The Body Covers: The 12th Conference on Retroviruses and Opportunistic Infections
The Antiviral Benefits of 873140, a CCR5 Antagonist
February 24, 2005
HIV's entry inside the host cell is a multi-step process. First, HIV binds to the CD4+ receptor on the T lymphocyte or macrophage using a protein in the HIV membrane known as gp120. This binding changes the three-dimensional structure of gp120 and allows HIV to bind to a different protein in the host cell's membrane called the CCR5 co-receptor. That binding induces other three-dimensional changes and exposes another protein in HIV called gp41 that allows the fusion of HIV's membrane to the host cell and the entry of HIV's genetic material inside the host cell.Reference Abstract: Prolonged duration of CCR5 occupancy by 873140 in HIV-negative and HIV-positive subjects (Oral 77)
Since the discovery that people with a mutation in CCR5, although otherwise completely "normal," were naturally resistant to HIV infection, the so-called delta 32 patients, a lot of effort has been devoted in the pharmaceutical industry to create drugs that block CCR5.
There are different agents in development to block the different steps in HIV's entry process. One of them, enfuvirtide (T-20, Fuzeon), which blocks HIV from fusing with the host cell, has already been approved for clinical use.
Another one, now known as 873140, is a molecule being developed by GlaxoSmithKline (who bought the license from a Japanese company called Ono) that blocks the CCR5 co-receptor. 873140 is currently in Phase II clinical studies and is showing some promise.
Lalezari and colleagues conducted a Phase I study of 873140.1 At a dose of 600 mg twice daily, 873140 decreased viral load by 1.6 log10 in 8 patients. The half life of this compound in serum is relatively short, but in clinical studies it has been shown that the antiviral benefits persist even after the drug is no longer detectable in the serum. The presentation today gave us an explanation of why this happens -- it seems that the drug binds to the CCR5 co-receptor and stays bound to it for a while.
Demarest and his group at Glaxo also showed data that different drugs of this new class have different affinities for the CCR5 receptor and that the half life of this "post-antibiotic" effect varies among the different drugs in the class.2,3
Having a long half life has been the holy grail of drug development. We live in an era of once-a-day therapies and anything less than that is seen as "problematic." Having a compound that, although not present in serum, could still have antiviral properties might turn out to be critical for patients.
However, we should be cautious because having an extremely long half life could be a double-edged sword. On the one hand, it is a desirable characteristic in a drug because it simplifies the taking of the medicine. On the other hand, a long half life could be associated with the development of resistance if the drug is discontinued for any reason, as happens, for example, with nevirapine (NVP, Viramune) and efavirenz (EFV, Sustiva, Stocrin). Sometimes you may not get exactly what you wish for.
Since there were other presentations about 873140 during last year's CROI and ICAAC conferences, in many ways this presentation elicited a feeling of déjà vu. The main take-home lesson is that we have a better understanding of 873140's antiviral effect. The clinical significance of this prolonged binding to the CCR5 co-receptor will have to be seen in currently ongoing large antiretroviral trials.
Authored by: S Sparks, K Adkison, A Shachoy-Clark, S Piscitelli, James Demarest
Affiliations: GlaxoSmithKline, Research Triangle Park, NC, USA
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