Maraviroc is a novel small-molecule inhibitor of CCR5 with potent anti-HIV-1 activity. The compound is the end product of a high-throughput screen and medicinal chemistry program, which optimized the pharmacological and pharmacokinetic properties of the chemical series. Maraviroc inhibits HIV-1 gp120 binding to CCR5, thus preventing gp160-CCR5-mediated cell-cell fusion. The compound blocks chemokine binding and CCR5-mediated signaling, as was demonstrated in Ca2+ mobilization and γ-S-GTP binding assays. The reduction of basal γ-S-GTP binding observed in the latter may indicate that maraviroc is acting as an inverse agonist to promote the formation of CCR5 in an inactive state. This would functionally mimic the Δ32 “null” phenotype in human, which is known to have no apparent consequences for the immune status or general health of the subjects. In contrast, the consequences of partial or altered CCR5-mediated signaling cannot be determined from any known CCR5 genetic variations. It would require long-term clinical trials to assert the safety of inhibitors that would reproduce the above phenotype.
One of the attractive properties of a new class of inhibitors is the expectation that they will be effective against HIV-1 strains regardless of the previous drug experience of the patient. Consistent with this, maraviroc is active against R5 strains from drug-naive subjects, as well as against viruses isolated from patients with experience in one or more of the preexisting classes. Furthermore, there was a tight distribution of responses to the 200 viruses tested, as indicated by the biological cutoff of 1.7-fold. This compares well with biological cutoffs for existing antiretroviral drugs tested in a similar pseudotyped-virus assay, using recombinant RT/protease derived from patient plasma (33
). The distribution of the response to maraviroc is also tighter than that reported for the fusion inhibitor, enfuvirtide, which displayed a biological cutoff of 7.5 in the same assay when tested against baseline samples of patients enrolled in the “TORO” phase 3 clinical trials (M. Greenberg, Abstr. 2nd Eur. HIV Drug Resist. Workshop, abstr. 8, session 3, 2004). We have also extended our analysis to strains from diverse geographic origins. HIV-1 is comprised of three subgroups based upon phylogenetic clustering, of which the M (“Main”) group is responsible for the majority of global infections. This is further divided into nine recognized subtypes, or “clades,” clustering into independent branches based upon env
amino acid sequences. While clade B is responsible for the majority of infections in the Western world, the epidemic is predominantly caused by viruses from other clades (A and C in particular; see UNAIDS 2004 report on global AIDS epidemic), and global spread of various clades is increasing (37
). An earlier reported CCR5 antagonist, SCH-C, showed potent antiviral activity against most R5 strains but was poorly active against representatives from subtype G (43
). Encouragingly, maraviroc had potent cross-clade activity against all CCR5-tropic HIV-1 primary isolates tested, with a less than 10-fold difference between the most- and least-susceptible clades and a less than 30-fold difference between the most- and least-susceptible individual isolates (among more than 40 isolates tested). In particular, the two subtype G strains which we tested are within threefold of the geometric mean IC90
for all primary isolates, with the RU570 isolate falling within sixfold. This broad-spectrum activity is a desirable attribute for an anti-infective agent and may indicate that different antagonists have distinct binding patterns for CCR5, presenting the coreceptor to HIV-1 in diverse states.
The considerable structural differentiation between maraviroc and previously reported CCR5 antagonists underpins their different pharmacological and pharmacokinetic behaviors. Maraviroc is a basic compound (tropane) which shows a pan-cognate chemokine blockade for both binding and signaling inhibition as reported here. This is in contrast to ONO4128/GW873140 (a zwitterionic spirodiketopiperazine [25
]), which does not inhibit RANTES binding to CCR5 but does inhibit RANTES signaling via this receptor (26
Preclinical pharmacokinetic profiling indicates that unbound drug minimum concentrations in serum in excess of the antiviral IC90
are readily achievable through once- or twice-daily administration, a prediction that has been achieved in recent clinical trials (S. Abel, E. Van Der Ryst, G. J. Muirehead, M. Rosario, A. Edgington, and G. Weissgerber, Abstr. 11th Conf. Retrovir. Opportun. Infect., abstr. 547, 2003; A. L. Pozniac, G. Fatkenheuer, M. Johnson, I. M. Hoepelman, J. Rockstroh, F. Goebel, S. Abel, I. James, M. Rosario, C. Medhurst, J. Sullivan, M. Youle, and E. Van Der Ryst, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. H-443, 2003). Pharmacokinetic differences with respect to oral bioavailability and clearance have been observed between the CCR5 antagonists in clinical development (1
; S. Abel, C. Russell, C. Ridgway, and G. Muirehead, Abstr. 6th Int. Workshop Clin. Pharmacol. HIV Ther., abstr. 76, 2005; D. Schurmann, R. Rouzier, R. Nougerede, J. Reyes, G. Fatkenheuer, F. Raffi, C. Michelet, A. Tarral, C. Hoffmann, J. Kiunke, H. Sprenger, J. vanLier, A. Sansone, M. Jackson, and M. Laughlin, Abstr. 11th Conf. Retrovir. Opportun. Infect., abstr. 140LB, 2004; J. Demarest, K. Adkison, S. Sparks, A. Shachoy-Clark, K. Schell, S. Reddy, L. Fang, K. O'Mara, S. Shibayama, M. Berrey, S. Piscitelli, Abstr. 11th Conf. Retrovir. Opportun. Infect., abstr. 139, 2004).
