Multiple doses of PEG-uricase, a novel polyethylene glycol conjugate of porcine uricase (urate oxidase), have shown substantial and sustained reductions in plasma urate levels in patients with severe, refractory gout, according to phase II data¹ presented at the 69th Annual Meeting of the American College of Rheumatology in San Diego, California. Savient Pharmaceuticals, Inc, the manufacturer of the drug, has reported that it will begin phase III testing in early 2006.

In the phase II, randomized, open-label, multicenter, parallel study, 41 patients (mean age 58.1 years; mean disease duration 14 years) were randomly assigned to receive 12 weeks of treatment with intravenous PEG-uricase (Puricase) at one of four dose regimens: 4 mg every 2 weeks (n = 7); 8 mg every 2 weeks (n = 8); 8 mg every 4 weeks (n = 13); or 12 mg every 4 weeks (n = 13). 

Patients who received 8 mg of PEG-uricase every 2 weeks had the greatest reduction in plasma urate, with levels <6 mg/dL, the study showed. Substantial and sustained lower plasma urate levels were observed in the other PEG-uricase treatment dosing groups.

"One of the things that all rheumatologists see is a handful of gout patients with severe devastating disease that is painful and debilitating and ruins quality of life, and we are helpless in the absence of a therapy that can clean out these uric-acid pools," says lead researcher John S. Sundy, MD, PhD, assistant professor of rheumatological medicine at Duke University Medical Center in Durham, North Carolina. "What we have seen so far with PEG-uricase in terms of its effects and safety is very encouraging."

Different mechanism of action

PEG-uricase works differently than the gold standard, allopurinol and febuxostat (which is nearing approval by the US Food and Drug Administration). "Allopurinol and febuxostat inhibit the enzyme xanthine oxidase and prevent the formation of new uric acid in the body, but PEG-uricase degrades uric-acid stores," Dr. Sundy explains.

Niche seen in treatment-resistant gout patients

"Puricase is really focused on degrading existing stores of uric acid in those with treatment-failure gout," he says. "In patients with a new diagnosis of gout and a couple of flares, PEG-uricase wouldn't be the first choice; I would try allopurinol or potentially febuxostat (pending its approval)." In contrast, Dr. Sundy says, "the target population for PEG-uricase would be those patients in whom you are not able to achieve therapeutic success."

Tophi reduction seen in two patients

In two case studies, there was anecdotal radiographic evidence that treatment with PEG-uricase unexpectedly resolved tophi. "This is a nonintended outcome, but it is a very encouraging observation," Dr. Sundy asserts. It is unknown whether tophi were resolved in patients at other investigational sites, as clinical outcome measures were not part of the protocol design. In the current phase II trial, 70% of patients presented with tophaceous gout.

Thirty-eight patients experienced an adverse event that was possibly treatment-related, most commonly gout flare. As expected with biological administration, there was a high rate of infusion reaction, the study found.

There were no anaphylactic reactions. Of the nine serious adverse events reported, five were described as possibly treatment-related: gout flare (3), hypersensitivity reaction (1), and anemia (1).
 
Reference

1. Sundy JS, Becker MA, Baraf  HSG, et al. A phase 2 study of multiple doses of intravenous polyethylene glycol (PEG)-uricase in patients with hyperuricemia and refractory gout. Presented at: 69th Annual Meeting of the American College of Rheumatology; November 12–17, 2005; San Diego, Calif. Abstract 1836.