Mechanism of Action/Scientific Background from CIBC report
Mobilization allows hematopoietic progenitor cells (HPCs, or stem cells) to be collected from the peripheral blood rather than the bone marrow.When transplantation was first introduced, HPCs were obtained by directly aspirating the bone marrow in the iliac crests of the pelvic bone. However, while HPCs tend to collect in the marrow, they also detach and travel hroughout the peripheral circulation. Collecting HPCs from the peripheral blood rather than the marrow is less painful, cheaper, more convenient, and leads to better outcomes.Mobilizing agents such as G-CSF and Mozobil help release HPCs from the bone marrow into the peripheral blood, optimizing their collection prior to ablation and transplant. Several processes normally draw HPCs into bone marrow. Stromal cells in the bone marrow produce stromal derived factor-1 (SDF-1, also known as
CXCL12), a chemotactic protein produced by osteoblasts ( protein produced by osteoblasts and bone marrow epithelial cells that attracts HPCs to the marrow. The receptor for SDF-1 is CXCR4, a G-protein coupled receptor (GPCR) found on the surface of HPCs. CXCR4 signaling also upregulates expression of adhesion proteins that keep HPCs in the marrow. Other hemokines and the VLA-4 and LFA-1 integrins are also believed to play a role in this process. Once HPCs are in the bone marrow,they adhere to and interact with the bone marrow microenvironment.
Mozobil disrupts HPC trafficking by binding to CXCR4, releasing HPCs into the peripheral blood. Mozobil is a bicyclam erivative that reversibly competes with and inhibits the binding of SDF-1 to CXCR4. This prevents the signals that cause homing of the HPCs into the marrow. Interestingly, these effects were discovered during testing of Mozobil for its original indication, HIV. Following injection, subjects developed leukocytosis, an increased number of white blood cells in the circulation. The leukocytes had the cell surface molecule
CD34, which is a marker of HPCs.AMD070 is an orally available derivative of Mozobil in early-stage clinical trials for HIV. Similar to Mozobil, AMD070 inhibits the T-cell CXCR4 receptor, which acts as a co-receptor for entry of the HIV virus into the cell. HIV entry occurs initially through interactions between surface gp120 and the CD4 receptor, followed by interaction with co-receptor CCR5 or CXCR4, then gp41- related fusion (Exhibit 7). Most current HIV therapies target the subsequent viral replication process by inhibition of reverse transcriptase or protease. However,there are several drugs in development targeting prevention of viral entry,through blockage of CD4, CCR5, and CXCR4. These drugs act earlier in the viral life cycle and potentially have different side effect and resistance profiles from existing drugs. We believe AMD070 is the only CXCR4 antagonist in clinical development for HIV.
A phase I pharmacokinetic/pharmacodynamic study demonstrated good bioavailability and tolerability of AMD070. The study, conducted at Johns Hopkins and the University of Washington, enrolled 12 healthy male volunteers.AMD070 was administered in single escalating doses of 50-400mg. Side effects were minimal, with 3 of 12 subjects reporting mild headaches. At 12 hours, the plasma concentrations with the 400 mg dose exceeded the EC90 levels determined to produce antiviral activity in vitro. White blood cell counts increased in a dose-dependent manner up to 2.9-fold, providing strong support for AMD070’s activity against the CXCR4 receptor.
Two proof-of-principle phase Ib/IIa studies of AMD070 in HIV patients are ongoing. The first study, known as ACTG 5210, was initiated in March 2006 and is being conducted along with the U.S. Adult AIDS Clinical Trials Group (ACTG), supported by the National Institutes of Health. The second study,known as XACT (X4 Antagonist Concept Trial), is being conducted at two centers. Both trials are open-label, dose-escalation studies each enrolling up to 48 HIV-infected patients each. Following a two-week washout of current antiretroviral therapy, patients will be treated with AMD070 for 10 days. Patients will be followed up for up to 80 days.
The goal of the trials will be to examine reduction in the level of CXCR4 virus, as measured by the PhenoSense assay. The bar for efficacy at each dosing level will be at least a 1.0 log reduction in CXCR4 virus levels in at least 4 of 6 patients within the dosing cohort. The studies will also collect additional harmacokinetic and safety data.
Initial efficacy data from the first cohort of the XACT trial showed some potential activity in reducing X4 virus. In the first 8 patients, 4 patients had “significant” reductions in CXCR4 viral load, averaging 1.3 log. We believe that additional information is necessary to determine the clinical relevance of this result. Dosing has continued, and more complete efficacy data could be presented at the Conference on Retroviruses and Opportunitistic Infections (CROI) in February 2007.
A drug-drug interaction trial of AMD070, known as the XIST study, is also ongoing. This study, initiated in May 2006, is testing pharmacokinetic parameters of certain P450 inhibiting drugs in the presence of AMD070. This study is taking place at a single center and will enroll up to 30 healthy subjects.
The effectiveness of targeting CXCR4 is not yet ell-understood. HIV strains use either CCR5 (“R5 viruses”) or CXCR4 (“X4 viruses”), or both coreceptors for entry into cells. The X4 strain is less common but is associated with greater pathogenicity and later-stage disease (Exhibit 8). There are various ways that CXCR4 inhibitors such as AMD070 could be used clinically. CXCR4 inhibitors could be used in patients with R5 strains potentially help prevent endstage switching to the more pathogenic strain, be used as disease-specific therapy in the small percentage of patients with exclusively X4-tropic strains, or be used to lower viral loads in patients with dual-tropic strains. In an early trial of Mozobil, the most potent antiviral effects (0.9 log viral load decrease) were observed in a patient whose virus used exclusively CXCR4. We believe the data on AMD070 at CROI could provide further insights into where the drug could be positioned. |
