The Arthritis Advisory Committee's call for FDA to tailor labeling to restrict claims of efficacy to the clinical trial population for Human Genome Sciences' lupus drug Benlysta (belimumab) will likely push a decision on the drug beyond its Dec. 9 user fee date.

Concerned that the pivotal trials evaluated the biologic in a limited segment of the lupus patient population, panel members opted, in a 13-2 vote, to support approval of the drug as long as labeling informs patients and physicians about the studies' shortcomings.

"The drug has shown some efficacy in the subpopulation of lupus patients, but I think that the labeling has to be more specific to this subpopulation," Gabor Illei, NIH, voiced the majority's position.

If FDA goes along with the approval and labeling recommendations made at the Nov. 16 advisory committee, it would have only 16 working days to decide whether to rewrite the indication or describe study limitations elsewhere in the labeling, and negotiate those changes with HGS.

Advisory Committee Votes

10-5 that belimumab demonstrated substantial evidence of efficacy for reducing disease activity in adult patients with active, autoantibody-positive, systemic lupus erythematosus receiving standard therapy
14-1 that the safety profile of belimumab is sufficient to approve the biologic for the proposed indication
13-2 that belimumab should be on the market, with caveats in labeling to denote which subgroups were effectively treated in trials

Trials Have Few Severely Ill Patients

A major concern for panel members was the scarcity in the two pivotal trials of patients with severe lupus kidney disease or active central nervous system lupus. Rather, the most commonly involved organ systems in patients at baseline were musculoskeletal and mucocutaneous (Also see "Variety of Issues Undermine Efficacy Data As FDA Takes Benlysta To Advisory Panel" - Pink Sheet, 12 November, 2010.).

Because of the limited patient population in the trials, it is difficult to extrapolate the data to the larger lupus population, David Pisetsky, Duke University Arthritis Center, said. "Non-renal, non-CNS disease is all we've been able to look at because of the study design. … This really does have to be clarified in a very significant way to avoid the perception that it's really for all active [lupus]. … There have to be a lot of limitations here."

Christy Sandborg, Stanford University, urged that labeling not be "overly restrictive." Benlysta is likely to be used in patients with CNS and renal lupus, she said, and suggested that labeling "actually state that these were populations that were not specifically tested."

Those limitations are not mentioned as part of the labeling summarized in HGS briefing documents and could require extensive discussions as FDA tries to craft labeling with an eye toward discouraging off-label use.

The labeling proposal notes only the lack of adequate and well-controlled trials in pregnant women and nursing mothers, limited data for geriatric patients, and that efficacy and safety have not been established in pediatric patients.

The company does plan to do a lupus nephritis trial, or at least a proof-of-concept study. Exclusion of patients with this condition from the Phase III trials was largely due to inexperience with the background therapies for treating the condition, William Freimuth, HGS VP-Clinical Research Immunology, Rheumatology and Infectious Diseases, said. Now that experience has been gained with using mycophenalate (Pfizer's CellCept), a study is more appropriate, he said.

In the case of studying Benlysta in patients with CNS lupus, there would need to be a great deal of consultation because it will be very difficult, he added.

Question Clarified Due To Panel Misgivings

An initial vote on the drug's efficacy had elicited a more mixed vote, with 10 panel members saying the drug is effective and five saying it is not. But several members explained that their negative vote was based on the drug's failure to demonstrate efficacy for the requested broad indication: reduction of disease activity in adult patients with active, autoantibody-positive systemic lupus erythematosus in combination with standard therapy.

In light of that, Curtis Rosebraugh, director of the Office of Drug Evaluation II, simplified the question to avoid confusion: "If you think this should be on the market, vote yes, and then tell us what you think the label should be if you don't agree with the indication."

That rephrasing prompted three members to switch their votes, to support approval with labeling that specifies that the clinical trials did not include a broad range of patients.

Study Planned In African Americans

While the bulk of the panel's discussion centered on the failure of the Phase III trials to show efficacy in the lupus population as a whole, members also brought up the uncertainty surrounding efficacy in African Americans, calling for further studies in this group.

A failed Phase II study, which informed the design of the Phase IIII trials, showed belimumab to be effective in African American patients, but the Phase III trials found otherwise. HGS acknowledged the divergent results. "This does happen when one performs and evaluates results in small subgroups. We can't explain it," Daniel Odenheimer, HGS VP-Clinical Research General Medicine, said.

Sandborg acknowledged that it is "a very difficult population to understand as far as the risks and their disease severity." FDA does have precedent for labeling drugs to reflect a lack of efficacy shown in African American patients, as with several cardiovascular medications, and has even structured indications to be race-specific – Nitromed's heart failure combination BiDil is indicated solely for African Americans.

HGS is committed to further studying Benlysta in African Americans, Odenheimer said. He also noted that in black patients with SELENA SLEDAI scores above 10, there did appear to be a response. SELENA SLEDAI is one of the components of the composite primary endpoint ([A#00101122008]).

The study also showed a geographic disparity in the efficacy results. There was a numerically smaller difference in efficacy for patients in the U.S. and Canada, compared to other regions.

Sandborg thought this could be due to use of fewer steroids and more immunosuppressants than in other geographical areas. Because North American patients were on fairly effective background therapies and still had active lupus, she said, the delta changed and there might be a relatively smaller treatment effect.

Panel members accepted the safety of the drug by a near-unanimous vote of 14 to 1.

If FDA gives the okay, Benlysta would be the first drug approved for lupus in more than 50 years. The last was Bayer's Atabrine, the anti-malarial quinacrine, which cleared the agency in November 1958. Other approved drugs are the corticosteroid prednisone and Sanofi-Aventis' antimalarials Aralen (chloroquine) and Plaquenil (hydroxychoroquine).

Benlysta is a first-in-class monoclonal antibody that targets the protein B-lymphocyte stimulator. HGS and GlaxoSmithKline are co-developing and co-commercializing the biologic.

By Cathy Dombrowski

Benlysta Decision Likely To Be Delayed By Negotiations On Labeling

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