The initial clinical program for Johnson & Johnson's Xarelto (rivaroxaban) is more than twice as large as the last oral anticoagulant FDA reviewed - AstraZeneca's Exanta (ximelagatran) - but the additional data may not be enough to overcome concerns about liver toxicity.

¹ FDA's briefing materials for the March 19 meeting of the Cardiovascular and Renal Drugs Advisory Committee notes that safety findings were "notable for a numeric excess in the occurrence of serious alanine aminotransferase (ALT) elevations among patients receiving rivaroxaban."

The trials showed a 0.3 percent occurrence of ALT for rivaroxaban versus 0.2 in Sanofi-Aventis' Lovenox (enoxaparin) "as well as the occurrence of a composite liver marker - ALT > 3X upper limit of normal with total bilirubin > 2X upper limit of normal (0.2 percent versus 0.1 percent)," FDA said.

Liver toxicity is not the only concern weighing on Xarelto; incidents of bleeding and concerns about off-label use suggest that FDA may want to wait until more longer-term data is available before deciding on the drug (see ² Also see "Rivaroxaban Committee Review May Hinge On Concerns About Off-Label Use" - Pink Sheet, 17 March, 2009. ).

Hepatotoxicity concerns may also encourage FDA to wait. The agency notes that in the case of Exanta, which was voted down by the committee in 2004, there were no cases of "severe liver injury in the short-term (orthopedic) clinical trials; however, a strong signal was subsequently identified in long-term (atrial fibrillation) trials."

J&J has a much larger short-term data set for Xarelto than AstraZeneca had for Exanta. "At the time of the ximelagatran application submission, approximately 3,000 patients had been exposed for the short term usage (knee surgery), generally 12 days or less. In contrast, the rivaroxaban short term usage (knee and hip surgery) consists of exposure to approximately 6,200 patients," FDA notes.

The difficulties in assessing the product's liver risks are illustrated in the meeting's schedule itself. While bleeding, which FDA calls the "main safety finding" from the trials, will presumably be handled as part of the general discussion, hepatotoxicity gets its own 10-minute block of time.

The most recent ³ agenda, posted the morning of March 17, indicates that FDA has not yet settled on who will make its presentation on liver toxicity. Office of Surveillance and Epidemiology Medical Epidemiologist Kate Gelperin filed the review memo on hepatotoxicity that is included in the briefing materials. The memo summarizes the Xarelto data, but the bulk of OSE's submission on the subject is a reprint of a 14-page liver toxicity review created for the Exanta meeting.

The ghosts of applications past will be present at the committee review in a more physical sense too: the committee ⁴ roster includes AstraZeneca VP-Cardiovascular & Gastrointestinal Diseases Jonathan Fox.

The Limits of Risk Management

Xarelto (a Factor Xa inhibitor) has a different mechanism of action than Exanta (a direct thrombin inhibitor), and J&J is clearly hoping that difference will result in a different outcome for its product.

But another part of FDA's review suggests there may be too many unknowns for FDA to be comfortable with the liver risk, even in a product that acts differently. In the review of J&J's "safety surveillance plan," the agency notes the firm "has proposed a risk management program consisting of routine measures such as labeling, education (with targeted detailing by the sales force), and spontaneous adverse event reporting to assure appropriate prescribing consistent with the proposed indication." J&J is seeking to initially market the drug for prophylaxis of deep vein thrombosis and pulmonary embolism in patients undergoing hip replacement or knee replacement surgery.

Such a risk management approach would make sense, FDA notes, if the liver injuries were not caused by the drug.

However, "if future safety data from on-going clinical trials indicate that rivaroxaban is likely causally associated" with severe drug induced liver injury, FDA says "a formal risk management program with safe use strategies should be considered if the data identify the at-risk subpopulation and/or a monitoring approach that will prevent serious adverse hepatobiliary events. In the absence of such directive information, we believe additional risk management measures for rivaroxaban will not effectively minimize the risk of hepatotoxicity."

In other words, FDA seems to be asking J&J to rule out potential liver risks for Xarelto, or find a way to prevent them.

-M. Nielsen Hobbs (n.hobbs@elsevier.com)

Liver Toxicity Is Wildcard In Xarelto Committee Review

More from Archive

More from Pink Sheet