Pfizer will make available its investigational HIV drug Maraviroc to patients with limited treatment options due to drug resistance and intolerance to therapy, the company said last week.
At the same time, Monogram Biosciences will be providing a test to determine whether patients’ HIV is CCR5-tropic. And, because it is the only CLIA-approved CCR5-tropism test, Monogram stands to pocket substantial revenue when the drug is approved, because its label will likely require patients to confirm their CCR5-tropism status before being prescribed the drug.
During Pfizer’s annual R&D day in Groton, Conn. last week, Ethan Weiner, senior vice president of therapeutic area development, announced plans to provide the CCR5-antagonist through an expanded access program in over 30 countries. Pfizer will provide the drug in these countries through the EAP until it receives regulatory approval.
To be eligible for the program, patients “must be clinically stable with documented CCR5-tropic HIV-1 infection,” Monogram Biosciences said in a statement. These early users of Maraviroc will be tested on Monogram’s Trofile assay to establish their CCR5-tropism status.
Pfizer used Trofile to select patients for Maraviroc’s clinical development program. Pfizer and Monogram in May announced a non-exclusive collaboration to make Monogram’s Trofile assay available for patients worldwide. Pfizer at the time also invested $25 million in Monogram [see PGx Reporter 05-10-05].
Pfizer expects to file its CCR5-antagonist for approval by the US Food and Drug Administration in treatment-experienced patients by the end of the year, according to Andy Schmeltz, senior director of Pfizer’s worldwide virology and vaccines division. Schmeltz made his remarks last week at the Harvard-Partners Center for Genetics and Genomics conference on personalized medicine in Boston.
Additionally, Pfizer expects to seek a claim for Maraviroc in treatment-naïve patients, for which the pivotal trial is already enrolled. The company expects to file this additional indication with the FDA in mid-2007.
Pfizer did not release any of the findings from the treatment-experienced cohort during its R&D day, but said it will unveil the Phase III data at the annual Conference on Retroviruses and Opportunistic Infections in February.
Making of an Rx/Dx Alliance
During the HPCGG conference, the Pfizer/Monogram collaboration was upheld as a model for deals between pharmaceutical and diagnostics companies. Presenters repeatedly expressed the need for such alliances across disciplines for targeted medicines to come to market.
Pfizer and Monogram’s relationship began early in the development of Maraviroc, allowing for the two companies to become comfortable with the other’s processes. In 2003, Pfizer identified the need for a “technical enabler” to screen patients for Maraviroc’s clinical development program.
Keeping in mind that fewer than 25 percent of all candidates in Phase II trials succeed, Pfizer needed a molecular diagnostic to bolster the drug’s chances by selecting the group of patients likely to benefit from the drug.
Pfizer knew it needed a partner that had a sensitive, CLIA-approved assay. The potential partner also had to have experience in the HIV market and with handling samples in clinical trials, and it had to have experience working with pharmaceutical companies.
Monogram fit the bill. “We virtually have partnerships with every pharmaceutical company that’s in HIV,” Monogram Senior Vice President William Welch said during the HPCGG conference. “We use these partnerships to understand the core science and to plough the fields to harvest the patients that are best likely to benefit.”
Monogram CEO William Young told Pharmacogenomics Reporter this week that the Trofile assay is being used in 90 percent of all the clinical trials assessing HIV tropism and drug resistance. These other collaborations prompted the FDA to request a “master file” for the Trofile assay.
“So many sponsors were using our Trofile assay that FDA actually asked us to submit a master file on the assay and its validation data, so they would have access to that data as they reviewed various sponsors’ drug-development plans,” Young said.
Pfizer 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.
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.
“The bottom line at Pfizer is the recognition that if there was no assay then there was not going to be any sales of this medicine in which we had already invested hundreds of millions of dollars.”
Results from a Pfizer trial (Study 1029) presented at the International AIDS Conference in Toronto in August showed that “patients identified by the assay as having viruses using both the CXCR4 and CCR-5 receptors (dual/mixed tropic) did not respond virologically” to Maraviroc, Monogram said in a statement.
