GAITHERSBURG, Md. (February 18) ― The prospects for eventual approval of two new cyclooxygenase-2 (COX2) inhibitors, etoricoxib (ArcoxiaR) and lumiracoxib (PrexigeR), appear to be in doubt in light of research presented to a US Food and Drug Administration (FDA) advisory panel during a 3-day meeting here.

Data presented by a Merck researcher indicated that there were no clearly discernable differences in thrombotic event rates between etoricoxib and non-naproxen nonsteroidal anti-inflammatory drugs (NSAIDs) through 1 year, although there was a lower rate of cardiovascular (CV) events among naproxen users when compared to etoricoxib users. Notably, the data showed no difference between placebo and etoricoxib with respect to CV risk, although this conclusion was based on limited, short-term data.

The results stem from a pooled analysis of 12 studies of 6700 patients taking etoricoxib versus placebo, etoricoxib versus non-naproxen NSAIDs, or etoricoxib versus naproxen. The gastrointestinal (GI) safety of this drug has previously been demonstrated by the Etoricoxib vs Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) trial.

Two ongoing studies, the Multinational Etoricoxib Diclofenac Arthritis Long-term (MEDAL) trial and EDGE II, are expected to yield long-term CV safety information. Preliminary data from these trials was reviewed in November 2004, and a decision was made to allow them to continue, according to Sean P. Curtis, MD, senior director of clinical research at Merck Research Laboratories in Whitehouse Station, New Jersey. MEDAL will compare the CV safety of etoricoxib to diclofenac in 23,000 patients, and data should be available in 2006. EDGE II includes 4090 rheumatoid arthritis patients who will be followed for about 19 months.

Joel Schiffenbauer, MD, a medical officer at the FDA's Center for Drug Evaluation and Research in Rockville, Maryland, voiced concern about the design of EDGE as well as the two ongoing studies. He pointed out that diclofenac was the only active comparator used in EDGE, previous COX-2 use was allowed, and about 2600 patients had more than two CV risk factors. In his own review of data on etoricoxib, he noted that there appears to be an excess of CV-related deaths compared to placebo.

No definite answers yet on lumiracoxib

Data from the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) showed a GI advantage for lumiracoxib over NSAIDs that was reduced in patients also using aspirin. Additionally, this study found that, while a similar rate of CV events was observed in users of ibuprofen and lumiracoxib, the coxib was associated with a higher CV risk than naproxen.

"The sponsors of etoricoxib and lumiracoxib demonstrated very impressive gastrointestinal safety differences compared to [nonselective] NSAIDs," William White, MD, professor of medicine at the University of Connecticut Health Center, Farmington, Connecticut, tells CIAOMed. "I also feel, at least with etoricoxib, there was clearly a small CV signal compared with naproxen that looked like Vioxx at lower doses." This sort of comparison prompted some participants at the FDA hearing to refer to etoricoxib as "Vioxx-lite." Both drugs will have to overcome "big hurdles," Dr. White predicted. "The only way etoricoxib has a chance is if something comes up differently with the MEDAL study."

Garret A. Fitzgerald, MD, professor of medicine and pharmacology and chair of the department of pharmacology at the University of Pennsylvania School of Medicine in Philadelphia, called MEDAL "a useful trial," but cited different reasons than other researchers. "Diclofenac resembles Celebrex with respect to selectivity," he noted, adding that he thought of MEDAL as a trial comparing COX-2 selective drugs. The results will tell us, Dr. Fitzgerald continued, "whether a commonly used, relatively selective drug stacks up in a way that separates it from a longer-life, much more selective drug, etoricoxib."

Reference:
US Food and Drug Administration. Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee; February 16–18, 2005; Gaithersburg, Md.