Introduction

Amid the furor over the cardiovascular (CV) risk associated with cyclooxygenase-2 (COX-2) inhibitors, it is easy to forget that 3 agents in this class are in late-stage development in the US. These are etoricoxib (Arcoxia?), lumiracoxib (Prexige^?), and parecoxib (Dynastat^?), an intravenous prodrug of valdecoxib (Bextra^?).

The revelations regarding the withdrawal of rofecoxib (Vioxx^?) from the market due to increased risk of CV events and ongoing concerns about the CV risk associated with valdecoxib and celecoxib (Celebrex^?) have clearly had an impact. CIAOMed spoke recently with some key clinicians who indicated that they would approach with caution any new COX-2s entering the marketplace and would not use new COX-2s as first-line therapy if those agents became available to them.

The physicians who were interviewed also stressed the need for long-term data documenting CV safety of newer coxibs, noting that rofecoxib's CV risk in the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial became apparent at 18 months.

"Their place will be for people who don't need aspirin, have GI [gastrointestinal] risk, and?can't take traditional NSAIDs [nonsteroidal anti-inflammatory drugs]," said Leslie Crofford, MD, professor of internal medicine and chief of rheumatology at the University of Kentucky College of Medicine, Lexington. She predicted that the US Food and Drug Administration (FDA) will require next-generation COX-2 inhibitors to carry warnings about CV risk.

These views were echoed by Claire Bombardier, MD, professor of medicine at the University of Toronto, who said that she would be "much more cautious about monitoring blood pressure, edema, and CV risk profile" when using a next-generation COX-2, even if the agent had no CV signal.

The Next COX-2 Generation

Etoricoxib

Merck's successor to rofecoxib is available in 48 nations; however, the labeling, in many cases, outlines clearly that etoricoxib may be associated with CV or thromboembolic events. Given the potential for CV adverse reactions and a regulatory environment in the US that is looking very closely at all agents in the COX-2 class, what are the prospects for etoricoxib? "I'm not sure it will make it to the US market," Lee S. Simon, MD, a rheumatologist and associate clinical professor of medicine at Harvard Medical School in Boston, Massachusetts, told CIAOMed.

According to Steven B. Abramson, MD, professor in New York University School of Medicine's department of rheumatology/medicine, New York, "there is not enough data in the public domain on etoricoxib to be sure about the safety of etoricoxib's CV risk profile." The FDA indicated in October that the agency would require further safety and efficacy data about etoricoxib before considering approval.¹

With that in mind, Merck has said that a roughly 23,500-patient trial designed to study the CV safety of etoricoxib is expected to end in early 2006.² When those data are presented to the FDA, some patients will have taken the drug for up to 3 years. ² The company has released data demonstrating no statistical difference in serious adverse CV events between etoricoxib and diclofenac (Voltaren^?), but the average follow-up time was 9 months.³

Dr. Crofford said that physicians can probably manage any CV risk associated with etoricoxib if they are aware of it. Unlike rofecoxib, etoricoxib would likely start out with known CV risks that physicians and patients could consider. "All drugs have risks," she pointed out. Noting that rofecoxib was an excellent analgesic and provided "good, really good" GI protection, she said, "I'm surprised they pulled Vioxx even after the APPROVe study, as some patients likely would have continued to benefit from its use."

Lumiracoxib

Unlike the other next-generation COX-2s, the CV safety of lumiracoxib has been compared with that of traditional NSAIDS (ie, naproxen and ibuprofen) in a large (N = 18,325), 1-year study, the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET).⁴ Rates of myocardial infarction (MI) and of a combined CV endpoint (confirmed silent MI, confirmed or probable clinical MI, stroke, and CV death) did not differ significantly between lumiracoxib and either nonselective NSAID, regardless of aspirin use. In fact, none of the comparisons of CV risk made in the study were statistically significant.

Lead author of the study Michael E. Farkouh, MD, cardiologist and associate professor of medicine at New York University School of Medicine, told CIAOMed, "I cannot rule out a small [CV] signal there [with lumeracoxib]." The raw number of CV events was higher in the lumiracoxib group than among patients taking a traditional NSAID (59 [.86 per 100 patient-years] vs 50 [.75 per 100 patient-years]; hazard ratio, 1.14 [95% confidence interval {CI} .78 to 1.66]; P = .50%).⁴

CIAOMed interviewed rheumatologists who expressed caution about the use of lumiracoxib, and disagreed with some of the interpretations of TARGET findings. (See related story, "Interpreting TARGET: Who Faces CV Risk?")

Lumiracoxib differs from other coxibs in ways that may or may not affect CV risk. As a phenylacetic acid derivative, it is the only acidic coxib.⁵ It also has no sulfa group, Dr. Farkouh noted. However, it is unclear whether that distinction accounts for the CV findings in TARGET. Lumiracoxib is more selective for COX-2 than other coxibs on the world market. "I don't think we've figured out what caused the increase" in CV risk with rofecoxib, Dr. Farkouh said.

