Mild Was Enough

Final FDA backing for Benlysta may not provide roadmap for other lupus drugs

Leading up to last week's advisory committee meeting to discuss a BLA for lupus candidate Benlysta belimumab from Human Genome Sciences Inc., the outcome hardly looked like a slam dunk. Based on a pair of Phase III trials that met their primary endpoints but fell short on several other measures, FDA reviewers asked members of the Arthritis Advisory Committee to discuss whether the antibody's "marginal efficacy" was enough to justify potential risks suggested by small increases in cases of infections, cancer and suicides seen in trials.

It turned out neither concern overly troubled the panel, which voted 10-5 that the data demonstrated substantial evidence of efficacy and 14-1 that Benlysta's safety profile was sufficient. The final vote in favor of approval was 13-2, based largely on unmet need in an indication where a new drug has not been approved in more than 50 years.

"The efficacy is mild. But there is a need for drugs with even mild efficacy," said Lenore Buckley, professor of internal medicine and pediatrics at the Virginia Commonwealth University School of Medicine and a regular voting member of the panel.

However, Buckley and the other panelists who voted yes on approval made it clear that Benlysta's label should reflect the populations studied in Phase III trials, which excluded patients with severe lupus nephritis or CNS manifestations of the disease.

They also indicated additional study is needed in black patients, who account for about a quarter of lupus patients in the U.S. and tend to have more severe disease than the general lupus population. In a Phase II study of Benlysta, black patients did much better than non-blacks. But in the Phase III trials, black patients given Benlysta did worse than those given placebo.

HGS has proposed a broad indication for 10 mg/kg Benlysta to reduce disease activity in adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.

The company and partner GlaxoSmithKline plc have committed to studies in black patients in the postmarket setting, and said they are planning a proof-of-concept trial to investigate Benlysta's effect in lupus nephritis.

They do not currently have plans to study the compound in patients with CNS manifestations of the disease, which HGS said would require further consultation on study design.

It's now up to FDA to decide how best to implement the panel's recommendations for label restrictions and postmarket studies, making it unlikely the agency will be able to meet the BLA's Dec. 9 PDUFA date.

If the agency approves Benlysta, it will be a boon to patients, who have few therapeutic options, all of which come with severe and even life-threatening toxicities.

What an approval would mean for the more than 15 candidates in clinical trials is less clear, as the panel raised several questions about the design of HGS's Phase III trials, including the novel endpoint, the enrollment criteria and the lack of data in patients with the most severe manifestations of SLE as well as black patients.

Dying from drugs

Estimates of the prevalence of SLE vary widely, from about 300,000

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