL. Patients received AMD11070 monotherapy for 10 days. Coreceptor tropism, plasma HIV-1 RNA level, and CD4 cell count were measured at study entry, on day 5, and on day 10. Daily predose and serial samples on the last day of treatment were obtained for determination of plasma AMD11070 concentration.


RESULTS
Ten patients were given AMD11070 monotherapy (200 mg to 8 patients and 100 mg to 2 patients) twice daily for 10 days. The median baseline CD4 cell count was 160 cells/mm(3), and the median HIV-1 RNA level was 91,447 copies/mL. Four of 9 evaluable patients achieved a reduction in X4 virus population of >or= rlu. The median change in X4 virus population at the end of treatment was -0.22 log(10) rlu (range, -1.90 to 0.23 log(10) rlu). Three of 4 patients who responded to therapy showed a tropism shift from dual- or mixed-tropic viruses to exclusively R5 virus by day 10. There were no drug-related serious adverse events, adverse events of greater than grade 2, or laboratory abnormalities.


CONCLUSIONS
These results demonstrate the activity of AMD11070, the first oral CXCR4 antagonist, against X4-tropic HIV-1. The drug was well tolerated, with no serious safety concerns. AMD11070 is on clinical hold because of histologic changes to the liver observed in long-term animal studies; additional preclinical safety assessments are pending.
Moyle
Graeme
G
Chelsea Westminster Hospital, London, United Kingdom. gm@moyleg.demon.co.uk
DeJesus
Edwin
E
Boffito
Marta
M
Wong
Rebecca S
RS
Gibney
Colleen
C
Badel
Karin
K
MacFarland
Ron
R
Calandra
Gary
G
Bridger
Gary
G
Becker
Stephen
S
D000328:Adult; D000634:Aminoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002082:Butylamines; D018791:CD4 Lymphocyte Count; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D015728:Receptors, HIV; D016896:Treatment Outcome; D019562:Viral Load
D000634:Aminoquinolines; D019380:Anti-HIV Agents; D001562:Benzimidazoles; D002082:Butylamines; D006573:Heterocyclic Compounds, 1-Ring; D012367:RNA, Viral; D015728:Receptors, HIV; C494414:mavorixafor