Vioxx Cardiovascular Risk Is Unique To Molecule, Pfizer And Novartis Tell FDA

The cardiovascular safety signal observed in Merck's Vioxx may be caused by the formation of potentially toxic rofecoxib metabolites, Pfizer states in its briefing documents for FDA's upcoming review of COX-2 inhibitors.

"In contrast to celecoxib and valdecoxib [Pfizer's Celebrex and Bextra ], rofecoxib promotes oxidative damage to low density lipoprotein (LDL) and phospholipids," Pfizer states in ¹ briefing materials submitted for the upcoming FDA advisory committee meeting.

"This may occur either via a unique action between rofecoxib and membrane phospholipids or via the formation of potentially toxic rofecoxib metabolites."

"These processes may increase cardiovascular risk via damage to endothelial cells and effects on blood pressure, and clinical studies show that treatment with celecoxib can have beneficial effects on endothelial function that are not observed with rofecoxib."

The documents were released ahead of the Feb. 16-18 Arthritis Drugs/Drug Safety & Risk Management Advisory Committee review of COX-2 inhibitor safety (² , p. 6). [Editor's Note: To ³ watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.]

Possible mechanisms of cardiovascular risk - and whether the safety concerns appear to be a class issue or are limited to Vioxx - will be one of the major topics the committee will discuss.

"Hypotheses under consideration include a direct effect of loss of the influence of COX-2 on the endothelium, and an effect based on relatively small but sustained increases in blood pressure," FDA says in briefing materials to the committee.

The meeting was initially intended to be a post mortem on the Vioxx withdrawal, but was later expanded after Celebrex similarly showed a signal in a long-term trial (⁴ (Also see "Merck After Vioxx: No Merger, But No Big Near-Term Launches" - Pink Sheet, 4 Oct, 2004.), p. 3). The committee will also discuss three products in development (see ⁵ (Also see "FDA Discloses Safety Reviews Of COX-2s Arcoxia, Prexige and Parecoxib" - Pink Sheet, 14 Feb, 2005.)).

[Editor's note: FDA Drug Safety Advisory Committee member Curt Furberg, MD/PhD, and panel Chairman Peter Gross, MD, will discuss the outcome of the COX-2 advisory committee meeting at a Feb. 23 Drug & Device Dialogue audio conference. To register, visit ⁶ www.drugdevicedialogue.com or call 800-332-2181. ]

The safety of Celebrex was called into question after celecoxib demonstrated an increased cardiovascular risk compared to placebo in a polyp trial sponsored by the National Cancer Institute (⁷ (Also see "FDA Issues Caution On COX-2s, But Leaves Open Possibility For First-Line Use" - Pink Sheet, 3 Jan, 2005.), p. 17).

A cardiovascular safety signal was also found in a 1999 Celebrex study in Alzheimer's disease patients (⁸ (Also see "Bextra Use Suspended By Kaiser; Celebrex Alzheimer’s Data Under Scrutiny" - Pink Sheet, 7 Feb, 2005.), p. 3).

Following the Vioxx withdrawal, Pfizer told investors that Celebrex had not demonstrated an increased cardiovascular risk in any completed trial, and that the safety signal was specific to rofecoxib (⁹ (Also see "Pfizer Elaborates On Celebrex Safety Theory: Molecule Is “Unique”" - Pink Sheet, 6 Dec, 2004.), p. 8).

As the marketer of Celebrex and Bextra, Pfizer will attempt to isolate the cardiovascular safety signal as Vioxx-specific.

Pfizer also has a stake in the outcome of the meeting because the company is attempting to gain approval for parecoxib, Bextra's prodrug. FDA issued a "not approvable" letter for parecoxib in 2001; the company resubmitted the NDA at the end of 2004.

"There is no direct evidence that this increase in risk results from a class effect common to all selective COX-2 inhibitors, and no evidence that all selective COX-2 inhibitors have less favorable cardiovascular safety profiles than non-selective NSAIDs," Pfizer states.

Pfizer also used the committee briefing documents to refute a theory proposed by University of Pennsylvania researcher Garret FitzGerald.

In a New England Journal of Medicine editorial, FitzGerald argued that the increased risk of cardiovascular events is a class effect resulting from the inhibition of the COX-2 dependent formation of prostacyclin, which predisposes patients to myocardial infarctions or thrombotic stroke (¹⁰ (Also see "Vioxx Withdrawal Fuels Criticism Of DTC; Liability Exposure May Be Test" - Pink Sheet, 11 Oct, 2004.), p. 4).

