Background:  The chemokine receptor CXCR4 (X4) is used by HIV as a co-receptor in up to 50% of patients with advanced disease. X4 use is associated with rapid CD4 decline and disease progression. AMD11070 (070) is an orally bioavailable, small-molecule CXCR4 antagonist and potent inhibitor of HIV replication in vitro. The X4 Antagonist Concept Trial (XACT) investigates the safety and activity of 070 monotherapy for 10 days.

Methods:  XACT is a multicenter, dose-finding safety and activity study of 070 in patients with evidence of X4 virus determined by the Monogram Coreceptor Tropism Assay.  We dosed 10 patients with 070 as monotherapy twice daily for 10 days (200 mg, n = 8; 100 mg, n = 2). Patients were treatment naïve or at least 14 days without ART.  Patients had ³2000 X4 relative luminescence units (rlu) and an HIV RNA level of ³5000 copies/mL. Tropism (including X4 and R5 rlu), plasma HIV viral load and CD4 level were measured at baseline, day 5 and day 10. The primary endpoints were X4 rlu reduction ³1 log₁₀ and safety. Secondary endpoints included change in levels of CD4 and HIV RNA and pharmacokinetic parameters.

Results:  Median baseline CD4 and HIV RNA levels were 144 cells/mm³ and 160,757 copies/mL (n = 10). At screening, 9 patients had dual/mixed virus and 1 had X4 only.  One patient was deemed non-evaluable due to discrepant tropism assay results. Of 9 patients, 4 met the primary endpoint of ³1 log₁₀ reduction in X4 rlu. Among these responders the mean X4 log₁₀ rlu reduction was –1.56 (median = –1.50)_. The mean overall change in X4 log₁₀ rlu (n = 9) was –0.71 (median = –0.22). Of 4 responders, 2 showed a tropism switch from dual/mixed to exclusively R5 virus at day 5, while 1 other responder showed the same switch at day 10. There were no significant changes in CD4, lymphocyte counts and HIV RNA levels overall (n = 9) or just among the responders (n = 4). There were no drug-related serious adverse events or >grade 2 adverse events or lab abnormalities. The most common adverse events were mild gastrointestinal symptoms and headache. Pharmacokinetic analysis revealed no correlation between exposure and rlu response.

Conclusions:  Preliminary results have demonstrated the activity of AMD11070 against X4-tropic virus where an X4 rlu reduction of ³1 log₁₀ was observed in 4 of 9 patients.   AMD11070 was well tolerated. Further development of this first CXCR4 antagonist, including dose escalation and other preclinical and clinical studies, is ongoing.