Potential HIV combination therapy fails in Phase 3

LONDONV—ViiV Healthcare presented at the 20th International AIDS Congress in Melbourne, Australia, the analysis of the 48-week results from the Phase 3 MODERN study comparing maraviroc (MVC; marketed as Celsentri/Selzentry) dosed once daily with darunavir/ritonavir (DRV/r) to emtricitabine/tenofovir (FTC /TDF) with DRV/r in antiretroviral-naïve subjects. The study did not, in turns out, meet the non-inferiority endpoint. The proportion of study participants who were virologically suppressed (HIV-1 RNA <50 copies/mL) at week 48 was 77.3 percent for MVC+DRV/r compared to 86.8 percent for FTC /TDF +DRV/r.

MODERN was designed as a double-blind, double dummy non-inferiority 96-week study, intended to determine if an investigational two-drug regimen of once-daily MVC (a CCR5 receptor antagonist) and DRV/r (a boosted protease inhibitor) could provide comparable antiviral activity when compared to a three-drug regimen consisting of two once-daily nucleosides (FTC /TDF) and DRV/r in antiretroviral-naïve subjects. More MVC subjects discontinued due to lack of efficacy (8.3 percent for MVC+DRV/r vs 2.0 percent for FTC /TDF +DRV/r) and there were more protocol-defined treatment failures in the maraviroc arm (10.1 percent for MVC and 3.2 percent for FTC /TDF). There were no reports of viral resistance in subjects who failed in either arm of the study.

The secondary endpoints included safety and tolerability of maraviroc as well as the utility of genotypic and phenotypic testing and tropism change. There were no new or unique safety findings, and discontinuations due to adverse events were 4.8 percent for MVC+DRV/r and 4.5 percent for FTC /TDF +DRV/r. Category C events, grade 3/4 adverse events and laboratory abnormalities were similar between the two treatment arms.

The study was also designed to compare the performance of a genotypic tropism test with the phenotypic tropism test Trofile (ESTA, Monogram Biosciences) to determine whether patients had R5-tropic HIV-1 virus and were therefore eligible for maraviroc treatment. This was the first trial to compare the treatment outcomes of patients prospectively randomized to either a genotypic or phenotypic tropism test. The proportion of subjects meeting the primary endpoint were comparable between the two arms in predicting a clinical response (for the MVC arm, difference was 6.86 percent in favour of genotyping; for FTC /TDF, the difference was 0.3 percent).

“Although this investigational two-drug regimen was inferior to the three-drug regimen in this study, maraviroc remains a valuable antiretroviral therapy when used in combination with other antiretrovirals and dosed twice daily in adults with confirmed CCR5-tropic HIV.” said Dr. John Pottage, chief scientific and medical officer for ViiV Healthcare.

ViiV Healthcare decided to terminate the MODERN study in October 2013 following a preliminary review of the 48-week primary clinical efficacy data by the study’s external Independent Data Monitoring Committee (IDMC). This decision was not based on any new or unique drug-related safety events. The results presented this month are the first analysis of the 48-week primary endpoint of this study. Further analyses of the secondary objectives will be presented at future conferences.

“ViiV Healthcare is committed to supporting innovative clinical programs to better understand our therapies and the potential they could offer to people living with HIV.” said Dr. Dominique Limet, CEO of ViiV Healthcare. “The treatment of HIV has come a long way, but it is essential that we continue to pursue effective novel treatment strategies that minimise toxicity while maximising tolerability and convenience to meet our objective of delivering advances in care and treatment for all people living with HIV.”