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Multiple Stakeholders Come to Bat for Large Rheumatoid Arthritis PGx Trial


By Turna Ray

Multiple drug developers,
a payor, a diagnostic company, and several academic centers are working together to validate a gene expression signature and discover other markers that might help predict whether rheumatoid arthritis patients will respond to anti-TNF drugs.

The trial, called Biomarkers of Anti-TNF Treatment Efficacy in Rheumatoid Arthritis to Define Unresponse Populations, or BATTER-UP, will enroll around 1,000 patients being treated by one of several marketed anti-TNF RA drugs: Enbrel (Amgen/Pfizer), Remicade (J&J/Centocor), Humira (Abbott), Simponi (J&J/Centocor), or Cimzia (UCB).

BATTER-UP is funded by Biogen Idec, Bristol-Myers Squibb, Centocor Research & Development, Crescendo Bioscience, Genentech, Medco Health Solutions, Regeneron Pharmaceuticals, and Sanofi-Aventis. All of these firms, which are providing operational support for the trial, expect to benefit from advancing their knowledge of the mechanism of action of anti-TNF drugs in RA.

"The convergence of companies represents the interest in better understanding the heterogeneity of RA, a crippling and debilitating disease, so that treatment plans may be more appropriately personalized for individuals in need of a biologic therapy," Centocor spokesperson Brian Kenney told PGx Reporter.

The worldwide market for anti-TNF drugs is estimated to be around $13 billion and rapidly growing. TNF inhibitors are used to treat a variant of autoimmune disorders, including RA.

By using a gene signature to improve the efficacy rate of anti-TNF agents, these competing drug makers would be able to identify those who won't respond to anti-TNF drugs and guide them to alternative treatments.

Biogen Idec and Genentech market Rituxan, which is indicated as a treatment for RA with methotrexate after the patient has failed treatment with at least one TNF inhibitor. Biogen Idec invested in early studies that led to the discovery of an eight-gene signature predictive of RA patients' response to TNF-inhibiting drugs. This signature will be further investigated in BATTER-UP.

BMS markets Orencia, another RA treatment for patients who do not respond to anti-TNF therapy. Regeneron and Sanofi are collaborating on the development of REGN88, an interleukin-6 receptor antibody for RA in Phase I and II trials.

Crescendo Bioscience is developing a predictive diagnostic test to gauge response of RA drugs, called Vectra TS. The RA-focused diagnostics firm is involved in the BATTER-UP trial to learn about the markers linked to anti-TNF response.

"In BATTER-UP there are a wide variety of signatures or hypotheses that may want to be assessed by each party," William Hagstrom, CEO of Crescendo Bioscience, told PGx Reporter. "From our perspective, our participation is based on the goal of being able to see … what's a powerful signal that would allow the market to better understand which patients are likely to respond to anti-TNF therapies."

While the BATTER-UP trial will initially focus on validating a previously published gene signature predictive of patient response to anti-TNF agents, Crescendo Bioscience will use a "locked algorithm" to potentially evaluate a set of serum markers. Since its predictive RA test is still under development, it is currently unclear which specific biomarkers will be marketed under the brand name Vectra TS, the company noted.

Peter Gregersen, one of the lead investigators of the study and director of the Center for Genomics and Human Genetics at the Feinstein Institute of Medical Research, noted that approximately 30 percent of RA patients have a "robust" response to TNF inhibitors, while around one-third have no response at all. "And the rest sort of lie in between," he told PGx Reporter.

According to the Centers for Disease Control and Prevention, more than 2 million adults have RA in the US. The disease can lead to long-term joint damage that can be debilitating. According to the Arthritis Foundation, people with rheumatoid arthritis are two times more likely to die as persons of the same age without the disease.

"Companies want to find out who's not responding to these drugs, because there are a lot of competing products that are being developed," Gregersen said. "The obvious issue is that if you can tell someone is not going to respond to a TNF inhibitor, they might respond to some of the other biologics that are out there."

Gregersen worked with Biogen Idec on the earlier investigation to identify the eight-gene signature that will be evaluated in the BATTER-UP trial. "That [earlier study] was based on a relatively modest observation — say, less than 100 [people]," Gregersen said.

In that study, published in Genomics in December 2009, Gregersen and colleagues used an approach called the Convergent Random Forest method to identify eight transcripts predicting patients' response to anti-TNF treatment with 89 percent accuracy.

In BATTER-UP, the investigators are working to enroll around 1,000 RA patients, treat them with a TNF inhibitor, and assess their response prospectively at 12 weeks. Researchers will sample study participants at baseline and at the 12-week time point to assess serum, plasma, cellular, DNA, and RNA markers.

Gregerson could not provide a timeline for when BATTER-UP might be completed, noting that the current challenge is enrolling such a large number of patients.

Medco, as a collaborator in the BATTER-UP study and a member of the consortium's joint governing board, will contribute investigators to the study and will be handling patient recruitment, as well as managing the nursing staff that conducts patient visits.

According to Cynthia Ewel, clinical research director of personalized medicine R&D at Medco, BATTER-UP's goal of guiding the best treatment for RA patients fits in well with the PBM’s Personalized Medicine research program, which is interested in applying genomic strategies to improve treatment response, avoid unnecessary treatments, and incur savings to its customers.

"This is beneficial to Medco’s clients since they will not be paying for an expensive and ultimately ineffective therapy," Ewel told PGx Reporter. "Just as important, the patient is now moved quickly to an effective RA therapy, potentially saving them months of pain and morbidities associated with moderate to severe rheumatoid arthritis."

Medco makes the bulk of its revenues from the sale and dispensing of generic drugs, and has launched a program called Genetics for Generics through which the PBM aims to more efficiently dispense cheaper drugs through the adoption of genomic strategies.

Many of the drugs in the BATTER-UP trial are slated to go off patent in the next few years, but because they are biologics, generic versions of these drugs will likely not be available in the US, where the manufacture of generic biologics is prohibited.

As such, it is perhaps even more important for payor groups such as Medco to figure out how to administer these costly drugs to those most likely to benefit.

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