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In documents released Tuesday ahead of an FDA panel meeting on September 8, agency staff suggested that the regulator issue a complete response letter in reply to a marketing application seeking to expand approval of Johnson & Johnson and Bayer's Xarelto (rivaroxaban) to include the prevention of stroke in people with atrial fibrillation (AF). Shares in Bayer fell as much as 13 percent on the news.

FDA reviewers said "there is a lack of substantial evidence" that the once-daily oral anticoagulant "will have its desired effect when used as recommended," and "there is insufficient information about the drug to determine whether it is safe for use" in the proposed indication. The main safety concern seen with the drug was a risk of bleeding. However, agency staff remarked that "it might not be unreasonable to approve [Xarelto] as a second- or third-line treatment."

The advisory panel will be asked to vote on whether Xarelto should be cleared for long-term use to prevent strokes and other types of serious blood clots in patients with AF. The regulator will also ask the panel a series of questions about the ROCKET AF trial involving Xarelto, which compared the product to warfarin.

Patients in the study were considered higher risk than those in a trial of Boehringer Ingelheim's Pradaxa (dabigatran), which was approved last year by the FDA to prevent strokes in patients with AF. The agency noted that drug approval policies require new products to be as effective as existing products for life-threatening diseases. However, the regulator said that regulation doesn't apply if a new therapy is studied in a new population. The panel will be asked to discuss whether patients in the Xarelto study qualify as a new population when compared to patients in trials of Pradaxa.

In addition, FDA staff expressed concern that warfarin was not adequately used in the study, potentially giving Xarelto an unfair advantage in comparison. The reviewers also cited excess strokes recorded in patients who took Xarelto and were transitioned to warfarin, and recommended that Johnson & Johnson and Bayer conduct an additional trial to investigate a transition regimen. Goldman Sachs International analyst Richard Logan suggested that further studies of the agent may take two years, by which time he said Pradaxa "would likely be the standard of care, which could create a tougher hurdle" for Xarelto.

In additional documents posted on the FDA's website, Johnson & Johnson said Xarelto "demonstrates a highly favourable benefit to risk profile and offers an important clinical advance." The company is "confident in the effectiveness of [Xarelto] to prevent strokes in patients with atrial fibrillation," noted spokesman Ernie Knewitz. "This is not the final FDA assessment," Bayer spokesman Alexander Siedler remarked, adding that "we still have time to work with the FDA to satisfy the information needs they have."

Citigroup Global Markets analyst Matthew Dodds remarked that the questions the FDA presented for the panel to discuss are less severe than the agency staff report and take into account the higher risk population studied with Xarelto. However, Barclays Capital Group analyst Mark Purcell said that even if the companies can overcome the FDA's concerns, Xarelto would probably not be superior to warfarin and may be restricted to high-risk patients. "Even if approved somehow, Xarelto would likely be a commercial failure" in the AF population in the US, he added.

Xarelto is currently authorised in the US for the prevention of deep vein thrombosis in patients undergoing knee or hip replacement surgery. The agent is also under review for the prevention of stroke in people with AF in Europe, where Bayer has rights.

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