Two-Drug Combo Wins for Refractory Gout

MILAN -- About half of patients receiving infusions of a novel uricase analog, along with a proprietary rapamycin formulation, in two similarly designed phase III studies got their serum urate under control, after multiple other medications had failed to do so, a researcher said here.

Dubbed SEL-212, the treatment combines a pegylated form of uricase called pegadricase with "an immune-tolerizing nanoencapsulated rapamycin," explained Herbert Baraf, MD, of the Center for Rheumatology and Bone Research in Wheaton, Maryland, who presented the results at the European Alliance of Associations for Rheumatology (EULAR) annual meeting.

The rationale, he said, was that all uricase products seem to be inherently vulnerable to anti-drug antibodies that diminish their effectiveness. This has certainly been the case with the sole FDA-approved product, pegloticase (Krystexxa). That is where the immunosuppressant rapamycin comes in. Given 30 minutes prior to the pegadricase infusion, it's intended to forestall immune reaction to the enzyme protein. (Indeed, pegloticase's manufacturer last year won FDA approval to combine its product with methotrexate with the same goal.)

Each of the two trials -- one conducted exclusively in the U.S. and one in the U.S and several eastern European countries -- tested two doses of pegadricase (0.15 or 0.10 mg/kg) while the rapamycin dose was kept constant at 0.2 mg/kg. Infusions were given every 4 weeks. Serum urate level was the primary efficacy outcome: specifically, response was defined as serum urate below 6 mg/dL at least 80% of the time in multiple measurements taken during the final month of a 6-month treatment period.

To be eligible, patients needed to have had at least three gout flares in the previous 18 months or at least one tophus or a current diagnosis of gouty arthritis, plus serum urate of at least 7 mg/dL. Baraf said. They also must have failed to achieve serum urate control with at least one xanthine oxidase inhibitor. Patients received steroids, antihistamines, and other agents around the infusions to suppress short-term reactions, and prophylaxis against gout flares was also provided.

The U.S. trial had 112 patients and the multinational version enrolled 153. Both randomized patients 1:1:1 among the two active drug doses and placebo. Participants' baseline characteristics were similar in the two studies with one exception. Mean age was about 55, most patients were obese, and nearly all were men. Gout had been present for a mean of about 12 years and serum urate averaged about 8.5 mg/dL at enrollment. The major difference between the two samples was that patients in the multinational trial had much higher mean counts of tender joints (11 vs 3) as well as swollen joints (5 vs 2), although these varied widely between patients in all study arms.

With the higher dose, the primary endpoint was achieved by 56% of patients in the U.S. trial and 46% in the multinational study. The lower dose was somewhat less effective with response rates of 48% and 40%, respectively. In both cases, however, these outcomes were massively better than with placebo, which yielded responses in just 4% and 11% of patients, respectively.

Results were similar when restricted to the subgroup of patients ages 50 and older (about two-thirds of all participants), although in the U.S. trial, there was a larger gap between the dosages (response rate 65% for the high dose and 47% with the lower dose), whereas rates were nearly equal at 47%/44% in the multinational study.

Safety data were pooled from the two trials. About 45% of patients irrespective of assignment had gout flares. Infections were seen in 23%, 18%, and 17% of the high-dose, low-dose, and placebo groups, respectively. Infusion reactions were infrequent at about 7% of both active-treatment groups, while these occurred in 2% of placebo patients.

Serious adverse events were more common with SEL-212, although they were most frequent (15%) in the low-dose group, versus 7% with the high dose and 2% with placebo. Four of the events with active treatment were anaphylaxis episodes. Most of the others were classified as not treatment-related.

In light of these findings, co-developer Selecta Biosciences, based in Massachusetts, said the company will work with its Swedish partner, Swedish Orphan Biovitrum, to seek U.S. licensing early next year.

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