In addition to its low nanomolar antiviral (IC90
) potency and broad-spectrum antiviral activity, maraviroc has a prolonged CCR5 physical and functional occupancy (50
; P. Dorr, M. Macartney, G. Rickett, C. Smith-Burchnell, S. Dobbs, J. Mori, P. Griffin, J. Lok, R. Irvine, M. Westby, C. Hitchcock, B. Stammen, D. Price, D. Armour, A. Wood, and M. Perros, Abstr. 10th Conf. Retrovir. Opportun. Infect., abstr. 12, 2003). Both intrinsic antiviral potency and prolonged receptor occupancy are believed to be important factors that contribute to the antiviral efficacy of CCR5 antagonists in clinical trials. However, the continuous supply of de novo CCR5-expressing HIV-1-susceptible cells in patients indicates a pharmacokinetic profile that ensures sustained exposure of available antagonists to achieve clinically relevant reductions in viral load (K. Adkison, Y. Lou, L. Fang, A. Shachoy-Clark, J. Demarest, M. Berry, S. and Piscitelli, Abstr. 6th Int. Workshop Clin. Pharmacol. HIV Ther., abstr. 77, 2005). Achieving a complementary balance between primary antiviral CCR5 pharmacology and favorable pharmacokinetics to achieve sufficient exposure in vivo even without boosting with cytochrome p450 inhibitors is a key differentiating factor for maraviroc.
The pharmacokinetic and in vitro effects in the presence of other antiretrovirals and HIV-1 medications is an important consideration in light of the need for multiple drug therapy for maximal efficacy and reduced emergence of resistance. Combination studies in vitro demonstrate that maraviroc is not antagonistic to existing antiretroviral agents, and data in vivo reveal a drug-drug interaction profile commensurate with a convenient dosing regime, without affecting the pharmacokinetics of potential comedications (S. Abel, C. Russell, C. Ridgway, and G. Muirehead, Abstr. 6th Int. Workshop Clin. Pharmacol. HIV Ther., abstr. 76, 2005).
One of the major questions surrounding this new class of inhibitors is how resistance will develop in humans. Since CCR5 antagonists are selective for R5 viruses, selection for CXCR4-using variants would lead to virus escape. Indeed, treatment of R5-infected hu-SCID mice with AOP-RANTES (which exerts its antiviral activity through retention of CCR5 in intracellular compartments) resulted in emergence of X4 strains (28
). A possible explanation for this tropism switch is that since CCR5 is no longer expressed on the cell surface, the only viral variants that are positively selected are those with increased affinity for alternative coreceptors. In contrast to these data, in vitro studies aimed at generating HIV-1 resistance to CCR5 antagonists have not led to a rapid emergence of CXCR4-using variants (47
; C. Stoddart, S. Xu, J. Wojcik, J. Riley, and J. Strizki, Abstr. 10th Conf. Retrovir. Opportun. Infect., abstr. 614, 2003; M. Westby, C. Smith-Burchnell, J. Mori, M. Lewis, R. Mansfield, J. Whitcomb, C. J. Petropoulos, and M. Perros, Abstr. XIII Int. HIV Drug Resist. Workshop, abstr. 6, 2004). This is consistent with the observation that maraviroc blocks binding of the virus to CCR5 without altering receptor levels on the cell surface, thereby selecting for variants with increased affinity for the inhibitor-bound receptor. Despite these encouraging preclinical findings, the emergence of X4 HIV-1 variants during CCR5 antagonist therapy will need close monitoring during clinical trials. Three examples of emergence of CXCR4-using variants have been described during short-term monotherapy studies of CCR5 antagonists (M. E. Lewis, E. van der Ryst, M. Youle, T. Jenkins, I. James, C. Medhurst, and M. Westby, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. H-584b, 2004; K. Kitrinos, C. LaBranche, M. Stanhope, H. Madsen, and J. Demarest, Abstr. XIV Int. HIV Drug Resist. Workshop, abstr. 61, 2005). Clonal analysis of virus before and after treatment has shown that in each case virus emerged from preexisting CXCR4-using virus reservoirs rather than a switch of R5 variants on treatment.
Finally, a key attribute of any novel antiretroviral treatment is convenience of dosing and lack of side effects when taken chronically. With excellent safety windows, in particular against the hERG channel, which is responsible for QT prolongation, and no measurable activity across a range of immune function assays, maraviroc fulfilled our desired preclinical profile in terms of safety of administration and expected lack of significant side effects and immunological consequences. On the basis of the data above, we believe that maraviroc has the potential to become a safe, well-tolerated, and easily administered effective HIV-1 inhibitor with broad-spectrum anti-HIV-1 activity. Further clinical development is ongoing.