Maraviroc is designed to work differently from other available HIV medications. CCR5 antagonists block the virus from gaining access to healthy cells via the CCR5 co-receptor, a common pathway for viral entry. However, for 15 percent to 20 percent of treatment-naïve patients and 40 to 50 percent of treatment-experienced patients the HIV virus can use the CXCR4 co-receptor to infect white blood cells.
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. However, without Monogoram’s tropism assay Pfizer cannot identify the right population for its drug.
“What started out as a technical enabler really became a need for a commercial enabler,” Schmeltz said, describing the evolution of Pfizer and Monogram’s relationship with the Trofile assay.
“The reality is we need to make sure this assay is going to be available everywhere we want to market Maraviroc because every patient in our clinical development program was screened with this assay for CCR5-tropism,” said Schmeltz. “We knew that it was going to be in our label and would be required for eligibility to benefit from Maraviroc.”
Anatomy of a Theranostic Alliance
Any product label issued by the FDA for Maraviroc will likely include information requiring patients to confirm their CCR5-tropism status before being prescribed the drug, Schmeltz said in Boston. Additional information about the label will be known when the drug is approved.
Since Trofile is currently the only available CLIA-certified tropism test, Monogram stands to gain significantly from labeling language in this regard. In turn, the success of Pfizer’s product is also tied to the availability of a diagnostic test.
“If this assay is not available in every country we wanted to market Maraviroc in, then the medicine can’t be used,” Schmeltz said. “So, the bottom line at Pfizer is the recognition that if there was no assay then there was not going to be any sales of this medicine in which we had already invested hundreds of millions of dollars.”
According to Schmeltz, Pfizer and Monogram created a system where labs throughout the world consolidate genetic samples locally and ship them to Monogram’s facility in San Francisco. Pfizer will market the assay to Maraviroc prescribers, secure reimbursement with local plans, as well as handle education efforts regarding tropism testing.
The partnership “ensures test reimbursement so we can tap into the Pfizer scale and expertise in reimbursement with the local nuances with every country around the world,” Schmeltz said.
Welch said the Trofile assay is “a first in HIV where drugs are designed in conjunction with a molecular assay.” Pfizer held up Maraviroc as the first oral entry inhibitor that works against HIV resistance to all other drug classes.
Monogram also provides its CCR5-tropism assay for Schering-Plough’s CCR5-antagonist Vicriviroc, for which two Phase III clinical trials are planned but recruiting has not yet begun. Human Genome Sciences is currently recruiting patients for a Phase I clinical trial for its anti-CCR5 antibody CCR5mAb004. According to Young, Monogram does not intend to seek FDA clearance for the test (see story below).
Monogram Will Not File Trofile for FDA Clearance; Says FDA Satisfied
A lingering question surrounding the Trofile assay is whether Monogram will file the CLIA-approved test for FDA clearance.
“FDA is comfortable with the assay being CLIA-based,” Monogram CEO William Young told Pharmacogenomics Reporter this week. “We’ve asked that question a number of times as to whether they are comfortable with that regulatory status, and they say they are.”
This could be because the Trofile assay’s mechanism of action places it outside FDA’s Draft Guidance for Industry, Clinical Laboratories, and FDA Staff – In Vitro Diagnostic Multivariate Index Assays [see PGx Reporter 09-13-06].
“It falls outside of the current guidance document being reviewed for multivariate IVDs,” Young said. “The Trofile is really a biological measurement of co-receptor tropism. So it doesn’t fit the definition that FDA is trying to get at with their new guidance document.”
The draft guidance is meant to help untangle the regulatory uncertainty surrounding who oversees this fairly new category of devices. Moreover, the agency specifically appears to be trying to prevent another company from taking the same regulatory route as Genomic Health, which began selling its OncotypeDx breast cancer recurrence test without seeking regulatory approval.
The Trofile “is not something where you are measuring a bunch of factors and relating those to clinical outcomes. It’s basically a biological measurement of the patients’ virus and whether that virus makes use of CCR5 or CXCR4. So it’s a real measurement of that effect,” Young said.