Maraviroc – A CCR5 Antagonist for the Treatment of HIV-1 Infection

Despite the dramatic decline in human immunodeficiency virus type 1 (HIV-1)related morbidity and mortality following the discovery of the protease inhibitors and the advent of combination highly active antiretroviral (ARV) therapy in the mid1990s, many patients were still failing therapy due to resistance and/or intolerability (1). It was clear that more ARVs acting on different steps in the virus lifecycle, active against resistant viruses, and better tolerated were needed. The demonstration of the key role of the chemokine receptors CCR5 and CXCR4 in HIV-1 entry sparked interest in this process as a new ARV target (2, 3). CCR5 is the co-receptor for the majority of HIV-1 strains, and these viruses are termed CCR5 tropic (R5). Virus strains that use CXCR4 are called CXCR4tropic (X4), while strains that can use both receptors are dual-tropic (4). Virus from a patient can often contain mixtures of R5, X4, and dual-tropic strains, collectively called CXCR4-using. The key role of CCR5 in HIV-1 entry, coupled with the demonstration that individuals who were homozygous for a 32 base pair deletion in the CCR5 gene (CCR5∆32), and subsequently do not express functional CCR5, were highly protected from infection with R5 HIV-1, focused attention on CCR5 as an attractive target (5). Although some studies have demonstrated subtle effects of the CCR5∆32 mutation on immune function, such as decreased inflammatory scores in hepatitis C-infected individuals and recovery from hepatitis B in heterozygotes; while homozygotes are more susceptible to tickborne encephalitis and severe West Nile virus disease, these individuals suffer little apparent adverse effects on their health (5, 6). This, together with the fact that members of the G protein-coupled receptor superfamily are often tractable to development of potent, selective, and orally bioavailable drugs (7), led to the initiation of CCR5 ligand discovery programs by multiple groups, including a team from Pfizer Global Research and Development based at the Sandwich laboratories in the United Kingdom. Maraviroc (UK-427,857, MVC) was discovered through high-throughput screening of the Pfizer compound library using a chemokine radioligand-binding assay. The most promising compound from the screening process was optimized for potency against the receptor, antiviral activity, pharmacokinetic characteristics, and selectivity against human cellular targets through a large medicinal chemistry effort in which almost 1000 molecules were characterized (7). MVC binds in the transmembrane pocket of CCR5 and is a slowoffset functional antagonist that prevents internalization (7, 8). It has potent antiviral activity against a wide-range of HIV-1 isolates (7). Together with its excellent preclinical safety profile and acceptable pharmacokinetics, this resulted in it being nominated as a clinical candidate in December 2000 (7). It was always clear that the clinical development of CCR5 antagonists would be challenging, as these would be the first host-targeted ARV drugs and we were therefore venturing into uncharted territory. In order to pre-empt key issues, a clinical development team was established very soon after the start of the discovery program and I was recruited to lead the early development team, joining Pfizer in February 1999. We identified several key challenges to address in the design of the clinical program, in addition to demonstrating safety and efficacy. The first of these was that no commercially available, clinically validated assay to identify patients infected with R5 HIV-1 existed. This was critical, as MVC is active only against R5 HIV-1 strains (7). Secondly, in spite of the apparently healthy phenotype of individuals with CCR5∆32 (5, 6), concerns remained regarding the safety of long-term exposure to CCR5 antagonists, as blocking of CCR5 may be different from congenital absence of the CCR5 receptor, where the immune system has matured in the absence of CCR5 and compensatory mechanisms may have developed. Finally, in HIV-1 infected individuals, the incidence of CXCR4-using HIV-1 strains increases with disease progression and decrease in CD4 cell counts (9), although no causal link between CXCR4-using virus and CD4-cell depletion has been demonstrated. This has led to concerns that selective pressure from a CCR5 antagonist may drive the virus population to use CXCR4 and result in CD4 cell decline. Phase 1 single and multiple dose studies in healthy volunteers, conducted in 2001 and the first half of 2002, demonstrated that MVC was safe and welltolerated in multiple doses up to 300 mg twice a day (BID), had a pharmacokinetic profile compatible with once daily (QD) or BID oral dosing, could be combined with other ARVs, and that doses of ≥100 mg BID resulted in exposure above the geometric mean antiviral IC90 in vitro (7, 10). To demonstrate proof of pharmacology, CCR5 receptor saturation was measured using a bespoke ex vivo MIP1β internalization assay. Dose-dependent