February 28, 2007
Encouraging Data from Two Maraviroc Studies by Tim Horn
Twenty-four weeks of treatment with maraviroc, combined with an optimized background regimen (OBR), is associated with greater viral load reductions and CD4 count increases compared to placebo among HIV-positive patients with limited treatment options due to drug resistance. These new data, from two Phase IIb/III studies of Pfizer’s entry inhibitor, were reported on Tuesday at the 14th Conference on Retroviruses and Opportunistic Infections.
Bonus Coverage: AIDSmeds founder Peter Staley recently interviewed Dr. Calvin Cohen, research director of the Community Research Initiative of New England. Double click below to hear more about maraviroc, Pfizer's new CCR5 inhibitor.
To hear the full interview click here. After HIV binds to the CD4 protein on T-cells, the virus must then latch onto another receptor on the cell's surface – either CCR5 or CXCR4. Earlier in the course of HIV disease, most people have HIV that uses the CCR5 receptor. Later on, as HIV disease progresses, the virus can switch to the CCR4 receptor, although it is not clear why this happens. The virus' tendency to use CCR5 or CXCR4 is known as "tropism."
Maraviroc is one of two experimental entry inhibitors – Schering-Plough’s vicriviroc is the other – that is specifically active against virus that uses the CCR5 receptor. While some HIV-positive patients, notably those who have been infected with HIV for several years, have CXCR4-tropic virus, laboratory tests – including Monogram Bioscience’s Trofile assay – are being developed to help patients determine the tropism of their virus before they begin either of these compounds.
MOTIVATE-1 and MOTIVATE-2 are two 48-week clinical trials of maraviroc being conducted in treatment-experienced patients with CCR5-tropic HIV. MOTIVATE-1, being conducted in Europe, Australia, and North America, has enrolled 464 patients. MOTIVATE-2, underway in the United States and Canada, has enrolled 585 patients.
All patients enrolled in these studies had tried and failed drug regimens involving all three classes or oral HIV drugs in the past and had viral loads above 5,000 while on their previous treatment regimen. They were randomized to once- or twice-daily maraviroc, or placebo, in combination with an OBR (made up of three to six approved HIV drugs).
Because of potential drug interactions, OBR containing Rescriptor® (delavirdine) or a protease inhibitor – other than Aptivus® (tipranavir) – maraviroc dosing was 150mg either once or twice a day. Otherwise, the maraviroc dose was 300mg either once or twice a day.
The average viral load upon entering the study was 4.87 log and the average CD4 count was 176 cells.
After 24 weeks of treatment, the average viral load reduction in the placebo group was 1.03 log. In the once-daily maraviroc group, viral load dropped, on average, by 1.82 log. In the twice-daily maraviroc group, the average viral load reduction was 1.95 log.
While 31.4% had viral loads below 400 after 24 weeks in the placebo group, 54.7% and 60.4% had viral loads below this level in the once-daily and twice-daily maraviroc groups, respectively. Compared to the placebo group, the percentages of patients with viral loads below 400 were statistically significant in both maraviroc groups.
As for viral loads below 50 – undetectable using standard ultrasensitive assays – 24.6% saw this result in the placebo group after 24 weeks, compared to 42.2% in the once-daily maraviroc group and 48.5% in the twice-daily maraviroc group. Here, too, the differences between the maraviroc groups and the placebo group were statistically significant.
CD4 counts increased by 52 cells in the placebo group, compared to CD4 increases of 107 cells in the once-daily maraviroc group and 111 cells in the twice-daily maraviroc group.
The average viral load upon entering MOTIVATE-2 was 4.85 log, and the average CD4 count was approximately 160 cells.
Average viral load reductions, after 24 weeks, were 0.93 log in the placebo group, 1.95 log in the once-daily maraviroc group, and 1.97 log in the twice-daily maraviroc group.
Viral loads below 400 were documented in 23.1% of placebo recipients, compared to 55.5% of once-daily maraviroc recipients and 61.3% of those in the twice-daily maraviroc group.
Undetectable viral loads (below 50 copies) were seen in 20.9% of the placebo recipients, 45.6% of the once-daily maraviroc recipients, and 40.8% of the twice-daily maraviroc takers.
CD4 counts increased by 64 in the placebo group, 112 in the once-daily maraviroc group, and 102 in the twice-daily maraviroc group.
The differences between the two maraviroc groups and the placebo group, with respect to CD4 counts and viral loads below 400 and 50 after 24 weeks, were statistically significant.
Combined Study Results
In both studies, side effects were similar in all three treatment groups, with 84% to 89% of the study participants experiencing at least one mild adverse effect. While discontinuation rates due to side effects were slightly higher in the maraviroc groups compared to the placebo groups, the differences were not statistically significant. Between 84% and 91% experienced a side effect while in the study.
In MOTIVATE-1, there were four deaths in each of the once-daily and twice-daily maraviroc group, compared to zero deaths in the placebo group. In MOTIVATE-2, there was one death in the placebo group, two deaths in the once-daily maraviroc group, and one death in the twice-daily maraviroc group. However, according to the study investigators, no deaths were related to the medications used.
As for factors that contributed to the success of maraviroc treatment, patients with low (below 100,000 copies) or high (greater than 100,000 copies) viral loads did equally well.
Among patients with drug-resistance tests at study entry showing high-level resistance to all of the approved antiretrovirals, meaning that they didn't have an "active" drug to include in their OBR, those in the once-daily maraviroc group (18%) and twice-daily maraviroc group (29%) were more likely to have viral loads below 400 after 24 weeks, compared to those in the placebo group (3%), The differences between the maraviroc groups and placebo group was not statistically significant. Among patients who did have active agents to include in their OBR, the response to maraviroc treatment was significantly better.
Given that CCR5 inhibitors targets a cellular receptor instead of a viral enzyme, drug resistance is thought be much less of a problem with maraviroc. However, there has been evidence of patients’ viruses switching from CCR5-tropic to CXCR4-tropic while a CCR5 inhibitor is being used.
In these two studies, 31 patients in the once-daily maraviroc groups and 32 patients in the twice-daily maraviroc groups saw their viruses switch to CXCR4-tropic or dual-tropic (capable of binding with either CCR5 or CXCR4). In these patients, viral load reductions and CD4 count gains were blunted.
As summarized by the study presenters, maraviroc plus OBR is associated with significant virology control and CD4 count increases in treatment-experienced patients. Compounded by its comparable safety profile to regimens consisting of currently approved antiretrovirals, maraviroc’s expected approval for the treatment of drug-resistant HIV is good news.
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 [Abstract 104 b LB]. [Abstract 104 a LB]. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, 2007.
Nelson M, Fatkenheuer 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 [Abstract 104 a LB]. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, 2007.