Monogram’s Trofile assay may be able to identify a new patient population for Pfizer’s HIV drug maraviroc, according to data presented by Monogram at a recent scientific conference.
The Trofile assay helps clinicians determine whether a CCR5 antagonist like maraviroc may be a good therapeutic option. The test confirms whether an individual’s virus exclusively uses the CCR5 co-receptor (R5-tropic) and thus will respond to maraviroc, or uses the CXCR4 co-receptor (non-R5 tropic) and will not benefit from the drug.
However, among the 20 percent to 40 percent of HIV strains classified as dual- or mixed-tropic, some have shown varying ability to use either the CXCR4 or the CCR5 receptor to infect health cells.
According to two Monogram studies presented at this year’s Conference on Retroviruses and Opportunistic Infections, different dual-tropic subgroups demonstrated the ability to use CXCR4 and CCR5 co-receptors “with different efficiencies and respond differently to CCR5 or CXCR4 inhibitors.”
This variation “could impact patient responses to co-receptor inhibitors such as maraviroc in subjects infected with dual-mixed tropic virus,” Monogram said in a press release announcing data presented at the conference, which took place Feb. 25-28 in Los Angeles.
In contrast, results from a Pfizer trial (Study 1029) presented at the International AIDS Conference in Toronto last year showed that “patients identified by the assay as having viruses using both the CXCR4 and CCR5 receptors (dual/mixed tropic) did not respond virologically” to maraviroc.
Pfizer used Monogram’s Trofile assay in clinical trials to determine patients most likely to respond to maraviroc and the companies recently entered into a non-exclusive agreement to make the assay available to patients worldwide [see PGx Reporter 12-06-06].
According to Pfizer, about 80 percent to 85 percent of treatment-naive HIV patients and about half of the treatment-experienced population may be eligible for maraviroc treatment. With the help of the Trofile assay, if it is determined that mixed-tropic patients can also benefit from maraviroc, the population for maraviroc stands to be even larger.
Industry observers have upheld the Pfizer/Monogram collaboration as a model for deals between pharmaceutical and diagnostics companies for bringing targeted medicines to market. Ultimately, if maraviroc is approved by the FDA, the drug and Monogram’s assay will be the only marketed Rx/Dx combination for treating CCR5 tropism.
Maraviroc was recently granted accelerated approval status by the US Food and Drug Administration, and the drug is currently available in 30 countries as part of an expanded access program. An FDA Advisory Panel is scheduled to discuss Pfizer’s NDA for maraviroc on April 24.
Pfizer previously said it has used the Trofile assay to screen 4,000 patients in maraviroc’s Phase IIb/III clinical trials. The test yielded a 3-percent false-negative rate in Phase IIa trials and had a 95-percent success rate assessing 18,000 clinical trial samples.
At the CROI meeting last month, Monogram also presented data from a head-to-head trial of Trofile and the conventional MT2 cell syncytia formation assay, in which the MT2 assay failed to classify the status of 50 percent of the samples for which the Trofile assay generated results.
“This demonstrates how valuable Trofile will be to clinicians should maraviroc and other co-receptor inhibitors receive regulatory approval,” Monogram said in a release.
“Without prescreening for co-receptor tropism, the antiviral activity of maraviroc would have been diluted by the inclusion of subjects unlikely to respond to the drug, especially in the highly treatment-experienced subjects that were targeted in the Pfizer trials.”
“Without prescreening for co-receptor tropism, the antiviral activity of maraviroc would have been diluted by the inclusion of subjects unlikely to respond to the drug, especially in the highly treatment-experienced subjects that were targeted in the Pfizer trials,” the company added.
Concurrently, Pfizer also released data from two 24-week, double-blind, placebo-controlled Phase IIb/III studies, called Maraviroc Plus Optimized Therapy in Viremic Antiretroviral Treatment Experienced Patients, or MOTIVATE 1 and 2.
“In both studies, approximately twice as many patients treated with maraviroc plus optimized background therapy [OBT] for either once or twice daily dosing achieved undetectable viral loads (<50 copies/mL HIV RNA) compared to those receiving placebo plus [optimized background therapy],” Pfizer said in a release.
Monogram’s Trofile assay was used to optimize background therapy in the clinical trials for maraviroc. OBT included three to six antiretrovirals, with or without low-dose ritonavir.
In MOTIVATE 1, patients received maraviroc 150 mg once daily or 150 mg twice daily or placebo plus OBT. Patients’ baseline characteristics included a median Cd4 between 150-168 and a median HIV-1 RNA of 4.85 log; 43 percent had Fuzeon in their regimen and between 66 percent and 72 percent had two or less active drugs in OBT.
Viral load reductions were -1.95 log in the maraviroc twice daily group, -1.82 log in the maraviroc once daily group, and -1.03 in the placebo plus OBT group. Results from MOTIVATE 2 were very similar to MOTIVATE 1. Although results from both studies were reported at 24 weeks, the clinical studies are currently ongoing.
Pfizer is also studying the utility of maraviroc in treatment naïve patients, for which the clinical trial is fully enrolled.