From HTS to Market: the Discovery and Development of Maraviroc, a CCR5 Antagonist for the Treatment of HIV - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 201

plus Optimised Therapy In Viremic Antiretroviral Treatment Experienced
patients) were superiority studies and enrolled antiretroviral-treatment experi-
enced patients with CCR5-tropic virus and ongoing viremia. 57,58 A total of 1049
patients were randomised and received either a 300mg equivalent maraviroc
dose once daily (qd), twice daily (bid) or placebo, each in combination with an
''optimised background regimen'' comprising a cocktail of existing antiretroviral
drugs. The third study, MERIT (Maraviroc versus Efavirenz Regimens as Initial
Therapy), enrolled treatment-naı¨ ve patients with CCR5-tropic virus and was a
non-inferiority study comparing maraviroc to efavirenz, each given in combi-
nation with two nucleoside reverse transcriptase inhibitors. 59 The primary end-
points of all three studies were based on maraviroc's safety and ecacy at 48
weeks, with long-term follow-up of 2-5 years.
In the MOTIVATE trials, patients who received maraviroc as 300mg qd or
bid within an optimised background regimen achieved on average an
approximately 1 log 10 drop in viral load over background therapy alone. 60
Maraviroc was well tolerated, with no compound-related effects on immune
function or hepatic transaminase levels.
Initial analysis of the MERIT trial showed that maraviroc was non-inferior
to efavirenz using the plasma viral load cut-off of o 400 copies mL 1 , but failed
to meet the pre-specified non-inferiority criteria using the more stringent test of
o 50 copies mL 1 . 61 Patients with exclusively CCR5 virus had been selected for
the study 62 using a viral tropism test (Trofile t ) which had a reported 100%
sensitivity for detecting CXCR4-using virus when it accounted for at least 10%
of the viral population, but only 83% when the viral population fell below

5%. iii Monogram Biosciences, the company providing the tropism test, have
since replaced their original version with an enhanced Trofile t assay, which
achieves 100% sensitivity in the detection of CXCR4-using strains at just 0.3%
incidence. 63 Following discussion with regulatory authorities, the screening
samples from MERIT were re-analysed with the enhanced version, and as a
result virus from a significant number (9.6%) of patients in the maraviroc
treatment group were reclassified as CXCR4-using at baseline. Re-analysis
using this new data demonstrated that maraviroc was shown to be non-inferior
to efavirenz. 64
Maraviroc received accelerated regulatory approval in the US and
Europe in 2007 as the first prescribed CCR5 antagonist for the treatment of
CCR5-tropic confirmed HIV-1 infection in treatment-experienced patients.
Maraviroc is sold under the tradename Selzentry t (Celsentri t in Europe and
Canada). 65

B

9.13 Resistance to Maraviroc
A fully-mapped binding pocket model of CCR5 has been recently described
for five different chemotypes. 66

This depicts the binding site for these

iii This highlights that the ability to detect X4-using virus depends on the proportion of minority
strains in the overall viral population.