The Xarelto Trials That Might Have Been

Johnson & Johnson/Bayer’s Xarelto (rivaroxaban) was cleared for stroke prevention in atrial fibrillation patients unencumbered by new post-marketing studies – but not for lack of suggestions. FDA reviewers had urged further studies on topics ranging from alternate dosing regimens and reversal of drug activity to transitioning to warfarin.

The leadership of FDA’s Division of Cardiovascular and Renal Products appears to be taking a minimalist approach to post-marketing activity for novel oral anticoagulants, even though the review process for the new wave of drug candidates has produced no shortage of suggestions for trials both pre- and post-marketing.

Prevention of stroke and systemic embolism in atrial fibrillation patients is the first major battleground for the next-generation anticoagulants. Review documents for the most recent approval, Johnson & Johnson/Bayer HealthCare LLC’s Xarelto (rivaroxaban), provide a look inside FDA’s analysis and decision-making, revealing the ferment of ideas for future studies that came out of a review marked by intra-agency division over whether the drug should be approved at all (see related story, (Also see "Xarelto Tested FDA’s Comparative Efficacy Powers, But Conservative View Prevailed" - Pink Sheet, 1 May, 2012.)). And yet, the Nov. 4, 2011 approval letter lists no post-marketing commitments or requirements native to the stroke prevention in AF application.

The primary reviewers wanted more study of a regimen for changing therapy from rivaroxaban to warfarin, but review team leader Aliza Thompson wondered why “one needs to be able to write labeling that describes how to transition to an alternative chronic therapy?”

The unencumbered approval letter for Xarelto in AF patients is consistent with the Oct. 19, 2010 approval of Boehringer Ingelheim Corp.’s Pradaxa (dabigatran) for an AF indication. Despite recommendations by various review disciplines for post-marketing studies, primarily regarding dose exploration or dabigatran-related bleeding, FDA did not ask Boehringer Ingelheim for new clinical studies after approval. In particular, Pradaxa efficacy reviewer – and Xarelto cross-discipline team leader – Aliza Thompson called for post-marketing studies of the increased risk of gastrointestinal bleeding and measures to stop drug-related bleeding (Also see "Pradaxa Review Shows FDA Doubts About The Power Of REMS To Change Prescribing Practices" - Pink Sheet, 1 Apr, 2011.). The Pradaxa approval in AF patients, the drug’s first FDA approval, did come with two post-marketing requirements, both for in vitro studies of drug transport and interactions.

Xarelto’s Nov. 4, 2011 approval letter does list relevant post-marketing analyses assigned under the drug’s first approval, a separate NDA reviewed by the Division of Hematology Products for prevention of deep vein thrombosis and pulmonary embolism in orthopedic surgery patients. The AF approval letter reminds the sponsors of earlier post-marketing requirements regarding pharmacovigilance to track major bleeding and a trial to identify appropriate dosing in renally impaired patients, as well as noting its post-marketing commitment to study alternative tablet strengths to allow for better dose titration in orthopedic surgery patients, who take a lower dose than the AF population.

Transition To Warfarin Regimen Warrants REMS, Not Further Study

The finding of an increased rate of strokes in rivaroxaban patients after completing ROCKET, when patients in the rivaroxaban arm returned to warfarin treatment, was one of the major issues in the review. In days 3-30 after stopping study medication, 18 ischemic and four hemorrhagic strokes were reported in rivaroxaban patients, compared with six strokes (four ischemic and two unknown) in the warfarin group.

FDA identified two options to explain the stroke findings: a rebound hypercoagulable state upon ceasing rivaroxaban or what Thompson called “a poorly handled transition from rivaroxaban to warfarin.” FDA leaned toward the latter explanation, making a regimen for transitioning rivaroxaban patients to warfarin, which had not been part of the ROCKET trial design, an important review issue – and one that drew suggestions for further study.

Instead, the increased risk of stroke when transitioning off rivaroxaban and onto warfarin is handled with a boxed warning in labeling and a communication-focused Risk Evaluation and Mitigation Strategy that features letters to physicians and professional organizations and a Medication Guide for patients (Also see "Bayer/J&J's Xarelto Approval For Stroke Prevention Sets Up Marketing Battle With Pradaxa" - Pink Sheet, 4 Nov, 2011.).

