The possibility that patients may stop responding to Pfizer’s investigational HIV drug maraviroc due to resistance or co-receptor switching may require them to be periodically tested with Monogram’s Trofile assay, a US Food and Drug Administration advisory panel said last week.
The Antiviral Drugs Advisory Committee’s unanimous recommendation April 24, which also urged the accelerated approval of maraviroc, raises concerns that the additional cost of periodic testing may discourage patients from using the drug.
Pfizer used Monogram’s Trofile assay to determine which patients to enroll in maraviroc clinical trials. The phenotypic assay confirms whether an individual’s virus exclusively uses the CCR5 co-receptor (R5-tropic) and thus will respond to the drug. According to Pfizer, between 80 percent and 85 percent of treatment-naive HIV patients and about half of the treatment-experienced population fall into this category.
However, if the assay finds that HIV uses the CXCR4 co-receptor (non-R5 tropic) or uses both the CXCR4 and CCR-5 receptors (dual/mixed tropic), the patient will not benefit from the drug.
Committee members expressed concerns about Trofile’s ability to manage the subset of CCR5-tropic patients who are unresponsive to the drug and, therefore, were not being properly optimized.
Testing these patients a second time at the point of failure may shed light on whether their lack of response to maraviroc was because the virus has become resistant to one of the concomitant drugs, or because the virus is switching from the CCR5 to the CXCR4 co-receptor.
“The big concern here is that there will be some population, a subpopulation of up to 10 percent based on the assay … that are not going to be responsive, but that are not going to be optimized,” Craig Hendrix, associate professor at Johns Hopkins University and a temporary voting member on the committee, said during the panel’s deliberations.
The ability of the assay to manage these patients “is not so clear,” Hendrix said. “You would want to make sure you were on two good drugs for all the viruses you knew you had, so if you switched to the dual or mixed [tropism status], you’d probably stop or at least re-optimize in some way.”
If periodic testing is necessary, other panelists pointed out that the cost of Trofile and the time it takes to receive test results will play a key role in a patient’s decision to adopt maraviroc. According to the FDA, it will take two to three weeks for Monogram’s labs to turn around Trofile results.
“My concern is that once we have the assay I understand it takes quite a while to read. There is a several-week lag,” committee member Sheila Weiss Smith, associate professor at the University of Maryland School of Pharmacy, said at the meeting. “I am wondering how often it would even be used? Would this be something that, once this is out, [physicians] would just give the drug and see if there is a response and follow it, and if it stopped working, then do a test?
“I’m wondering, if it is expensive and time consuming, would [the test] be used if it wasn’t actually on the label?” she added.
Trouble With Trofile?
Maraviroc, which Pfizer proposes to brand as Celsentri, has been granted accelerated approval status by the FDA, and is currently available in 30 countries as part of an expanded access program.
Pfizer and Monogram last year entered into a non-exclusive agreement to ensure that the assay will be available to patients worldwide at the same time the drug is launched [see PGx Reporter 12-06-06].
Pfizer used Trofile to screen patients who were CCR5 tropic and enrolled them into two multicenter, double-blind, randomized Phase IIb/III trials – Studies 1027 and 1028 – comparing the safety and efficacy of maraviroc 300 mg twice daily, 300 mg once daily, or placebo. All subjects receive optimized background therapy with three to six approved antiretroviral treatments.
“With the dosing used in Phase IIb/III studies, the virologic success on maraviroc with OBT was shown to be 64 percent,” the FDA states in briefing documents to the committee. “The virologic success can be increased to 72 percent by doubling the dose in patients with [a minimum drug concentration of] less than 75 ng/mL.”
In Pfizer’s briefing documents to the committee, the company claims that the Trofile assay can detect a 10-percent minority population of CXCR4-using HIV clones with 100-percent sensitivity, while 5 percent of the CXCR4-using population can be detected with 83-percent sensitivity. The assay can reliably determine patients’ tropism status up to 1,000 copies of HIV-1 RNA/mL for amplification.
However, in clinical trials “if viral load was ≤500 copies/mL, tropism was not determined at that time point or the result was censored,” Pfizer reports in its briefing documents.
“I don’t know how anyone can say how you can use this as a management tool at this juncture with what the test doesn’t do for people with a viral load of under 500,” Lynda Dee, the committee’s patient representative and a member of AIDS Action Baltimore, said during the meeting. “Not only are we talking about resistance and only one drug, but maybe outgrowth of CXCR4 virus may be more dangerous and do a lot of damage.”
“I just wish we had a better assay,” she said. “I think if the efficacy of this drug wasn’t so clear, I might say that we shouldn’t do anything to approve this yet.”
In FDA’s report, the agency expressed concern regarding “the potential for co-receptor switching.” The agency requested Pfizer monitor co-receptor tropism changes and issue monthly reports to monitor tropism-switching, viral load, and CD4+ cell counts in all clinical trials.
“I just wish we had a better assay. I think if the efficacy of this drug wasn’t so clear, I might say that we shouldn’t do anything to approve this yet.”
According to Pfizer, clinical trials have shown that 90 percent of patients experience a tropism switch within four to six weeks of virologic failure. However, “the emergence of CXCR4 doesn’t appear to either be an absolute predictor of nonresponse or to help measurably in terms of the ability to determine when a virologic failure has occurred,” Pfizer said in its document.
One weakness of the assay is its inability to differentiate between a true dual tropic virus and a heterogeneous mixture of CCR5 and CXCR4 monotropic viruses, according to Pfizer’s briefing documents. Therefore, the assay scores patients as “dual/mixed tropic” if there is any detectable replication in the CCR5-expressing and CXCR4-expressing cells.
In an interview with Pharmacogenomics Reporter this week Monogram CFO Alf Merriweather noted that most patients are going to have some mix of CCR5 and CXCR4, which means there will be “a small number of patients whose CXCR4 is present, but not to a significant degree, who would not be detected by the assay.”
Merriweather said Trofile was “significantly more sensitive at looking at tropism [than] any other way.”
Monogram recently 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 statement.
Committee member Hendrix suggested that although the proportion of patients who failed the drug is small, testing patients’ tropism status a second time when patients fail therapy may shed light on the biology of co-receptor switching.
Dee, the patient representative, thought that periodic testing was a good idea in theory but not realistic given the cost of testing. “Considering clinical care and cost, I don’t think it would be practical to do it once they failed. I think it would be better to find out what’s going on before failure, or if there is something we can use that would be helpful clinically to indicate whether you should stay on this drug or not,” Dee said.
“I just remember how difficult it was initially when viral load testing became widely available and people didn’t know how to read it,” she added.
Merriweather noted that the price of Trofile or maraviroc have not been set. He added that the two companies are currently speaking with payors and that the price of the Rx/Dx combination will be determined in the next few months.