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Novel Indication Trips up Humira, Snags Cimzia at Arthritis Adcom

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By Mari Serebrov
Washington Editor

The FDA's Arthritis Advisory Committee struggled to flip its mind around a broad novel indication of axial spondyloarthritis (axSpA) Tuesday, voting 7-6, with one abstention, to recommend FDA approval of UCB SA's Cimzia to treat active axSpA.

The panel wasn't as divided as the numbers suggest, as members voting on both sides of the question expressed frustration with the wording of what they considered a broad and ambiguous indication. The committee also voted 8-5, with one abstention, that the data the Brussels-based company presented from one pivotal trial was adequate to show a clinically meaningful effect.

The committee encouraged the FDA and sponsor to work on the wording of the indication. One possibility is that Cimzia (certolizumab) could be approved to treat ankylosing spondylitis (AS), a subgroup of axSpA identified according to the 1984 modified New York criteria that require x-rays to demonstrate structural changes, or an expanded subgroup identified by either x-ray or MRI evidence of inflammation.

Earlier in the day, the committee voted 12-1, with one abstention, against recommending approval for Abbvie Inc.'s Humira (adalimumab) for nonradiographic axSpA (nr-axSpA), citing the need for more efficacy data and a better defined patient population. Humira is already approved in the U.S. for AS and is approved in Europe for both AS and nr-axSpA.

The one positive vote came from patient representative Michael Smith, who said, "I represent the outcome we're all trying to prevent." Although Smith said he thought the criteria for the indication were too loose, he recommended approval for the benefit of the patients who might be helped by having access to anti-TNF drugs. Currently, no drug has been approved in the U.S. for nr-axSpA.

Abbvie tripped over the fact that it submitted the results of one trial to support the supplemental biologic license application for Humira. And more than half the subjects in the study had AS, which is must better characterized than other forms of axSpA.

Noting the "significant unmet medical need," John Medich, vice president of immunology clinical development at AbbVie, said the vote isn't going to stop the Chicago company from pursuing the broader indication. The company plans to meet with the FDA to determine a path forward to develop Humira as a treatment for nr-axSpA, a long-term, chronic disease that affects patients in the prime of life.

Tuesday's votes came on the heels of a full-day discussion on the merits of creating axSpA as a new indication based on criteria developed by the Assessment of Spondyloarthritis International Society (ASAS) as a way of treating the disease before it caused the irreversible structural damage associated with AS. (See BioWorld Today, July 23, 2013.)

The ASAS criteria, published in 2009 and approved unanimously by more than 150 rheumatology experts worldwide, offers two classification arms, both of which include lower back pain that lasts at least three months, with age of onset younger than 45. In addition, the patient must have sacroiliitis, as evidenced by x-ray or MRI, with at least one typical SpA feature – such as arthritis, psoriasis or Crohn's disease. In the alternative, a patient could have the genetic HLA-B27 marker with at least two SpA features. (See BioWorld Today, July 19, 2013.)

While Europe and other markets have adopted the ASAS criteria, the FDA's Janet Maynard cited limitations in the use of the criteria, given their "relative recent publication." The agency's concerns revolve around the lack of longitudinal studies based on the ASAS criteria and perceived differences between the nr-axSpA subgroup and patients with AS.

Despite those reservations, the FDA told UCB a year after ASAS published the criteria that it might be reasonable to look at axSpA as an indication for Cimzia, Maynard said. But in a meeting last year with the company, the agency raised regulatory concerns about use of the ASAS criteria.

Throughout this week's meeting, the FDA and panel members were apprehensive that broadening the indication would lead to misclassification by primary care physicians not that familiar with axSpA or to off-label use. Either one would expose patients needlessly to the expensive anti-TNF drugs, which can have serious side effects, they reasoned.

Cimzia's "already out there, and it already could be prescribed by primary care physicians for this indication," Irwin Russell, director of fibromyalgia research and consulting at the Arthritis and Osteoporosis Center of South Texas, reminded his colleagues. Russell voted for Cimzia approval, and although he voted against the expanded Humira label, he urged Abbvie to do what's needed to get the drug approved for nr-axSpA.

"People can prescribe it, but no one's going to pay for it," said David Felson, chairman of the clinical epidemiology unit at the Boston University School of Medicine. Because of the cost of the biologics, most payers would insist on FDA approval of the indication before they would reimburse for it, he added.