Division of Risk Management analyst Danielle Smith explained in a Nov. 4, 2011 approval memo that the risks attending discontinuation and the risk of decreased drug absorption if the drug is not taken with the evening meal both warrant a REMS “because the risks are both life-threatening and preventable.” The REMS stresses that “discontinuing Xarelto without introducing an adequate alternative anticoagulant places non-valvular atrial fibrillation patients at an increased risk of thrombotic events, including stroke, and to follow recommendations in the [label] on how to convert atrial fibrillation patients from Xarelto to warfarin or other anticoagulants.”

The primary medical review team of Martin Rose (efficacy) and Preston Dunnmon (safety) had also seen issues in need of further study when looking at the same transition quandary. “Rigorous assessment of the coagulation system in patients who have been withdrawn from long-term rivaroxaban therapy has not been performed, and the existence of abnormalities in such patients predisposing them to thrombotic events has not been ruled out,” Rose and Dunnmon stated in an Aug. 10, 2011 review.

“In addition, a transition regimen to warfarin upon discontinuation of rivaroxaban has not been clinically validated with respect to bleeding risk or risk for thrombotic events,” the medical reviewers said. Regulatory Project Manager Alison Blaus’ summary review explains that the transition strategy adopted in labeling was based on clinical pharmacology data, because no formal strategy was used in ROCKET.

“It seems prudent to require the sponsor to demonstrate in a clinical study in AFib patients receiving rivaroxaban therapy that the proposed transition regimen is safe and effective,” the medical reviewers said. “The study should focus on delineating bleeding risk; a study to rigorously delineate thrombotic event risk would be too large, although thrombotic events could be secondary endpoints.” They suggested that “an open label trial in patients taking rivaroxaban chronically (perhaps at least 90 days) and then switched to warfarin would be appropriate. The goal would be to rule out a specified rate of major bleeding over the 60 to 90 days after the transition.”

“No Regulatory Precedent” Requires Testing Of Transition To Alternative Therapy

Rose and Dunnmon concluded that such a study was needed prior to approval because of “insufficient information about the drug to determine whether the product is safe for use under the conditions prescribed, recommended or suggested in its proposed labeling.” The clinical reviewers noted that in other recent anticoagulant trials in AF patients – the Sportif V trial of AstraZeneca PLC’s failed ximelagatran, dabigatran’s RE-LY trial, and Pfizer Inc./Bristol-Myers Squibb Co.’s ARISTOTLE study of apixaban – provisions were made for “a short period of dual therapy with study drug and open-label warfarin … to continue anticoagulation during the lag period of INR control at the start of warfarin therapy.”

However, Thompson pointed out “there is no regulatory precedent (thus far and based on an n of one – dabigatran) for requiring a development program to test in patients with atrial fibrillation the effectiveness of a transition strategy for achieving a therapeutic INR on warfarin (much less its effects on bleeding and/or thrombotic events during the transition).” And she noted the situation is improbable in a real-world setting. More fundamentally, she said, “why for this therapy (or for any other therapy that is intended to be used chronically) one needs to be able to write labeling that describes how to transition to an alternative chronic therapy?”

“From a regulatory standpoint, it does not seem sensible to make it a requirement that applicants conduct clinical studies testing how to transition from their particular chronic therapy to another/all marketed chronic therapies,” Thompson stated. Nonetheless, she did endorse a boxed warning about the risk of strokes and embolic events in AF patients who stop rivaroxaban, a boxed warning that is indeed featured in labeling.

Hematology Consult Proposed Studying Alternative Hypothesis

While the review team spent most of its energy addressing the ”poorly handled transition to warfarin” explanation for the post-discontinuation stroke findings, regulatory diligence required in-depth appraisal of the alternate explanation: the rebound hypercoagulable state hypothesis. The cardio-renal division consulted the Division of Hematology Products, which had approved Xarelto for its initial DVT/PE claim. The Aug. 9, 2011 consult request explains that “the sponsor has done nothing in our view to rule out the existence of a hypercoagulable state in patients who take rivaroxaban for an extended period and then stop suddenly.”

The Division of Hematology Products reviewer, Ashkan Emadi, acknowledged the possibility of a transient hypercoagulable state post-rivaroxaban discontinuation, but urged caution because the event numbers are small and the mechanism for a correlation is speculative. Emadi suggested the sponsor design “a small study with shorter study duration and appropriate correlative endpoints with respect to rivaroxaban and warfarin half lives, the time of discontinuation of rivaroxaban and initiation of warfarin.”

