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Nov 22, 2010
 |  BioCentury  |  Regulation

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 to as many as 1.5 million patients in the U.S. The disease primarily affects women of child-bearing age. It presents with a constellation of signs and symptoms that wax and wane, and causes permanent damage to multiple organ systems. The manifestations of lupus include arthritis, pleuritis, pericarditis, stroke, seizure, nephritis, vasculitis, anemia, thrombocytopenia, alopecia, photosensitivity and malar rash.

According to briefing documents from HGS, patients have two to five times the risk of mortality of the general population.

About 90% of SLE patients have anti-nuclear autoantibodies, which target components of the cell nucleus and mediate broad tissue damage. Apart from this one commonality, patients present with such a wide variety of signs and symptoms that diagnosing the condition often takes years.

FDA estimated that more than three-quarters of SLE patients have mucocutaneous and musculoskeletal symptoms. About one-half to two-thirds have renal involvement. Neuropsychiatric symptoms including mood disorders, anxiety and psychosis occur in about two-thirds of patients. Most patients also experience a variety of general symptoms including extreme fatigue, malaise, fever, anorexia and weight loss.

Exacerbations of symptoms, called flares, are often life-threatening, leading to extended hospital stays and sometimes requiring lengthy rehabilitation to regain basic functions such as speech and walking.

The agency noted that while mucocutaneous and musculoskeletal symptoms are debilitating and reduce quality of life, they are not generally fatal. In contrast, renal involvement is associated with poor outcomes and mortality.

"Nothing about this chronic disease is typical, except the suffering," Brenda Blackmon told the panel during the open public hearing. Blackmon's daughter was diagnosed with SLE at age 23 and three years later landed in the ICU on life support after her lupus attacked her brain. She then had to undergo lengthy rehabilitation.

Patients and panel members alike spoke of the dearth of treatments, and the significant toxicities of drugs that are used off label as standard of care. The last drug approved for the indication was the antimalarial quinacrine in 1958.

SOC for mild to moderate SLE consists of NSAIDs, antimalarial drugs and corticosteroids. Life-threatening flares, such as those affecting the kidneys, CNS or vasculature, are treated with high-dose corticosteroids, immunosuppressive agents such as cyclophosphamide and azathioprine, or both.

In many cases the drugs themselves do irreversible damage, sometimes leading to death. Corticosteroids in particular cause weight gain, hypertension, increased susceptibility to infection, bone thinning, mood swings and cataracts, among other serious side effects.

Evanne Graté, who has had lupus for 25 years, told the panel she had developed CNS lymphoma, had to undergo dialysis and contracted a life-threatening MRSA infection requiring surgery as a result of long-term use of predisone and CellCept mycophenolate mofetil. Roche markets CellCept, a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), in the U.S. to prevent organ rejection.

"My life was not threatened by lupus, but by its treatments," she told the panel.

Thus, the hope is that Benlysta will provide a less toxic alternative that will...

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