Allopurinol alone found inadequate for gout control

Allopurinol, considered the standard of care for gout, may be inadequate to lower uric acid levels in patients with gout, according to new safety and efficacy data from a large study presented at the American College of Rheumatology (ACR) 2013 annual meeting recently in San Diego, Calif.

AstraZeneca and Ardea Biosciences presented results from the LASSO (Long-term Allopurinol Safety Study evaluating Outcomes in gout patients) study, a multinational, 6-month, open, prospective study involving 1,735 patients with gout.

Gout has been associated with serious health problems including cardiovascular disease, diabetes, and kidney damage. It is the most common form of inflammatory arthritis with a prevalence of 8 million in the United States.

Adult patients who were enrolled in the study had to meet American Rheumatology Association (ARA) criteria for the classification of acute arthritis of primary gout and had to have experienced at least 2 gout flares in the preceding year. Patients who had received urate-lowering therapy other than allopurinol before the trial underwent a 7-day washout period before initiating or re-initiating allopurinol therapy, which was prescribed according to approved product labels and/or institutional standards of care. The study protocol encouraged upward titration of the allopurinol dose to a medically appropriate dose as determined by the investigator.

There was a high rate of adherence to therapy (97% across doses) and the most commonly used dose was 300 mg. The main efficacy end point was the proportion of patients with a serum uric acid (sUA) level of <6.0 mg/dL at the end of the study.

Results of the LASSO study showed no new safety signals with allopurinol doses of approximately 300 mg/day. Interestingly, however, the study found that among patients on allopurinol, fewer than half (43%) reached the sUA goal of <6mg/dL, the level recommended by the ACR and the European League Against Rheumatism (EULAR). 

“The LASSO findings highlight that allopurinol, the most common way of treating gout, is inadequate to control this chronic disease in many patients. By not getting to the recommended goal, continuously high levels of sUA in these patients can result in the formation of crystals throughout the body. In the near term this can cause acute flares and longer term can lead to serious health issues such as joint damage, tophi, and impaired quality of life,” said James Mackay, chief operating officer of Ardea Biosciences at AstraZeneca.

“This is important for physicians, those who pay for healthcare, and especially patients because not getting to goal leaves these patients at risk for further disease progression and the long-term consequences of gout,” said Mackay who is also the global product vice president of lesinurad, an investigational drug in phase 3 development for the treatment of chronic hyperuricemia in patients with gout.

Lesinurad is an investigational uric acid re-absorption inhibitor (SURI) that AstraZeneca is developing as an oral, once-daily chronic treatment for gout. Lesinurad is being studied in an ongoing phase 3 clinical development program as a combination treatment with allopurinol in patients not reaching target sUA on allopurinol alone (CLEAR1 and CLEAR2 studies), and as a combination treatment with febuxostat in patients with tophaceous gout (CRYSTAL study). Lesinurad is also being studied as a monotherapy for a smaller number of patients who are intolerant to allopurinol or febuxostat (LIGHT).

Allopurinol, the most commonly used treatment to lower blood uric acid levels in gout, is a generic treatment that has been available for more than 50 years. It is a xanthine oxidase inhibitor, a class of drugs intended to reduce the body’s production of uric acid. Allopurinol is recommended at doses between 100 mg and 900 mg per day, depending upon disease severity.

“LASSO shows the inadequacy of the current approach to the treatment of gout,” Mackay said. “Not only did most patients not get to goal, but the study shows that even among a subset of patients titrated to higher final doses-above the most commonly used dose of 300 mg/day-only 54% reached the target sUA level. The results of this study, the largest ever of allopurinol, are consistent with published literature confirming many patients do not reach sUA targets with allopurinol therapy as currently used and continue to carry the long-term burden of gout.”

In a separate presentation at the ACR meeting, rheumatologist Max Hamburger used a different study methodology (patient encounter surveys) to reach a very similar conclusion. He found a high percentage (50%) of gout patients treated by rheumatologists are not at the treatment goal of <6.0 mg/dL, even after 6 months on higher dose urate- lowering therapy.  His study defined higher dose urate-lowering therapy as >300 mg/day of allopurinol or ≥80 mg/day of febuxostat.