Maraviroc phase 2b/3 results in treatment experienced CCR5-tropic patients
Simon Collins, HIV i-Base
Results from a planned 24-week analysis of the phase 2b/3 studies of maraviroc (MVC) (Motivate 1 and 2) were presented by Howard Meyer and Elna van der Ryst in two linked late-breaker oral presentations. [1, 2]
Both studies had a similar design comparing the CCR5 antagonist maraviroc or placebo, both with optimised background therapy (OBT) in triple-class experienced R5-tropic patients, with Motivate-1 (n=601) based in the US and Canada and Motivate-2 (n=475) based in Europe, Australia and the US.
Patients were randomised 1:2:2 to receive placebo or MVC (300-mg dose equivalent) once daily (QD) or twice daily (BID) plus OBT (3 to 6 ARVs with or without low-dose ritonavir). The MVC dose was reduced to 150 mg once or twice daily when all PIs except tipranavir, or if the NNRTI delavirdine, were included in the OBT. The primary endpoint was the mean change in HIV-1 RNA from baseline to week 24.
Baseline CD4 and viral load were similar in each study, approximately 150-180 cells/mm3 (range 1->900 cells/mm3) and 4.8 logs (range 2.5-7.1 logs) across the arms. Approximately 60-75% of patients had 2 or fewer active drugs in their background regimen, and 37-45% used T-20.
Table 1: 24 week results in Motivate 1 and 2
|Motivate 1||Placebo + OBT (n=188)||MCV + OBT (n=232)||MVC + OBT (n=235)|
|Mean change in viral load – difference vs placebo (97.55 CI)||-1.3 log – N/A||-1.82 log – -0.79 (-1.14, -0.44)||-1.95 log – -0.92 (-1.28, -0.57)|
|% <400 copies/mL||31.4%||54.7% (<0.0001)*||60.4% (<0.0001)*|
|% <50 copies/mL||24.6%||42.2% (0.0006)*||48.5% (<0.0001)*|
|Mean CD4 change (cells/mm3)||+52||+107 (<0.0001)*||+111 (<0.0001)*|
|Discontinuations due to a/e’s, n (%)||6 (5.10)||11 (4.7)||10 (4.3)|
|Deaths, n (%)||1 (0.8)||2 (0.9)||1 (0.4)|
|Motivate 2||Placebo + OBT (n=91)||MCV + OBT (n=182)||MVC + OBT (n=191)|
|Mean change in viral load – difference vs placebo (97.55 CI)||-0.93 log – N/A||-1.95 log – -1.02 (-1.43, -0.62)||-1.97 log – -1.04 (-1.44, -0.64)|
|% <400 copies/mL||23.1%||55.5% (<0.0001)*||61.3% (<0.0001)*|
|% <50 copies/mL||20.9%||45.6% (<0.0001)*||40.8% (0.0005)*|
|Mean CD4 change (cells/mm3)||+64||+112 (<0.001)*||+102 (<0.001)*|
|Category C AIDS-defining events, n||11||17||11|
|Discontinuations due to a/e’s, n (%)||2 (2.2)||9 (4.9)||7 (3.7)|
|Deaths, n (%)||0||4 (2.2)||4 (2.1)|
This study reported no significant differences between virological responses based on T-20 use or when stratifying results based on baseline viral load. For example in Motivate-2 patients using T-20 or not using T-20, in either the placebo (-0.97 vs -1.12 log), maraviroc QD (-2.12 vs -2.17) or maraviroc BID (-2.45 vs -2.02) arms didnt show any advantage to this additional drug. Also in Motivate-2, baseline viral load (above or below 100,000 copies/mL) also had no impact on response (approximately -2.2 vs -2.1 logs in the maraviroc arms and -0.981.14 respectively in the placebo arm).
Side effects in both studies, including severe adverse events, AIDS-defining events, and laboratory (including liver enzyme) abnormalities occurred with similar frequency across groups. No deaths were related to study drug according to investigators
Two sets of results were presented as a combined analysis: the percentage of patients suppressed to <50 copies/mL by number of active drugs at baseline (Table 2) and an analysis of tropism shift (Table 3).
Table 2: Percentage of pts (n) suppressed to <50 copies/mL by number of sensitive drugs at baseline
|No. active drugs||Placebo + OBT||MCV QD + OBT||MCV BID + OBT|
|0||3% (35)||10% (51)||29% (56)|
|1||9% (44)||43% (130)||43% (134)|
|2||19% (59)||52% (88)||53% (104)|
|=3||55% (64)||55% (64)||68% (121)|
Table 3: Change in CD4 count (n) from baseline by tropism at failure
|Placebo + OBT||MCV QD + OBT||MCV BID + OBT|
|All failures||+14 (97)||+49 (60)||+71 (77)|
|R5 > R5||+15 (80)||+61 (18)||+138 (17)|
|R5 > D/m or X4||+67 (4)||+37 (31)||+56 (32)|
Although these results were in highly experienced patients, only just over half the people screened for these studies (56%) had R5-tropic virus, making it more likely that maraviroc will need to be placed earlier in treatment failure.
It is essential for a tropism test to be used prior to using CCR5 inhibitors. This will limit the ability to use maraviroc as a switch treatment as, similar to resistance tests, the current test needs a viral load level of at least 1000 copies/mL to produce a result.
The tropism assay costs approximately $800 and sample have to be sent to the US. It is unclear whether Pfizer will subsidise these costs.
- Nelson M, Fätkenheuer G, Konourina I et al. Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Viremic, ART-experienced Patients Infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-Week Results. Oral abstract 104aLB.
- Lalezari J, Goodrich J, DeJesus E et al. Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Viremic ART-experienced Patients Infected with CCR5-tropic HIV-1: 24-Week Results of a Phase 2b/3 Study in the US and Canada. Oral abstract 104bLB.
http://www.retroconference.org/2007/Abstracts/30635.htm The oral presentations can be viewed online from the CROI website (see Tuesday, 6.30-7.30pm, New Antiretrovirals Late Breaker session).