“This is a drug that may have dramatic effects on the worst of the patients that rheumatologists treat for gout.”—Herbert S. B. Baraf, M.D.
MSKreport.com sat down with Herbert S.B. Baraf, MD, the medical director of the Center for Rheumatology and Bone Research, and a practicing rheumatologist in Wheaton, Maryland, to discuss these new developments in the treatment of gout. Dr. Baraf is also a clinical professor of medicine at George Washington University Medical Center in Washington, D.C. and a co-author of many of the key pegloticase publications.Impressive efficacy in very difficult cases
Regarding the studies reported at ACR, Dr. Baraf said, “In the two phase III trials of this agent, 40% to 60% of subjects taking pegloticase who had failed available treatment for gout achieved the primary endpoint which was defined as serum uric acid readings <6 mg/dL in at least 80% of measurements at the 3- and 6-month time points. There was also significant improvement in clinical outcomes. Plasma uric acid responders showed significant resolution of tophi as early as 3 months after pegloticase infusions were initiated. As expected, the number of gout flares among participants taking pegloticase increased in the first 3 months relative to placebo. In the last 3 months of these 6-month studies, the flares trended less frequent than did placebo. Measures of physical function and quality of life were significantly improved in pegloticase treated subjects as compared to those patients treated with placebo.”
The two trials were replicate double-blind phase III studies that enrolled 212 patients with treatment-failure gout. Subjects were randomized to intravenous pegloticase or placebo. Eligibility criteria included active gout, defined as ≥3 gout flares in the previous 18 months, had ≥1 joints affected by chronic gouty inflammation, or had existent tophi. The serum urate level had to be greater than 8 mg/dL at screening. Patients were either intolerant of allopurinol or unresponsive to the highest medically appropriate dose. Participants received 8mg of pegloticase every 2 weeks, 8 mg of pegloticase every 4 weeks, or placebo in a 2:2:1 ratio. Dr. Baraf said that study participants tended to have high levels of comorbidites such as hypertension, chronic renal disease, heart disease, and diabetes.
Greatest benefit expected for hard-to-treat patients
Dr. Baraf noted that a biologics license application (BLA) for pegloticase was filed with the FDA on October 31, 2008. If approved, he said, the patients likely to benefit most from pegloticase would be those who have poor responses to existing uric–acid-lowering drugs, or who cannot tolerate those agents.
“A high percentage of these patients have extensive tophaceous disease,” Dr. Baraf said. “These are patients with a lot of gouty attacks per year. They are at the far end of the gout spectrum. The company’s filings with the FDA define treatment-failure gout as an orphan population. If you look at the whole two or three million patients with gout, we are talking about a small percentage.”
Anti-pegloticase antibodies remain a concern
As with many biologicals, the development of antibodies is associated with less efficacy and more adverse events. “More than 89% of patients treated with pegloticase were positive for anti-pegloticase antibodies,” Dr. Baraf said. “The antibody titer was significantly associated with plasma urate non-responder status, and high antibody titers were associated with a higher incidence of infusion reactions. As a simple matter, one need not test for antibody to determine loss of response since the patient’s uric acid level will serve that purpose.”
Patients who lose an initial response tend to do so by the fourth month of treatment. “We can test a patient’s uric acid level in the hours or days after an infusion of pegloticase, and if it is at baseline, they are not responding. If it is significantly less than 6 mg/dL, we know that they are responding well,” Dr. Baraf said.
New drug may have dramatic effect on hardest-to-treat gout
“This is a drug that may have dramatic effects on the worst of the patients that rheumatologists treat for gout. It’s not for mild or moderate gout. For those in whom it is effective, pegloticase can provide life-changing results and a quantum of difference,” Dr. Baraf said.
“I have seen some phenomenal responses,” he added. “For example, an engineer in his mid-40s in an open-label extension trial had oozing tophi on all of his fingers and had not walked in 4 or 5 years. He had been getting around in a motorized scooter. After 3 months of twice weekly treatment, he walked for the first time. After being on open label drug for a year, his tophi had fully resolved. The last time we saw him, he walked into the office from the parking lot and advised us that he had gotten a motorcycle license.”
Dr. Baraf also described a woman with burned-out lupus nephritis who presented with severe tophaceous gout involving her hands that required 15 mg/day of prednisone. “Initially, she had severe flares after treatment, but at 6 months, she was able to play tennis and her tophi had fully resolved. These and other patients in my care have had dramatic responses,” Dr. Baraf said.
Flares, infusion reactions most common adverse events
The most frequent adverse events seen with pegloticase were gout flares and infusion reactions. Eleven percent of patients discontinued treatment because of infusion reactions, and there was a 5% incidence of anaphylaxis, similar to the rate seen with other infused biologic agents.
“Predictably, there is also a risk of flaring during urate-lowering therapy,” Dr. Baraf said. “Whenever you raise or lower uric acid, you increase the risk of an attack. There was a heightened risk of attacks among patients taking pegloticase in the first few months relative to placebo. Rheumatologists know that colchine or nonsteroidal anti-inflammatory drugs should always be started prior to initiating uric acid lowering treatment.”
Some cardiovascular (CV) events were seen in patients taking pegloticase, but these are difficult to interpret due to the 4:1 randomization of treatment versus placebo and the high level of comorbidities in the trial participants. Investigators continued pegloticase in five of the eight patients with CV events, and there was no clear association with treatment. “The numbers are so small that we can't draw a conclusion that there is a definitive cardiovascular risk with the drug,” Dr. Baraf said.
References
1. Sundy JS, Baraf HS, Becker MA, et al. Efficacy and safety of intravenous (IV) pegloticase (PGL) in subjects with treatment failure gout (TFG): Phase 3 results from GOUT1 and GOUT2. Presented at: American College of Rheumatology 2008 Annual Scientific Meeting; October 24-29, 2008; San Francisco, Calif. Presentation 635.
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