“Until further studies are performed in this patient population, we recommend a period of overlapping (bridging) rivaroxaban and warfarin with close laboratory (such as INR) evaluations, should rivaroxaban be discontinued,” Emadi concluded, outlining a strategy consistent with the approved labeling.

“I do not think that a post-marketing study is needed to address this issue,” Thompson responded to the hematology consult’s proposal. “I agree that one cannot exclude a possible rebound hypercoagulable state,” she explained, but “I think that the available data suggest that the finding likely reflects a poor handling of the transition to warfarin.” She pointed to an analysis of patients who prematurely discontinued the study “showed a high but similar event rate in the two treatment arms, arguing against a significant hypercoagulable state following discontinuation of rivaroxaban.”

“Moreover, even if the observed events are because of a rebound hypercoagulable state, the absolute incidence of such events and risk difference (rivaroxaban minus warfarin) was low in ROCKET … a difference in absolute incidence of 0.35%,” Thompson stated. “Hence, even if rivaroxaban causes a rebound hypercoagulable state, such an effect, in aggregate, does not appear to be marked.”

Reversing Rivaroxaban

Thompson proposed a post-marketing study of a more practical and realistic problem: finding methods to reverse rivaroxaban’s activity. “There is no established antidote for rivaroxaban,” she noted. “GI bleeding was more common on rivaroxaban and in the U.S. rates of major bleeding were high.”

“A post-marketing study is needed to address methods for reversing rivaroxaban’s anticoagulant activity and hence ensure that rivaroxaban’s risks do not exceed its benefits,” Thompson said. She suggested a range of options to explore, including preclinical studies; enhanced pharmacovigilance (possibly building on the pharmacovigilance PMR from the Xarelto DVT approval that includes cases of major bleeding); or a “clinical study testing the effects of a promising agent/intervention on bleeding in patients experiencing a clinically significant bleed or in patients who require urgent invasive or surgical procedures.”

FDA Thinks Twice-Daily Dosing Is Likely Better, But Won’t Compel Study

The primary clinical review team concluded that “the sponsor must perform a clinical study to evaluate the efficacy and safety of a lower dose and/or additional dosing regimens, including at least one BID regimen, before this product is approved.” Based on clinical pharmacology studies, the reviewers suggested that twice-daily dosing could have improved safety thanks to lower peak and higher trough blood levels of rivaroxaban, and could be associated with improved efficacy as well.

FDA had been wary of the sponsor’s 20 mg once-daily dose for stroke prevention in AF from the planning phases of the ROCKET trial. In September 2006, FDA issued an advice letter questioning the rationale for the 20 mg daily dose. The clinical reviewers emphasized that “agreement was not prospectively achieved on the dose(s) to be tested prior to the execution of the ROCKET trial.”

The medical reviewers acknowledged that dose selection for ROCKET was not a clear-cut decision given the patient population. “Dose-finding studies in patients with AFib may not be feasible as they carry a high risk of stroke for patients with potentially too low doses of the investigational anticoagulant.”

While dosing of rivaroxaban in studies for other indications is different, the reviewers found it suggestive. Bayer and J&J have mounted an extensive clinical program behind Xarelto, enrolling an estimated 75,000 patients. As of 2011, 65 clinical trials had been completed, with seven more ongoing, the clinical reviewers calculated. Patient populations included the orthopedic surgery patients and AFib patients of the first approvals, as well as extensive plans to broaden the drug’s use. Pending sNDAs would add claims for treatment of DVT/PE and prevention of recurrent venous thromboembolic events and reducing the risk of thrombotic cardiovascular events in acute coronary syndrome patients (see Xarelto development chronology, (Also see "Xarelto Development Timeline" - Pink Sheet, 1 May, 2012.)).

“The information from ACS studies (where rivaroxaban is given to prevent arterial circulation thrombotic events, as in ROCKET) is consistent with the data from the VTE studies suggesting that [twice-daily] dosing may have a better benefit/risk profile than once-daily dosing,” Rose and Dunnmon said.

FDA often urges sponsors to study multiple doses or regimens in Phase III, Thompson noted, but the division’s interpretation of the regulatory framework precludes it from requiring such investigations (see related story, (Also see "FDAer Eyes Improvements In Anticoagulant Trial Design" - Pink Sheet, 1 May, 2012.)).