New Drug May Relieve Severe, Tough-to-Treat Gout

The injectable drug pegloticase offers relief to some patients, but carries risk of serious side effects

For some gout patients afflicted with a particularly severe, crippling form of the disease who find standard treatments either intolerable or ineffective, a recently approved alternative appears to afford relief.

A new injectable treatment called pegloticase (brand name Krystexxa) has no effect on most severe gout patients, but researchers say that for the roughly four in 10 patients who do respond positively, the improvement can be significant.

Use of pegloticase was approved by the U.S. Food and Drug Administration in September 2010.

However, the treatment is expensive and the study found a high rate of side effects, some extremely serious, suggesting that health providers have to weigh the costs and benefits on a case by case basis.

"What we're focusing on here are the approximately 3 percent of gout patients who have the most advanced form of disease," said study senior author Dr. Michael A. Becker, professor emeritus of medicine at the University of Chicago.

"About 80 percent of the time these patients are intolerant of the long-standing medication for gout, allopurinol," Becker explained. "For the other 20 percent, the medication either just doesn't have sufficient efficacy or takes too long to take effect.

"So pegloticase is clearly a niche agent designed specifically for these worst cases," Becker said. "It is an expensive alternative requiring carefully monitored intravenous infusions for a prolonged period of time. And there is a potential for infusion reactions, which can be -- although usually aren't -- severe.

"But the bottom line is that this treatment offers hope for people who have been deemed otherwise not amenable to treatment with conventional agents," he concluded.

Savient Pharmaceuticals, which has licensed the exclusive rights to technology relating to pegloticase, funded the study and had input into it.

The study authors noted that approximately 6 million men and women in the United States suffer from some form of gout, an illness that stems from an inability of the body to adequately dispose of uric acid accumulation. Over the last two decades the number of Americans who struggle with the disease has gone up by roughly 50 percent.

For such individuals, mounting uric acid levels give rise to tiny needle-like crystal formations, which in turn lodge in joints and tissues (most notably the big toe), causing inflammation and frequently debilitating pain.

Since 1966, orally administered allopurinol (Lopurin, Zyloprim) has been the treatment of record, helping many patients by lowering the production of uric acid while draining out unsustainable deposits through the kidneys. A second oral treatment option, called febuxostat (Uloric) was approved two years ago.

But for a small minority of patients, the pills either don't work, work too slowly or prompt severe side effects. Their gout can lead to joint disease, deformity, chronic pain, disability and diminished quality of life. And for such individuals there has been no "plan B."

For some of these patients, Becker explained, bi-weekly (every two weeks) intravenous infusions of pegloticase containing a modified version of a pig enzyme called "uricase" (lacking in humans) work by quickly converting uric acid into an alternate and easily excretable fluid.

To see how effective this novel approach might be, the study authors conducted two six-month trials in tandem, involving a final total of 212 patients with severe, chronic and previously untreatable gout who were being cared for at 56 different rheumatology facilities throughout the United States, Canada and Mexico.

Patients were randomly divided into three groups: one to receive 8 milligrams of pegloticase bi-weekly; a second to receive the drug once a month; and the third placed on injectable saline (a placebo).

The result: all patients receiving pegloticase experienced a rapid drop in their uric acid levels to ranges considered normal. However, in some cases the uric acid decline was temporary, the investigators found.

The study indicated that the new treatment will not help all of the estimated 120,000 to 180,000 Americans with this most severe type of gout. In fact, the medication appeared to elicit an all-or-nothing response, greatly helping some patients while having almost no effect on others.

Ultimately, the research team found that 42 percent of the bi-weekly pegloticase patients maintained normal uric acid levels for a minimum of 80 percent of the half-year study period. The same was true among 35 percent of the monthly pegloticase patients. Those given saline solutions saw no improvement at all.

Overall, the quality of life went up among both sets of pegloticase patients, as did mobility and function; there was also a reduction in pain. What's more, many of the lumps typically associated with long-term gout (called "tophi") resolved in roughly 40 percent and 20 percent of the bi-weekly and monthly pegloticase patients, respectively.

However, the authors said 90 percent of pegloticase patients experienced at least one side effect, most commonly a brief flare-up of gout. Such flare-up side effects are also a common feature among allopurinol patients in the immediate period following treatment launch.

More seriously, about one-quarter of the bi-weekly pegloticase patients and 42 percent who had monthly injections experienced infusion-related immune responses at the drug injection site. In 5 percent to 8 percent of patients, the reaction was serious, and five patients experienced anaphylaxis.

Dr. Tuhina Neogi, an associate professor of medicine at Boston University School of Medicine, said: "The vast majority of patients can be appropriately and adequately managed with existing medications. The target for this new approach is clearly not the run-of-the-mill gout patient."

"But for that very small group of patients for whom none of the other options work, or for whom there are intolerances, this is a new way to go," Neogi said.

"And what's worth pointing out," she added, "is that this works by way of a completely different mechanism of action than our existing drugs. Rather than turning off the uric acid faucet or pulling open a drain, this drug goes in there like a bucket and simply removes the stuff. So this is truly unique and exciting."