Johnson & Johnson/Bayer HealthCare AG’s pursuit of the broadest label of any of the novel anticoagulants for Xarelto (rivaroxaban) has hit a road bump with an FDA “complete response” letter for use in acute coronary syndromes patients.

J&J’s Janssen Research and Development LLC announced on June 21 that FDA declined to approve the rivaroxaban sNDA for reducing the risk of thrombotic cardiovascular events in patients with acute ACS. The application sought approval for use in combination with aspirin alone or aspirin plus clopidogrel (Bristol-Myers Squibb Co./Sanofi’s Plavix and generics) or ticlopidine.

The “complete response” letter was issued more than one week ahead of the application’s June 29 user fee date under a priority review. Janssen said it is evaluating the letter and will respond to the agency’s questions.

ACS would have been the third claim approved for rivaroxaban, a Factor Xa inhibitor. The drug gained initial approval in July 2011 for prevention of deep vein thrombosis and pulmonary embolism after hip or knee replacement surgery, and in November 2011 for stroke risk reduction in patients with atrial fibrillation Also see "Bayer/J&J's Xarelto Approval For Stroke Prevention Sets Up Marketing Battle With Pradaxa" - Pink Sheet, 4 November, 2011..

Janssen also has pending sNDAs for treatment of deep vein thrombosis or pulmonary embolism, and prevention of recurrent venous thromboembolism Also see "Xarelto Filing Puts It Out Ahead In Venous Thromboembolism" - Pink Sheet, 2 May, 2012.. Janssen has said that, collectively, the filings could give rivaroxaban the broadest range of indications in the U.S. for any of the new anticoagulants on the market or entering the market Also see "Janssen Looks To Differentiate Anticoagulant Xarelto With Broad Label" - Pink Sheet, 2 April, 2012..

Missing Data In ATLAS Proves Problematic …

The ACS application was based upon results from the 15,526-patient ATLAS ACS 2 TIMI 51 trial, in which rivaroxaban was associated with a statistically significant reduction in the risk of the primary endpoint, a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, albeit with increased bleeding.

Prospects for approval of the ACS claim grew considerably dimmer after an FDA advisory committee recommendation against the new use.

At a May 23 meeting, the Cardiovascular and Renal Drugs Advisory Committee voted 6-4, with one abstention, against an ACS claim. Committee members cited questions about the ATLAS efficacy and safety results due to the large amount of missing follow-up data, particularly missing vital status on patients who withdrew consent in the study Also see "ATLAS Data Not Strong Enough To Support Xarelto’s Use In ACS, FDA Panel Says" - Pink Sheet, 23 May, 2012..

Across all subjects in the study, 15% discontinued the trial prematurely, including more than 8% who withdrew consent. Vital status was unknown for more than 1,000 subjects at the end of the trial, despite the sponsors’ efforts to retrospectively track down such information.

The issues related to missing data were the focus of a review and presentation at the advisory committee meeting by FDA medical team leader Thomas Marciniak, who argued that the problems invalidated the study’s efficacy results. Some advisory committee members suggested the ATLAS trial’s design may have contributed to the high amount of missing follow-up Also see "ATLAS Trial Design Blamed For Missing Data On Xarelto ACS Use" - Pink Sheet, 4 June, 2012..

The risk for increased bleeding also prompted some panel members to challenge the wisdom of adding an antithrombotic like rivaroxaban to the current dual anti-platelet therapy standard of care, consisting of aspirin and a thienopyridine Also see "Xarelto Review Sparks Debate Over Feasibility Of A Three-Drug ACS Regimen" - Pink Sheet, 28 May, 2012..

… And FDA Likely Seeks More Clarity

Janssen declined to provide details about the agency’s “complete response” letter.

“We are confident in the robust study results of the ATLAS ACS 2 TIMI 51 trial and the positive benefit-risk profile of rivaroxaban in patients with ACS,” Janssen R&D Vice President, Cardiovascular Franchise Medical Leader Paul Burton said in a statement. “We will continue to work with the FDA to fully address their questions as quickly as possible.”

The company said it has been in “ongoing, productive discussions” with the agency and is reviewing options to provide FDA with the data needed to determine the rivaroxaban’s approvability in ACS.

While it is possible that FDA may have requested a new clinical trial, another option could be that the agency sought further investigation into the vital status of patients who withdrew from ATLAS. At the advisory committee meeting, Center for Drug Evaluation and Research Deputy Director for Clinical Science Robert Temple suggested that there is always room for further analyses, although it may not be feasible to use country-by-country death index or registry data to track down vital status for patients across the 44-nation trial.

In a June 22 note, Leerink Swann analysts Seamus Fernandez and Danielle Antalffy said that while the “complete response” letter was unsurprising given the advisory committee vote, “we question the agency's urgency to approve … new antiplatelet options. We believe the concept of approving triple-antiplatelet therapy will be challenging for the FDA, given potential safety concerns.”

Availability of the two newest thienopyridines – Eli Lilly & Co.’s Effient (prasugrel) and AstraZeneca PLC’s Brilinta (ticagrelor) – “suggests that the FDA may not be motivated to urgently approve Xarelto for ACS without greater clarity on follow-up,” the analysts said.

FDA’s cardio-renal review division is expected to take action on another high-profile novel anticoagulant in the coming days. The user fee date for Bristol-Myers Squibb/Pfizer Inc.’s Factor Xa inhibitor Eliquis (apixaban) is June 28; the sponsors are seeking approval for stroke prevention in atrial fibrillation patients.

Published data from the pivotal ARISTOTLE study suggest two advantages for apixaban not seen with either Xarelto or Boehringer Ingelheim GMBH’s direct thrombin inhibitor Pradaxa (dabigatran) in the stroke a-fib population – an all-cause mortality benefit and a reduced risk of major bleeding compared with warfarin Also see "BMS/Pfizer’s Eliquis On Priority Review Path Toward March 2012 Approval" - Pink Sheet, 29 November, 2011..

Xarelto Label Expansion Plans Slowed By FDA “Complete Response” On ACS Claim

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