Upholding Standards: Should the FDA approve a new lupus drug with unclear benefits?

If you are one of the estimated 300,000 to 4 million patients in the US who suffer from lupus, you may feel excited about a drug called Benlysta (generically, belimumab).  There is a need for better drugs to treat symptoms, reduce the use of other medications that can have imperiling side effects, and reverse disease progression.  The US Food and Drug Administration (FDA) plans to decide whether to approve belimumab by December 9th.

For unknown reasons, in lupus the immune system attacks the body, leading to a chronic inflammatory disease.  The illness can vary greatly for each patient and between patients.  Flares can appear unexpectedly and with an unpredictable severity, several times a year.  Symptoms often are “general” (fever, weight loss and fatigue) and organ-specific, including joint pain, skin lesions, kidney injury, and heart injury among others.  In severe cases, a patient may die from kidney failure, severe infection, stroke or other causes.

A lupus diagnosis is no longer a death sentence.  Sixty years ago, the 5-years survival rate was 40%, whereas since the 1980s it has been over 90%.  This may have occurred as physicians learned to identify and treat the disease sooner or use medications “off label” to help patients.  While the only FDA-approved medications for lupus are aspirin, prednisone and the anti-malarial drug hydroxychloroquine, some patients also find benefit from immune suppression drugs like cyclophosphamide and other glucocorticoids related to prednisone.  Yet taking these medicines brings many side effects, often severe.  They can include increased risk of severe infection, body weight increase and redistribution, rashes, eye cataracts, and increased risk of major cardiovascular illness including heart attack and stroke.

Enter the hope for belimumab.  Its makers, Human Genome Sciences and GlaxoSmithKline, conducted two Phase 3 trials that each enrolled 800 to 900 patients, all of whom received standard of care medicines like prednisone.  In addition, the patients either received placebo or belimumab.  Trial researchers tracked patients’ symptoms to determine whether they responded to the drug.

Did the drug reduce lupus symptoms?  In one trial with patients who were from Asia and Latin America, 58% of patients receiving the target dose of belimumab responded compared to 44% in the placebo arm.  This difference reached statistical significance, meaning it was highly unlikely for these groups to have differed solely by chance.  But in the second trial, with patients in the US, Canada and Europe, the improvement was smaller at 12 months (43% response compared to 34% with placebo) and disappeared by 18 months.  In addition, patients of African-American or African heritage worsened with belimumab.  In the first trial, 46% of these patients responded compared to 64% on placebo.  In the second trial, it was 33% for belimumab versus 39% for placebo.

Was the drug safe?  Of 2,133 patients treated, death was 1.8 times more likely for patients on belimumab (0.9% of patients) than on placebo (0.4% of patients), and this was a statistically significant result.  71% of patients treated with the drug got an infection (of any severity) compared to 67% of those receiving placebo.  Serious infections were slightly more frequent with belimumab than placebo (6% of all patients in the Phase 2 and 3 trials, versus 5% for placebo).

Considering these findings, will the FDA approve the drug?  On the one hand, some industry analysts have written, approval would encourage other lupus drug makers.  Yet lowering the bar would only benefit short-term industry interests at the expense of patients.  Difficult problems require innovation and perseverance.  Perhaps suggesting it would not lower its standards, in a briefing to the FDA’s recent advisory panel, the agency raised several major criticisms of the belimumab results.

Yet surprisingly, the panel voted 13 to 2 in support of belimumab.  Meeting minutes have not yet been released.  Reuters quoted one panel member as saying, “The efficacy is mild, but I think there is a need for drug even with mild efficacy.”   The FDA is not required to follow the panel’s recommendation, though several journalists have indicated it usually does.  One additional variable is that the drug may cost $20,000 to $30,000 per year.  While this is expensive, it is not nearly as expensive as some drugs for cancer or other rare diseases (see list here), though it would rack up costs as patients took it chronically.

One compromise is the FDA could approve the drug with restrictions.  For instance, the drug might be permitted only for patients the drug helped, such as those of Caucasian heritage or with skin or musculoskeletal forms of the illness.  Or it may be restricted to 12 months or less of continuous therapy.  In a few weeks we will learn of the decision.  Hopefully it will be made in the interest of patients first.

Further reading:

  1. Mayo Clinic overview of lupus
  2. Mayo Clinic overview on of glucocorticoid drugs
  3. UpToDate patient information on lupus
  4. Article on lupus epidemiology
  5. Articles on FDA panel backing Benlysta:
    1. FierceBiotech 11/16/2010
    2. LA Times 11/17/2010
    3. New York Times 11/17/2010
  6. FDA Arthritis Advisory Commitee 2010 meeting materials
  7. FDA and the clinical trial process for drugs seeking approval
  8. The clinical trials discussed above are BLISS-52 (HGS press release) and BLISS-76 (press release).
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