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AnorMED Hopes to Develop Investigational Entry Inhibitor AMD-070 to Block HIV from Entering Healthy Cells
by Chael Needle

May 2003

Drugs that target HIV replication process after cells have been infected have dominated anti-HIV medications currently in use. A new investigational class of drugs, entry inhibitors, prevents HIV from entering a cell in the first place by blocking receptors on the cell surface. While the CD4 receptor is the primary receptor necessary for HIV to attach to a cell’s surface (T-helper cells have lots of CD4 receptors), CCR5 and CXCR4 are two secondary receptors that are also essential for infection to take place. Entry inhibitors, with their potential ability to prevent the HIV-infection of cells, would be an obvious boon to the anti-HIV armamentarium, especially now that many patients have been challenged by an increasing resistance to the older classes of drugs. An entry inhibitor would be “an excellent complement to the methodologies currently available,” says Dr. Michael Abrams, Ph.D., president and CEO of AnorMED, a company currently developing several entry inhibitor compounds, including AMD-070. “Before the approval of Fuzeon, the only targets being used were reverse transcriptase and the viral protease. All the HAART regimens were based on those two targets, so you got increasing viral resistance to those various drugs. Going after the entry part of the viral life cycle is a whole new way to circumvent resistance.”

At the Tenth Retroviral and Opportunistic Infections conference in Boston this year, AnorMED presented preclinical data on AMD-070 that “showed excellent in vitro anti-HIV activity in a wide variety of clinical isolates of virus that use CXCR4. And dual tropic HIV strains,” says Dr. Abrams. “Dual tropic strains are HIV strains that use either CXCR4 or CCR5 to receive the virus into the healthy cell. Referring to AMD-070’s potential as part of combination therapy, Abrams also commented that the investigational drug “showed in vitro synergy with all approved anti-HIV agents,” as well as a suitable toxicology and pharmacology profile necessary for oral dosing. In the research process, compounds are tested together in vitro to determine synergy, whether they work well together. But, says Abrams, “the real clinical synergy we see is to use the drug in combination with a CCR5 inhibitor. And there are several of those currently in development by other companies. We estimate that roughly half of patients have a combination of both CXCR4- and CCR5-using strains in their disease. And so a combination of these two inhibitors would be an effective new treatment for HIV.
“The inhibition of CXCR4 as a viral target was validated in our AMD-3100 clinical trial, where we showed reduction in the CXCR4 component of patients’ viremia,” says Abrams, referring to results of a Phase Ib/IIa clinical study of AMD-3100 presented at the 2002 Ninth Retroviral and Opportunistic Infections Conference. AMD-3100 is the prototype CXCR4 inhibitor for AMD-070; AMD-070’s structural difference from AMD-3100 allows the drug to be formulated as a pill. Based on this preclinical data, AnorMED recently filed an Investigational New Drug application with the FDA. Though more research is needed to determine the resistance profile of AMD-070, Abrams points out that “it was relatively difficult to get resistance to AMD-3100 in vitro, as we published in a number of papers. It’s interesting to note that the target for the CCR5 and CXCR4 inhibitors is a host protein not a viral protein. That may mitigate to a better resistance profile.”

Different strains of HIV favor different secondary receptors. “There’s literature that claims that the CXCR4-using strain tends to emerge in the later stages of infection, whereas CCR5 is responsible for the initial stages,” says Abrams. If and when researchers move on to Phase II, they will determine if a patient’s viral strain is CXC4R- or CCR5-using by employing an assay developed by ViroLogic “that can quantify the percentage of CCR-5- versus CXCR-4-using viral strains in a patient. The first step, however, is to research the bioavailability and pharmacology of AMD-070 in a Phase I [trial] slated to begin during the second half of this year. In addition to researching AMD-070, AnorMED is also at work on preclinical candidates that target the CCR5 receptor as well as exploring other uses of the CXCR-4 inhibitor as a treatment for rheumatoid arthritis, other inflammatory diseases, and possibly even cancer. Though AMD-3100 has been abandoned as an anti-HIV treatment, AnorMED is researching its efficacy in stem cell transplantation, a cancer treatment used to re-establish immune systems that have been ravaged by radio- and chemotherapies.

Chael Needle wrote about the Antiretroviral Pregnancy Registry for the April issue.