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

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Review CCR5 Antagonists: Host-Targeted Antiviral Agents for the Treatment of HIV Infection, 4 Years On Antiviral Chemistry & Chemotherapy 2010 20:179–192 (doi: 10.3851/IMP1507) Review CCR5 antagonists: host-targeted antiviral agents for the treatment of HIV infection, 4 years on Mike Westby1* and Elna van der Ryst1 1Pfizer Global Research and Development, Sandwich, Kent, UK *Corresponding author: e-mail: [email protected] The chemokine coreceptor 5 (CCR5) antagonists are anti- are in various stages of clinical development. In 2005, we retroviral agents with an extracellular, host-targeted reviewed the limited clinical data then available on CCR5 mechanism of action against HIV. Maraviroc, the first- antagonists. In this follow-up review, we revisit the field and in-class CCR5 antagonist, received regulatory approval in assess the clinical and virological data that have emerged 2007, becoming the first oral antiretroviral from a new in the 4 years since, with particular reference to maraviroc class in more than 10 years. Other compounds in this class for which the most comprehensive data currently exist. Introduction Chemokine coreceptor 5 (CCR5) antagonists are a new supporting the current and future role of small-molecule class of antiretroviral agents that inhibit HIV replica- CCR5 antagonists in the treatment of HIV infection. tion by binding to CCR5 on the surface of host target cells and preventing entry of viral strains reliant on this Status of CCR5 antagonists in clinical coreceptor for infection. The first and only currently development in 2005 approved agent within this class, maraviroc, received marketing authorisation in the USA, Europe and other Of the three small-molecule CCR5 antagonists in regions of the world in 2007, with an indication for clinical development in 2005, only maraviroc (Figure treatment-experienced adult patients with only CCR5- 1A) is currently approved for clinical use. Develop- tropic (R5) HIV-1 detectable. Other compounds in this ment of aplaviroc was discontinued in 2006, follow- class are currently at various stages of clinical devel- ing reports of severe idiosyncratic hepatotoxicity in opment. In 2005, we reviewed the role of the CCR5 Phase IIb treatment-naive and Phase III treatment- receptor in HIV-1 entry and the potential of CCR5 experienced studies [2–4]. These reports of hepatotox- receptor antagonists as therapeutic anti-HIV-1 agents icity included cases of simultaneous increases in serum [1]. We reviewed the various categories of agents and alanine aminotransferase and bilirubin breaching the compared the three small-molecule CCR5 antagonists ‘Hy’s Law’ threshold, considered by the US Food and that had progressed to clinical development: maravi- Drug Administration (FDA) to identify drug-induced roc, vicriviroc and aplaviroc. At that time, several key hepatotoxicity of particular clinical concern [5], and a questions needed to be addressed by large-scale clini- case of increased alanine aminotransferase that dem- cal trials, concerning not only the clinical efficacy and onstrated a clear dechallenge-rechallenge reaction [2]. long-term safety of these agents, but also the pathways Development of vicriviroc [6] (Figure 1B) has been to CCR5 antagonist resistance in vivo and the effect slowed by poor early virological results in dose-ranging of therapeutic administration of CCR5 antagonists on studies and by safety concerns over a cluster of unex- CXCR4-using virus populations. The purpose of the plained malignancies in a Phase II trial of treatment- current review was to provide an update on develop- experienced patients. Development of vicriviroc for ments in the field of CCR5 antagonist therapy since treatment-naive patients was suspended for several years 2005, including the outcomes of the various Phase II/III following interim results from a Phase II dose-ranging trials conducted over the past 4–5 years, the progress study in which treatment-naive patients with CCR5- that has been made in our understanding of resistance tropic (R5) virus received either 600 mg of efavirenz to CCR5 antagonists and the evolving body of evidence once daily or 25, 50 or 75 mg vicriviroc once daily, each ©2010 International Medical Press 1359-6535 (print) 2040-2066 (online) 179 M Westby & E van der Ryst in combination with a then standard-of-care Combivir rollover study for ACTG 5211 (study P04100AM4), at (zidovudine/lamivudine) backbone [7]. Patients in both a revised dose of 30 mg once daily in combination with the 25 mg and 50 mg vicriviroc arms had significantly background therapies containing a ritonavir-boosted higher rates of virological failure than did patients in protease inhibitor (PI) at a dose schedule modelled to the efavirenz comparator arm and the trial was termi- provide a vicriviroc exposure equivalent to 200 mg nated in late 2005. An interim review of a Phase II study once daily in the absence of ritonavir