MAUI, HAWAII – The recently approved uric acid–lowering drug lesinurad received a lukewarm reception at best when introduced during a ‘highlights of the year in gout’ session presented at the 2016 Rheumatology Winter Clinical Symposium.
Panelist Martin J. Bergman presented a dispassionate overview of the data from four pivotal randomized trials which in late December 2015 resulted in Food and Drug Administration approval of lesinurad (Zurampic) at 200 mg/day in combination with a xanthine oxidase inhibitor, but not as monotherapy at 400 mg/day.
Bruce Jancin/Frontline Medical News
Dr. Martin J. Bergman
After highlighting the drug’s safety concerns, including the black box warning about lesinurad’s risk of acute renal failure and its numerous potential drug interactions, Dr. Bergman opened the floor to discussion. An audience member immediately shot up his hand and asked, “Isn’t this drug a crappy drug?”
Dr. Bergman, chief of rheumatology at Taylor Hospital in Ridley Park, Pa., answered diplomatically: “It’s not the strongest drug, it’s not the best. Is this going to be something which revolutionizes the care of gout? I don’t think so. But it does give us a way to get to the treatment goal of a serum uric acid below 6.0 mg/dL in gout patients unable to get there on allopurinol or febuxostat [Uloric] alone. “
Faculty member Dr. Eric M. Ruderman was blunt in his appraisal of lesinurad: “I really don’t understand the place for this drug.”
“In the trial of combination therapy with febuxostat [the 324-patient CRYSTAL study] it didn’t meet the primary endpoint at the 200 mg/day dose. It’s amazing to me that the FDA will approve a drug when one of the pivotal trials didn’t meet the primary endpoint at the dose they approved. That’s bizarre. And in the trials with allopurinol [CLEAR 1 and 2, with a total of 1,213 patients] they didn’t use maximum-dose allopurinol. So I don’t see where this drug adds anything to our treatment paradigm,” said Dr. Ruderman, professor of medicine at Northwestern University in Chicago.
In the pivotal clinical trials, the 400 mg/day dose was more effective than 200 mg/day, but it was also associated with a doubling of serum creatinine in 1 in every 12 treated patients, as compared with a 1%-2% incidence at 200 mg. That’s why the FDA didn’t approve the higher dose.
Dr. Eric M. Ruderman
Lesinurad is a selective inhibitor of uric acid resorption which acts in the proximal tubule on URAT1, an inhibitor of uric acid transport.
Arhalofenate, a promising investigational gout drug, shares the same mechanism of action, but in addition it blocks release of interleukin-1beta. In a 239-patient, phase IIb trial presented at the 2015 annual meeting of the American College of Rheumatology, arhalofenate effectively reduced the rate of gout flares while lowering serum uric acid levels, and most notably it did so with no treatment-related serious adverse events and no cases of elevated serum creatinine. This is a drug to keep an eye on, according to Dr. Bergman.
Copanelist Dr. Orrin M. Troum of the University of Southern California, Los Angeles, presented highlights of other significant recent studies in the field of gout, some of them quite surprising:
• Colchicine reduces cardiovascular events in gout patients. A comparison between 501 Medicare gout patients on colchicine and an equal number of matched gout patients not on colchicine showed that during a median 16.5 months of follow-up, the colchicine users had an adjusted 49% reduction in the composite endpoint of acute MI, stroke, or TIA. They also had a 73% reduction in all-cause mortality, according to Dr. Daniel H. Solomon, professor of medicine at Harvard Medical School, Boston, and coinvestigators (Ann Rheum Dis. 2015 Nov 18. doi: 10.1136/annrheumdis-2015-207984).
“Once my gout patients stop clutching their chest when they see the price of colchicine, which actually increases their cardiovascular risk, they are very excited when I tell them about this study,” Dr. Bergman quipped. “This study controlled for other comorbidities and for serum uric acid levels. Those relative risk reductions are not to be sneezed at.”
• Treating gout improves survival. In a prospective case-matched cohort study, Taiwanese investigators compared 764 gout patients on urate-lowering therapy with an equal number of matched gout patients who did not take a urate-lowering drug. During 6.5 years of follow-up, the group on urate-lowering medication had a 71% lower risk of cardiovascular mortality and a 53% reduction in all-cause mortality, compared with gout patients not on urate-lowering therapy. Moreover, in a separate analysis comparing 1,189 gout patients not taking urate-lowering therapy and three times as many matched controls without gout, the gout patients had a 2.43-fold greater rate of cardiovascular mortality and a 1.45-fold increased risk of all-cause mortality (J Rheumatol. 2015 Sep;42[9]:1694-701).