Nov. 24, 2008 — Uloric should be the first new gout drug to be approved inover 40 years, an FDA expert panel recommends.
Currently, allopurinol (trade name, Zyloprim) is the only FDA-approved drugthat prevents formation of the uric acid crystals that cause gout. However,side effects — including potentially fatal reactions — limit the amount ofallopurinol that can be tolerated. Most gout patients do not receive fullyeffective doses of allopurinol.
In clinical trials sponsored by Takeda, Uloric’s manufacturer, an80-milligram dose of Uloric worked better than allopurinol; a 40-milligram doseworked at least as well as allopurinol.
Unlike allopurinol, very little Uloric is excreted through the urine, makingUloric safe for patients with kidney problems. Gout patients with impairedkidney function have to take very low doses of allopurinol, making the drugeven less effective for these patients.
In 2005, the FDA refused to approve Uloric because there were slightly moredeaths and heart problems in patients taking the drug than in patients takingallopurinol. As people with gout problems already are at higher risk of heart disease, the FDA issued an”approvable” letter, noting that Uloric could be approved if thissafety question were addressed.
Takeda then performed a large new phase 3 clinical trial that enrolled moregout patients than the two previous phase 3 trials combined. The new studyfound no more deaths and no more heart problems in patients taking Uloric thanin patients taking allopurinol.
Based on the safety and efficacy data, the FDA panel recommended by a 12-0vote that the FDA approve Uloric at both the 40-milligram and 80-milligramdoses. Takeda suggests the higher dose is more effective in subjects with moresevere gout.
Takeda has offered to continue studying Uloric after FDA approval. A phase 4clinical trial would compare Uloric to allopurinol for the reduction of goutflare-ups.
And because drugs with the same mechanismof action as Uloric and allopurinol may affect theophylline bronchodilators, Takeda hasagreed to conduct a postmarketing phase 1 study of Uloric’s interactions withtheophylline.
Gout occurs when blood levels of uric acid rise. At blood levels above 7mg/dL — and above 6 mg/dL in the extremities — crystals can form that lodgein the joints and other body tissues. These crystal deposits provoke an immuneresponse that results in extremely painful swelling and in inflammatory arthritis that can permanentlydestroy the joints.
(For more on the causes, symptoms, and treatment of gout, see WebMD’s Gout PicturesSlideshow.)
About 1.4% of men and 0.6% of women have gout. But prevalence rises withage. After age 80, about 9% of men and 6% of women develop gout.
The body converts a chemical called xanthine into uric acid via an enzymecalled xanthine oxidase or XO. Allopurinol and Uloric each inhibit XO andprevent the formation of uric acid.
Allopurinol is approved in doses up to 800 milligrams. However, it’s rarelydosed above 300 milligrams per day and is often ineffective. Allopurinol sideeffects include upset stomach, headache, diarrhea, and rash. Although rare,allopurinol hypersensitivity syndrome can develop. It’s fatal 20% to 30% of thetime.
The most common side effects seen in patients taking Uloric during clinicaltrials were upper respiratory tract infections, muscle and connective-tissuesymptoms, and diarrhea. The drug was well tolerated, and these side effects didnot increase over long-term use.