Dr. Abramson pointed out that lumiracoxib has a short plasma half life (3 to 6 hours), ⁴ which could be an advantage in that it may reduce systemic drug exposure. Another possible correlate to the potential CV?risk-associated COX-2s is a rise in blood pressure. In TARGET, changes in systolic and diastolic blood pressure were significantly smaller with lumiracoxib than with traditional NSAIDs (P = .0001). Still, Dr. Abramson noted, "None of these screens is predictive" of CV risk.

Novartis, the manufacturer of lumiracoxib, reportedly has postponed seeking FDA approval until 2007.⁶ The company has been granted approval to market lumiracoxib in the United Kingdom but has indicated that it will not sell the drug there until it receives approval throughout the European Union. It has temporarily withdrawn its application for European Union approval, pending review of COX-2 inhibitors by the European Medicines Agency Committee on Medicinal Products for Human Use, scheduled for January 17-20.⁶

Parecoxib

Pfizer said it expected to file for FDA approval of parecoxib in December 2004.⁷ As an IV formulation, parecoxib has been tested in postsurgical pain. In postcoronary artery bypass graft (CABG) patients, parecoxib alone or combined with valdecoxib was associated with an increased risk of CV events.⁸

Avoiding Another Vioxx

To prevent another Vioxx-like situation with newer COX-2s, Dr. Abramson has recommended the creation of a COX-2 Initiative, modeled after the Osteoarthritis Initiative. "The National Institutes of Health, FDA, and pharmaceutical manufacturers would come together with money and expertise, and look at large numbers of patients and multiple sites?to address questions that individual institutions can't answer," he said. The result, Dr. Abramson suggested, might be a blue-ribbon panel that would issue a consensus on surrogate markers of CV risk, such as COX imbalance, endothelial dysfunction, blood pressure changes, and impact on C-reactive protein. By doing so, pharmaceutical firms could study these parameters in early development of coxibs. The initiative also could generate markers that help predict which patients are most likely to experience an MI or other CV event while taking a coxib, he said.

A COX-2 Initiative also could define criteria for determining the contribution of large population databases to a body of evidence. "What emerged with Vioxx was a combination of large, randomized trials (eg, VIGOR, APPROVe) supported by 3 or 4 population databases" to produce evidence for a CV signal, Dr. Abramson said. "However, population databases may give the wrong answer, perhaps due to channeling bias or other unknown factors," as in the case of estrogen replacement therapy preventing heart disease, he said. "We need a set of standards to validate the clinical information within specific databases" to evaluate findings such as how much the database captured, whether it considered over-the-counter NSAID use, and whether it contains both office-based and hospital data, Dr. Abramson explained.

Dr. Crofford said that clear answers require resources and time. "Cardiologists have had the resources to perform multicenter studies with 40,000 to 50,000 patients," she said. "That's what we need to do in order to study the cardiovascular risks of COX-2 inhibitors."

References

1. Research and Development News: Arcoxia^TM Significantly Reduced the Risk of Upper Gastrointestinal Side Effects Compared to Three Other NSAIDs, Data Presented at EULAR Congress Show. Merck Web Site. October 29, 2004. Available at: Merck.com Accessed October 30, 2004.

2. Hovey HH. Merck Doctor: Naproxen appears to help heart like aspirin. Dow Jones Newswires. October 19, 2004. Available at: http://online.wsj.com/article/0,,BT_CO_20041019_006309,00.html . Accessed October 20, 2004.

3. Wall Street Journal online news roundup. Merck finds Vioxx successor Arcoxia easy on stomach. Available at: http://online.wsj.com/article/0,,SB109819783426449334,00.html . Accessed October 20, 2004.

4. Farkouh ME, Kirshner H, Harrington RA, et al, for the TARGET study group. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet. 2004;364:675-684.

5. Brune K, Hinz B. Selective cyclooxygenase-2 inhibitors: similarities and differences. Scand J Rheumatol. 2004;33:1-6.

6. Greil A. Novartis Delays Prexige Filing, Awaiting EU Safety Review. Dow Jones Newswires. November 30, 2004. Available at: http://online.wsj.com/article/0,,SB110181172989086627,00.html . Accessed December 1, 2004.

7. Hovey HH. Pfizer exec: in productive dialogue with FDA about Lyrica. Dow Jones Newswires. November 30, 2004. Available at: http://online.wsj.com/article/0,,BT_CO_20041130_006309,00.html . Accessed December 1, 2004.

8. Pfizer provides information to healthcare professionals about its Cox-2 medicine Bextra ? (Valdecoxib) [press release]. New York, NY: Pfizer Inc; October 15, 2004. Available at: http://www.pfizer.com/are/news_releases/2004pr/mn_2004_1015.html. Accessed October 17 , 2004.