New Fusion Inhibitor AMD-3100 Begins Phase II
AnorMED Inc. begins Phase II trial for AIDS drug; Efficacy studies to begin on anti-HIV drug with novel mechanism of action
PRNewswire - Thursday May 27, 1999
VANCOUVER, May 27 /CNW-PRN/ - AnorMED Inc. announced today that it has opened enrollment in a Phase II clinical trial for its HIV treatment AMD-3100. The trial is being conducted in HIV-infected patients at three centres in the United States and is designed to test the safety, pharmacokinetics and anti-viral activity of this compound.
Dr. Michael J. Abrams, AnorMED's President and CEO, said the initial Phase I trial just completed at The Johns Hopkins University School of Medicine in Baltimore, Maryland, showed AMD-3100 was safe and well-tolerated at several dosages when given to healthy individuals. The preclinical and Phase I clinical trial results on AMD-3100 were presented at the 6th Conference on Retroviruses and Opportunistic Infections in Chicago February 6, 1999 by Dr. Craig Hendrix of The Johns Hopkins University.
Abrams said the Phase II trial will include 20 to 30 patients and is expected to be completed by the middle of 2000. Initial enrollment of the trial will be at Johns Hopkins University School of Medicine followed by two additional sites in the U.S. that are currently being qualified.
"In addition to testing AMD-3100's safety and pharmacokinetics in HIV-infected patients, the trial will be seeking the first evidence of the drug's anti-viral activity in people," said Abrams. "Our preclinical testing showed AMD-3100 to be a potent and selective inhibitor of HIV infection with a mechanism of action that is different from any approved product."
Abrams said AMD-3100 prevents HIV present in the blood from entering and infecting cells. HIV must attach to receptors called "chemokine receptors" before it can enter and infect a cell. AMD-3100 prevents HIV from binding to one receptor - called CXCR4 - and therefore prevents infection of the cell. The critical role of the CXCR4 receptor has only become known in the last three years.
AMD-3100 is a relatively simple synthetic molecule and its unique mechanism of action also makes it a promising drug for combining with other HIV therapies. In pre-clinical studies, HIV was relatively slow to develop resistance to AMD-3100 compared with other anti-HIV agents. The development of resistance has historically been a problem with anti-HIV drugs.
Although AMD-3100 is currently administered by injection, AnorMED has an active discovery program to synthesize versions of AMD-3100 that can be administered orally and to identify new small molecules that inhibit other HIV related chemokine receptors such as CCR5.
Following is a reprint of the abstract presented at the Human Retrovirus Conference in Feb '99.
Chemokine CXCR-4 Receptor Blocker, AMD-3100: Clinical and Pre-clinical Studies of Pharmacokinetics and Safety.
C HENDRIX1*, C FLEXNER1, R MACFARLAND2, C GIANDOMENICO2, SCHWEITZER3, G HENSON2 1Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2AnorMED, Langley, BC, Canada; 3Novartis, Ltd., Basil, Switzerland.
AMD-3100, a bicyclam, inhibits the entry of HIV-1 into CD4+ T cells via selective blockade of the chemokine CXCR-4 receptor (in vitro IC50 2-5 ng/ml against T-tropic strains).
In preclinical studies in rats, single oral doses (20 mg/kg) of AMD-3100 were poorly absorbed and highly variable (oral bioavailability = 3.0% [0.5%-9.6%]). The half-life of total radioactivity of parent drug was 0.9 hours after a single dose and 0.7-0.8 hours after repeated dosing. Renal clearance was the primary route of excretion. In a four week subcutaneous dosing study in rats and dogs over a range of doses (0.25, 1,4 mg/kg/day) maximum plasma concentrations occurred within 1-2 hours with good dose proportionality.
In six healthy volunteers, we conducted an open-label, dose-escalation evaluation of the pharmacokinetics and safety of a single 15 minute IV infusion of AMD-3100, 10 µg/kg (N=3) or 20 µg/kg (N=3). No serious adverse events were noted during these study cohorts. Median peak serum concentrations (Cmax) were 48 ng/mL (range 38-56) and 118 ng/mL (range 96-119) for the low and high dose cohorts, respectively. For all 6 subjects, the median terminal half-life of AMD-3100 was 2.77 hours (range 1.96-3.27) in these subjects with a clearance (CI/F) of 8.19 L/hr (range 6.74-11.2) and volume of distribution (Vss) of 0.29 L/kg (range 0.25-0.48). The Cmax in the 10 µg/kg and 20 µg/kg cohorts roughly correspond to sustained concentrations in SCID-hu Thy/Liv mouse studies (40 ng/mL and 117 ng/mL), which resulted in 0.4 and 0.8 log10 reductions in HIV p24 antigen production after 2 weeks.