boosting [9]. No in treatment-experienced patients (ACTG 5211), which systemic malignancies were reported during 2 years of compared the effects of 5, 10 or 15 mg vicriviroc once follow-up of patients in the ACTG 5211 rollover study daily plus optimized background therapy (OBT) with [10]. At the time this review was written, a new Phase the effects of OBT plus placebo, recommended the ter- II/III study in treatment-naive patients, in which vicri- mination of the 5 mg treatment arm because of subop- viroc (30 mg once daily) plus atazanavir/ritonavir was timal responses. The study was subsequently unblinded being compared with atazanavir/ritonavir plus teno- early following reports of six cases of malignancy in the fovir/emtricitabine (Truvada), had entered its second vicriviroc arms and two cases in the placebo arm (one of stage following an interim safety analysis at 24 weeks whom received placebo for 7 months followed by vic- (clinicaltrials.gov identifier: NCT00551018). riviroc for 3 months prior to developing a malignancy Maraviroc was approved for clinical use by the US whilst off treatment 1 month after virological failure on FDA in August 2007 and by the European Agency vicriviroc) [8]. Vicriviroc Phase II and III clinical devel- for the Evaluation of Medicinal Products the follow- opment in treatment-experienced patients, includes a ing month. Maraviroc is licensed for administration Figure 1. Chemical structures of CCR5 antagonists A F H3C F H N N N N N O B H3C CH3 H3CO CH3 N CH3 H3C N N F3C C N N N O N N O CH H 3 N N O H3C F D CH3 N H3C H N H C O 3 H C-SO H O O N 3 3 S O N (A) Maraviroc, (B) vicriviroc, (C) PF-232798 and (D) TBR-652. 180 ©2010 International Medical Press CCR5 antagonists for the treatment of HIV infection twice daily with other antiretrovirals in treatment- Virological and immunological efficacy experienced patients with R5 HIV-1. Approval was based on favourable 48-week results from two large An overview of published virological efficacy data Phase III studies (Maraviroc Plus Optimized Therapy for vicriviroc, maraviroc and aplaviroc is shown in in Viremic Antiretroviral Treatment Experienced Table 1. Data from studies of aplaviroc are some- Patients [MOTIVATE] 1 and 2) of maraviroc admin- what limited because of its early withdrawal from istered once or twice daily plus OBT compared with development. Early (12 week) descriptive data from placebo plus OBT in treatment-experienced patients the ASCENT [4] and EPIC [3] studies in treatment- with R5 virus determined at screening with pheno- naive patients indicate lower virological response rates typic testing [11,12]. Maraviroc has also demonstrated in patients receiving aplaviroc once or twice daily at efficacy in treatment-naive patients in the Phase III doses between 200 and 800 mg in combination with MERIT (Maraviroc versus Efavirenz Regimens as nucleoside analogue reverse transcriptase inhibitors Initial Therapy) study, although non- inferiority to (NRTIs) or lopinavir/ritonavir than in patients receiv- efavirenz was not demonstrated in the primary analy- ing an efavirenz or lopinavir/ritonavir active control. sis at week 48 [13]. However, in a post-hoc analy- Efficacy data for vicriviroc in its final dosing modality sis, favourable results for the MERIT end points at of 30 mg once daily in combination with a boosted weeks 48 [13] and 96 [14] were seen in a subset of PI are also limited, with 48-week blinded therapy data MERIT patients eligible for study inclusion based on [21] and 96-week open-label extension data [22] from a more sensitive screening tropism assay. Maraviroc the 116 patient Phase II VICTOR-E1 trial the most was granted a treatment-naive indication by the US complete available at time of writing. This study com- FDA in November 2009. pared the safety and efficacy of vicriviroc (20 or 30 mg Four other agents targeting the CCR5 coreceptor once daily) with placebo, each with an OBT containing are known to be in Phase II development. PF-232798 a boosted PI in treatment-experienced patients with R5 (Figure 1C) is a second-generation small-molecule oral virus. Mean changes from baseline in HIV-1 RNA and CCR5 antagonist with potency similar to maraviroc the proportions of patients with <50 copies/ml at week and the potential for once daily dosing. PF-232798 48 were significantly greater in both vicriviroc arms has shown activity against a laboratory-generated than in the placebo arm, and virological and immu- maraviroc- resistant R5 virus [15]. Another small- nological responses were preserved through week 96 molecule oral CCR5 antagonist, INCB9471 (Incyte, in those who were rolled over to open-label vicrivi- Wilmington, DE, USA), has shown promising results in roc (30 mg) at week 48. Better vicriviroc pharmaco- a Phase IIa trial in treatment-naive and treatment-ex- kinetic exposure and higher response rates among perienced patients with once daily dosing over 14 days patients with high baseline viraemia and fewer active [16].
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