Discovery Yields Potential Gout Treatment
A new approach to treating gout -- a debilitating form of arthritis -- can normalize levels of uric acid in the blood within hours in patients who have failed to respond to any other treatments, and in some patients, eliminate the painful, needle-like crystals of uric acid that clump around fingers, toes and other joints.
Details of the use of the drug, pegloticase, among 212 patients with severe gout enrolled in two, phase III clinical trials, were released today at the annual meeting of the American College of Rheumatology.
“There hasn’t been a new drug for gout in the U.S. for over forty years,” says Dr. John Sundy, a rheumatologist at Duke University Medical Center and the lead investigator of the study. “While most gout patients do well with the drug allopurinol, there is a subset of about 50,000 patients in the U.S. who don’t respond to it or who can’t tolerate it and who have no real alternatives. These are the patients who might benefit from a new therapeutic option.”
For years referred to as “the disease of kings,” gout is often depicted as a disease of rich old men who eat and drink too much. Actually, it is not clear why some people develop gout and others do not, although there is some evidence that the disease has genetic and lifestyle underpinnings that leave some people more vulnerable than others. It’s estimated that anywhere from two to three million people in the U.S. suffer from gout. It is more common in men than women but Sundy says that after menopause, women are about as likely to develop gout as they are to develop rheumatoid arthritis
“Gout usually takes people by surprise,” says Sundy. “The typical patient is male, probably in his 40s or 50s, who suddenly develops searing pain in one of his big toes.”
It can spread from there. Affected areas become red and swollen and exquisitely painful. In extreme cases, gout can leave patients wheelchair-bound and unable to handle basic tasks like buttoning clothes, tying shoes or handling a knife or fork.
Gout occurs when there is so much uric acid in the blood that the body can’t get rid of it fast enough. When that happens, the excess precipitates into crystals that clump in and around joints and tendons, triggering inflammation. It turns out this is largely a human problem. Most mammals have a gene that makes an enzyme called uricase that breaks down uric acid into easily eliminated substances. But through an evolutionary quirk, that gene became mutated in humans. The result is that people have lost an effective way to get rid of excess uric acid -- a natural byproduct of purine metabolism in the body.
While current drugs treat gout by slowing the production of uric acid or speeding up ways to eliminate it, pegloticase, discovered by Michael Hershfield, MD, and Susan Kelly, PhD, at Duke and scientists at Mountain View Pharmaceuticals, addresses the root cause of the disorder. “Pegloticase is a manufactured enzyme that essentially does the same job that uricase was meant to do,” says Sundy. The drug, which is given as an infusion, breaks down uric acid into products the body can more easily eliminate.
Patients in the two trials, referred to as GOUT I and GOUT II, received 8 milligrams of pegloticase or a placebo every two or four weeks for six months. Researchers measured uric acid levels and crystal deposits (called tophi) over time.
They found that uric acid levels fell to target levels among all patients within six hours after receiving the medication and remained at target levels in about 40 percent of patients when measured three and six months later. There was also a significant reduction of the size and number of tophus deposits among those patients getting pegloticase, compared to those getting a placebo.
Almost all of the patients in all arms of the study experienced some side effects. The most common was gout flares, a frequent, albeit counterintuitive event that often occurs after beginning therapy to lower uric acid levels. The gout flares tended to diminish over time.
Twenty-six percent of the participants in the every two-week group and 46 percent of the patients in the every four-week arm of the study also experienced infusion-related effects, including back or chest pain, chills, nausea and headaches. Thirty-two patients withdrew from the studies because of side effects.
Almost 90 percent of the patients who received pegloticase developed antibodies to the drug and those with the strongest antibody response were more likely to experience side effects and have a less enduring response to the drug’s ability to lower uric acid levels.
“Overall, we are very pleased with what we are seeing,” says Sundy. “We are continuing to study the longer-term effects of pegloticase in an open label extension study. Many of the study participants appear to be doing quite well and are finally getting some long-awaited relief.”
Pegloticase is developed and produced by Savient Pharmaceuticals, Inc., which sponsored the studies.