Johnson & Johnson: approval for Xarelto will once again be denied.
By Hardik Patel, Lead Analyst
24 January 2014
I am Lead Analyst for oncology at Datamonitor Healthcare, based in the New York office. I have a Bachelor of Science deg...
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Johnson & Johnson’s Xarelto faces its third denial from the FDA after an advisory committee voted heavily against approval for ACS.
The Cardiovascular and Renal Drugs Advisory Committee met on 16 January to discuss Johnson & Johnson’s supplemental New Drug Application (sNDA) for its anticoagulant Xarelto (rivaroxaban). The committee voted 10 to 0, with one abstention, against approving Xarelto for use in acute coronary syndrome (ACS) patients. The panel stated that there was too much information missing from Phase III trial results to justify approval of a drug with possible serious side effects. The future of Xarelto in ACS will remain in question as the committee decision will lead to the third denial of this application by the US Food and Drug Administration (FDA).
Johnson & Johnson first submitted the sNDA in 2011 based on data from the Phase III ATLAS ACS 2 TIMI 51 trial. This first attempt was met with an advisory committee meeting voting 6 to 4 against approval. Subsequently, the FDA denied the application, asserting that there was too much data missing from the final trial results submitted to make a conclusive decision on the efficacy and safety of the drug. Johnson & Johnson collected follow-up data from patients who were unaccounted for and submitted this information to the FDA for reconsideration, only to be rejected again in March 2013.
In its latest attempt at approval, the company restructured the proposed indication by reducing the duration of use to only 90 days following an ACS event. It believed that trial data for this shortened duration would be convincing given that they were more complete. However, the review panel thought otherwise, stating that the data within this duration were not robust enough to clearly demonstrate efficacy and that the missing data outside of this duration could not be ignored. Furthermore, the panel suggested that the results from a trial testing the chronic use of Xarelto could not be reanalyzed and repurposed as evidence for the short duration indication.
Earlier this week, the panel met on another drug in a similar situation, but came to a very different conclusion. The committee voted 10 to 1 in favor of approving Merck’s anti-platelet therapy Zontivity (vorapaxar) for the reduction of atherothrombotic events in patients with a history of myocardial infarction. Like Xarelto, Zontivity also exposed patients to an increased risk of bleeding. In the drug’s Phase III TRA 2P-TIMI 50 trial, patients who had a history of stroke or transient ischemic attack were found to have the most risk of experiencing side effects, and were therefore excluded in the proposed indication for Zontivity.
Although both companies focused on subgroups of their respective studies and reduced the indications of their drugs in an effort to obtain approval, there were two distinct differences between the data sets. The data supporting Zontivity’s efficacy were much more robust (p-value=0.001) compared to Xarelto’s (p-value=0.024), allowing the analysis of subgroups to remain statistically significant. Secondly, the amount of missing data in the Zontivity study results was much lower (≈2%) in comparison to Xarelto’s results (≈10%). This significantly reduces the chance that missing data would affect the accuracy of the primary endpoints being measured and increases the reliability of the results.
The FDA is not required to follow the recommendations of the committee when making final decisions on drug approvals. However, in the case of these two drugs, Datamonitor Healthcare expects the FDA to uphold the panel’s conclusions. Given the commercial attractiveness of the ACS indication and Xarelto’s prior approval for ACS in Europe, Johnson & Johnson will likely continue to pursue approval for the indication in the US. However, the company would need to perform an additional confirmatory trial to demonstrate the drug’s clinical benefit in this patient population. Furthermore, the results of these committee meetings should prompt Johnson & Johnson and other companies with products within cardiovascular indications to more closely monitor the design and parameters of future late-stage clinical trials.