Washington Editor

ROCKVILLE, Md. - Members of an FDA arthritis panel generally agreed that the reduction or elimination of acute attacks would be an appropriate primary endpoint for clinical trials measuring the efficacy of drug candidates for gout.

As part of a two-day discussion on trial design and endpoints for drug candidates for chronic and acute gout, the FDA's Arthritis Advisory Committee asked Cardiome Pharma Corp. to present trial data from its pending new drug application for Oxyprim for chronic gout. The panel was not asked to vote on the NDA, which has been granted priority review and orphan drug status.

At issue here is the fact that Cardiome, of Vancouver, British Columbia, in December filed its Oxyprim NDA under Subpart H, meaning approval is based on a surrogate endpoint. And in that case, the surrogate endpoint (in the pivotal study) is reduction in serum uric acid (SUA).

John Cush, panel member and chief of rheumatology and clinical immunology at Presbyterian Hospital in Dallas, said it might be a leap to say that decreased SUA represents an improved quality of life for gout patients. While he is not opposed to using SUA as a surrogate, Cush said a more adequate measure would be the reduced number of gout attacks.

However, James Williams, another panel member and professor of medicine in the division of rheumatology at the University of Utah in Salt Lake City, argued that gout attacks are episodic events, so measuring a reduction would take a long time.

Indeed, Cush recommended a two-year duration for trials, while Wendy McBriar, a panel member and director of the Southern New Jersey Regional Arthritis Center in Voorhees, N.J., suggested that a year might provide companies with adequate data.

Gout is a metabolic disorder due to hyperuricemia (high SUA levels) and results in the deposition of monosodium urate crystals in the tissues of the body, particularly in the joints and kidney. It is the most common cause of inflammatory arthritis in men older than 40, Cardiome said.

Cardiome is requesting approval of Oxyprim (oxypurinol) to treat hyperuricemia in patients with symptomatic gout who are intolerant to allopurinol and have failed either re-challenge or desensitization with allopurinol.

Oxypurinol is the active metabolite of allopurinol, and like allopurinol, is a xanthine oxidase inhibitor. Oxypurinol has been used to treat allopurinol-intolerant patients since 1966 on a compassionate-need basis. Data on 533 patients in the compassionate-use trial as well as the 79-patient pivotal trial, which showed reductions in SUA, made up Cardiome's NDA.

The FDA is bound by federal law under the Prescription Drug User Fee Act (PDUFA) to take action on the Oxyprim application by June 23.

A briefing document provided by the FDA said Cardiome's pivotal study, referred to as OXPL213, demonstrated a highly statistically significant reduction in SUA (p<0.0001). However, it failed to achieve the primary endpoint of an average SUA decrease of 2 mg/dL between baseline and week 14 (the pre-specified statistical endpoint). Overall, the mean decrease found was 1.90 mg/dL, according to FDA notes, which referred to the mean decrease as "clearly indicative of significant activity of oxypurinol."

Cardiome gained rights to Oxyprim from ILEX Oncology Inc., of San Antonio, in 2002 after acquiring Paralex Inc. for $20 million in 2001. (See BioWorld Today, Dec. 24, 2001.)

Indeed, ILEX and the FDA set the design for the pivotal study.

Cardiome is pushing forward with a 240-patient Phase IV study expected to take about two years. The primary efficacy analysis would consist of a comparison of the mean number of acute gout attacks vs. the oxypurinol and placebo groups.

In order to participate in the study, said Alan Moore, Cardiome's executive vice president, clinical development and regulatory affairs, patients must have experienced six gout attacks. The firm expects to use 100 sites for the study and said it will enroll an average of two patients per site.

Moore said the Phase IV is a condition of Oxyprim's approval.

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