CCR5 Antagonists: Host-Targeted Antiviral Agents for the Treatment of HIV Infection, 4 Years on

Abstract

. We reviewed the various categories of agents and compared the three small-molecule CCR5 antagonists that had progressed to clinical development: maraviroc, vicriviroc and aplaviroc. At that time, several key questions needed to be addressed by large-scale clinical trials, concerning not only the clinical efficacy and long-term safety of these agents, but also the pathways to CCR5 antagonist resistance in vivo and the effect of therapeutic administration of CCR5 antagonists on CXCR4-using virus populations. The purpose of the current review was to provide an update on developments in the field of CCR5 antagonist therapy since 2005, including the outcomes of the various Phase II/III trials conducted over the past 4-5 years, the progress that has been made in our understanding of resistance to CCR5 antagonists and the evolving body of evidence supporting the current and future role of small-molecule CCR5 antagonists in the treatment of HIV infection. Status of CCR5 antagonists in clinical development in 2005Of the three small-molecule CCR5 antagonists in clinical development in 2005, only maraviroc ( Figure 1A) is currently approved for clinical use. Development of aplaviroc was discontinued in 2006, following reports of severe idiosyncratic hepatotoxicity in Phase IIb treatment-naive and Phase III treatmentexperienced studies [2][3][4]. These reports of hepatotoxicity included cases of simultaneous increases in serum alanine aminotransferase and bilirubin breaching the 'Hy's Law' threshold, considered by the US Food and Drug Administration (FDA) to identify drug-induced hepatotoxicity of particular clinical concern [5], and a case of increased alanine aminotransferase that demonstrated a clear dechallenge-rechallenge reaction [2].Development of vicriviroc [6] ( Figure 1B) has been slowed by poor early virological results in dose-ranging studies and by safety concerns over a cluster of unexplained malignancies in a Phase II trial of treatmentexperienced patients. Development of vicriviroc for treatment-naive patients was suspended for several years following interim results from a Phase II dose-ranging study in which treatment-naive patients with CCR5-tropic (R5) virus received either 600 mg of efavirenz once daily or 25, 50 or 75 mg vicriviroc once daily, each

Chemokine Receptors as Therapeutic Targets in HIV Infection

“…The efficacy, tolerability and toxicity profiles of PRO 140 have been assessed by several preclinical and clinical studies, which showed promising results (reviewed in [75]). Of note is the evidence of activity shown by PRO 140 against escape mutants with cross-class resistance to small molecule CCR5 inhibitors [76]; however, as a complex biological molecule requiring parenteral administration, PRO 140 faces a different set of development challenges compared to the orally bioavailable small molecule compounds [77]. Human CCR5mAb004 antibody also performed well in early clinical trials [22].…”

“…The limited information currently available from published results of clinical studies suggests that the escape process from small molecule CCR5 inhibitors in vivo bears similarities to that observed in vitro; clinical resistance is also likely to map to the V3 region of gp120, but the lack of consistency of observed mutations renders impossible the prediction of in vivo resistance by sequence analysis at present (reviewed in [72,77,117,141]). As mentioned above, two pathways of virological escape from the selection pressure of CCR5 antagonists have been identified: continued use of CCR5 via selection of R5 virus that can use drug-bound CCR5 for entry in addition to free coreceptor and expansion of pre-existing minority populations of dual-tropic or X4 virus (collectively called "CXCR4-using" viruses).…”

“…The development of Vicriviroc (VCV, Schering-Plough Research Institute; now Merck Research Laboratories, Figure 2B) was abandoned because it did not meet primary efficacy endpoints in late stage (Phase III in treatment-experienced subjects and Phase II in treatment-naïve individuals) clinical trials. Additional compounds are in preclinical or clinical development (reviewed in [77]). Previously designated as TBR-652 or TAK-652 ( Figure 2C), cenicriviroc is a small-molecule CCR5 antagonist licensed by the Takeda Pharmaceutical Company to Tobira Pharmaceuticals; cenicriviroc has pharmacokinetic data supportive of once daily dosing and a favorable tolerability profile in single-dose studies in healthy volunteers.…”

“…Small molecule CCR5 inhibitors (Table 1) prevent HIV-1 from entering its target cells, mainly CD4 + T cells and macrophages, by blocking the CD4-dependent binding of the viral surface envelope glycoprotein (gp120) to the most commonly used coreceptor CCR5 (reviewed in [22,67,72,77]). …”

“…PF-232798 ( Figure 2D), a second-generation small-molecule oral CCR5 antagonist with potency similar to MVC and the potential for once daily dosing, has demonstrated activity against a laboratory-generated MVC-resistant R5 virus. INCB9471 (Incyte, Wilmington, DE, USA) is yet another small-molecule oral CCR5 inhibitor that showed promising results in a Phase IIa trial in treatment-naïve and treatment-experienced patients with once daily dosing over 14 days [77]. Binding site.…”