"To date no specific mechanism of the increased cardiovascular risk observed in patients taking rofecoxib has been positively identified; in particular, there is no direct evidence that this increase in risk results from an imbalance in levels of" thromboxane A2 versus prostacyclin, Pfizer said.

"Moreover, there is evidence suggesting alternative hypotheses to explain the increased cardiovascular risk observed in patients taking rofecoxib, without postulating a class effect common to all selective COX-2 inhibitors."

Pfizer believes one explanation may be that Vioxx has a greater effect on blood pressure.

"When the effects of rofecoxib 25 mg QD and celecoxib 200 mg QD were compared directly in two randomized, double-blind clinical trials involving approximately 2,400 patients with controlled hypertension and osteoarthritis, significantly more patients with rofecoxib developed clinically significant elevations in systolic blood pressure" compared to Celebrex, Pfizer said.

Novartis, which is developing the coxib Prexige (lumiracoxib), offered an additional hypothesis to explain the cardiovascular signal in Vioxx. FDA issued a "not approvable" letter for lumiracoxib in September 2003 and requested additional safety data (¹¹ (Also see "Novartis Prexige NDA Re-Submission Expected In 2006; TARGET Data “Clean”" - Pink Sheet, 14 Jun, 2004.), p. 9).

While Novartis' Prexige outcomes study, TARGET, did not show a significant difference in events between lumiracoxib and NSAIDs, it did show an increased number of myocardial infarctions compared to naproxen (¹² (Also see "Prexige TARGET Study: Not Quite A Bull’s-Eye For Novartis" - Pink Sheet, 23 Aug, 2004.), p. 20).

Novartis appears to be walking a fine line in suggesting that naproxen may be somewhat cardioprotective - enough to explain the Prexige results - but not enough to explain Vioxx's safety signal.

"Several well-controlled studies have demonstrated that naproxen (500 mg bid) is capable of reducing platelet thromboxane production to an extent similar to low dose aspirin and, thus, prevent platelet aggregation," Novartis said. "In a meta-analysis of all naproxen observational studies, naproxen was associated with a 14% decrease in MIs."

"Assuming that naproxen could achieve the same level of reduction in MI as low dose aspirin (32%-44%), this reduction may be a contributing factor, but by itself appears inadequate to explain the 4-fold difference seen between naproxen and rofecoxib in the [Vioxx Gastrointestinal Outcomes Research] trial," the company said.

"Yet, this reduction by naproxen would largely account for the smaller difference observed between naproxen and lumiracoxib in TARGET in the non-aspirin treated population," Novartis said.

The Vioxx cardiovascular safety signal was apparent in the VIGOR study published in 2000. The study met its endpoint of gastrointestinal safety compared to naproxen but also showed an increased cardiovascular risk.

At the time, Merck argued that the result reflected a cardioprotective benefit of naproxen, a theory the company continues to support (¹³ (Also see "Merck’s “VIGORous” Defense Of Vioxx; Novartis, Wyeth Studies Might Help" - Pink Sheet, 18 Oct, 2004.), p. 5).

While some meta-analyses seem to support Merck's theory, it has been undercut by the Alzheimer's Disease & Prevention Trial (ADAPT) that showed an increased cardiovascular risk in the naproxen arm (¹⁴ (Also see "Aleve Warning Gives Pfizer Some Relief, But Is New Headache For FDA" - Pink Sheet, 3 Jan, 2005.), p. 20).

As a result, the safety of naproxen is far from clear and is one of the topics scheduled for discussion.

Since naproxen itself may not explain the cardiovascular safety signal, Novartis says, it is possible that Vioxx has some compound-specific prothrombotic effects. "There may therefore be another mechanism by which rofecoxib is exerting a prothrombotic effect," the company said.

Another "possibility relates to rofecoxib's unique metabolic pathway, a pathway distinct from the one utilized by lumiracoxib," Novartis said. "Metabolism by rofecoxib is through cytosolic reduction catalyzed by aldo-ketoreductase. In the vasculature this enzyme is responsible for detoxification of oxidized phospholipids."

Novartis also suggested that sulphone COX-2 inhibitors, such as Vioxx and Arcoxia , may increase the susceptibility of human LDL and plasma to oxidative modification compared to non-sulphone COX-2s.

"In contrast, lumiracoxib is metabolized by cytochrome P450 2C9, an enzyme not involved with production of vasoactive hormones or metabolism of oxidized phospholipids."