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The intravenous enzyme pegloticase (Krystexxa) is an effective therapy for many people whose gout doesn't respond to conventional treatment, researchers reported.

In two industry-sponsored clinical trials, significantly more patients taking the substance saw their plasma uric acid reach normal levels than did those on placebo, according to Michael Becker, MD, of the University of Chicago, and colleagues.

Adverse events included gout flares and infusion reactions that, in some cases, met the criteria for anaphylaxis, Becker and colleagues reported in the Aug. 17 issue of the Journal of the American Medical Association.

Pegloticase won FDA approval late last year, largely based on data from the two trials. Because of the adverse event profile, the agency urged physicians to give a corticosteroid and an antihistamine before treatment to minimize the risk.

In humans, uric acid is created when the body breaks down purine nucleotides. The substance is excreted in the urine, and high plasma levels can lead to gout.

In many other mammals, however, there is an extra step in purine metabolism – the enzyme urate oxidase (or uricase) breaks down the uric acid into a soluble substance, allantoin.

Giving pegloticase, a recombinant mammalian uricase, is an attempt to mimic that process for people with chronic gout who do not respond to oral urate-lowering therapy with allopurinol (Zyloprim), the researchers noted.

To test the enzyme, the researchers randomly assigned refractory gout patients to an 8 mg infusion of pegloticase twice a month for six months, to a similar dose once a month alternated with placebo to maintain blinding, or to placebo.

Analysis of the two trials, identical in design, included a total of 212 patients who had at least one infusion of the drug. The primary endpoint of both studies was a uric acid level of less than 6 mg per deciliter of plasma in months three and six of the six-month treatment period.

Pooled results showed:

• No placebo patients reached the end point.
• Among the 85 patients in the biweekly treatment group, 36 (42%) reached the primary endpoint; the difference from placebo was significant at P<0.001.
• Among the 84 patients who got the drug once a month, 29 (35%) reached the end point, and again the difference from placebo was significant at P<0.001.

More than 90% of patients in each arm of the studies reported at least one adverse event, but serious events occurred more frequently in pegloticase patients -- 24% of the biweekly group and 23% of the monthly group, compared with 12% of those getting placebo.

Gout flare was the most common event and was reported at roughly similar rates across the study arms, Becker and colleagues reported.

On the other hand, infusion-related reactions were the second most common, occurring in 26% of the biweekly group, 42% of the monthly group, and 5% of the placebo group. They were also the most common reason for stopping treatment, the researchers reported.

All told, there were seven deaths -- a patient randomized to placebo who died before the first infusion, three patients assigned to pegloticase who died during the treatment period, and three patients (one taking pegloticase and two on placebo) who died after the treatment period.

Becker and colleagues reported that the three deaths during the treatment period included two involving cardiac adverse events (a cardiac arrest and an arrhythmia) and one renal failure.

There was also a nonfatal MI, also in a pegloticase patient. No cardiovascular events were seen among placebo patients.

The "observed numerical imbalance" suggests that care should be taken in selecting patients for pegloticase treatment, the researchers cautioned, and those with cardiovascular comorbidities should be stabilized before the start of therapy.

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