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The Pulse of the Pharmaceutical Industry

Best New Medicine 2013

Written by: | | Dated: Friday, March 1st, 2013

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Stopping The Bleeding

Partner marketers Bristol-Myers Squibb and Pfizer are hoping to recover from major patent losses with the help of the Factor Xa inhibitor Eliquis, Med Ad News’ Best New Medicine of the Year.

Christmas came a few days late in 2012 for two of the pharmaceutical industry’s biggest players. On Dec. 28th, Bristol-Myers Squibb and Pfizer finally got the good news from FDA about a compound in which both companies had placed their hopes for many years – the Factor Xa inhibitor Eliquis was approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Eliquis is a good example of the long-time horizon of drug development for pharmaceutical companies, and how crediting present leadership for today’s successes and failures may be misleading. T e compound was acquired as a Phase I asset when Bristol-Myers Squibb purchased DuPont Pharmaceuticals in 2001. In 2007, with the compound finally in Phase III trials, BMS and Pfizer launched a worldwide collaboration to develop and market the drug. Now, a half-dozen years later, analysts at EvaluatePharma have projected that Eliquis will be the No. 14 pharmaceutical product in the world and No. 11 in the United States by 2018, with worldwide sales of $4.71 billion and U.S. sales of $2.7 billion between the two marketing partners. By comparison, Eliquis’ competitor Factor Xa inhibitor, Xarelto, is projected at $3.36 billion in sales worldwide and $1.67 billion in the United States in 2018.

Eliquis’ approval could not have come at a better time for its developers. Plavix, responsible for a third of Bristol-Myers Squibb’s revenue in 2011, lost its patent protection in May of 2012, while Pfizer’s longstanding top seller Lipitor, responsible for about a seventh of the company’s revenue, lost protection in December 2011.

By coincidence or not, the two companies’ stock prices have grown significantly in the past 18 months as their hopes for Eliquis began to come to fruition – from $16.66 in August 2011 to just north of $28 in early March 2013 for Pfizer, and from $26.38 to over $37.50 for Bristol-Myers Squibb in the same time frame.

Last year did not seem to start so well for Eliquis’ developers, though. March 1st, 2012, Bristol-Myers Squibb and Pfizer announced that FDA had extended the action date by three months the Eliquis new drug application for the prevention of stroke and systemic embolism in patients with atrial fibrillation, to June 28. Subsequent to the fi ling of the NDA, the companies submitted additional information about the Eliquis clinical program to FDA, which agency regulators decided constituted a major amendment to the application requiring additional time for review.

Four months later, at the end of June, FDA issued a complete response letter on Eliquis for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. FDA requested additional information on data management and verification from the ARISTOTLE trial but did not require any new studies.

Three months after the complete response letter, in late September, FDA acknowledged receiving the two companies’ resubmission of the Eliquis new drug application, assigning it a PDUFA date of March 17, 2013. A few days later, the companies announced the publication of trial results showing that the reductions in stroke or systemic embolism, major bleeding, and mortality demonstrated with Eliquis compared to warfarin in the ARISTOTLE trial were consistent across a wide range of stroke and bleeding risk scores in patients with nonvalvular atrial fibrillation.

Nov. 1, Bristol-Myers Squibb, Pfizer, and Portola Pharmaceuticals Inc. launched a clinical collaboration agreement to conduct a proof-of-concept study of PRT4445 and Eliquis. PRT4445 is a universal Factor Xa inhibitor antidote in clinical development designed to reverse the anticoagulant activity of any Factor Xa inhibitor. No agents are approved to reverse the activity of Factor Xa inhibitors.

The collaboration will be in effect during the clinical proof-of-concept study, which was projected to start by the end of 2012. T e study is designed to demonstrate the safety of PRT4445 and its ability to reverse the anticoagulation activity of Eliquis and other Factor Xa inhibitors, including betrixaban, Portola’s Phase III oral Factor Xa inhibitor. Bristol-Myers Squibb and Pfizer agreed to make an undisclosed cash payment to Portola upon initiation of the proof-of-concept study with Eliquis and will provide development and regulatory guidance for the study. Portola retains 100 percent global development and commercialization rights for PRT4445.

“Patient safety and improved patient outcomes have guided our clinical development program for Eliquis, including our efforts to identify a reversal agent for urgent clinical situations,” says Brian Daniels, senior VP, Global Development and Medical Affairs, Bristol-Myers Squibb. “With our partner Pfizer, we look forward to working with Portola to advance the scientific understanding of the role of PRT4445 as a potential antidote for Eliquis.”

Major bleeding events occur infrequently in patients taking Factor Xa inhibitors (1 percent to 4 percent per year in clinical studies) and standard measures are employed to manage these events. An agent specifically designed to reverse the activity of Factor Xa inhibitors may provide an antidote for patients who, in rare instances, experience an uncontrolled major bleeding event or require emergency surgery.

Late November began a run of major market approvals for Eliquis. Nov. 20, the European Commission approved the product for prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors. This was the first regulatory approval in any market for Eliquis for stroke prevention in patients with nonvalvular atrial fibrillation.

The marketing authorization for Eliquis was supported by the pivotal Phase III trials ARISTOTLE and AVERROES, which evaluated about 24,000 patients with non-valvular atrial fi brillation in the largest completed clinical trial program conducted to date in this patient population. The Eliquis clinical program is the only Phase III clinical program among the new oral anticoagulants to evaluate the safety and efficacy of Eliquis versus aspirin in patients who were unsuitable for vitamin K antagonist therapy.

“Today’s approval of Eliquis in the EU is the result of a strong collaboration between Bristol-Myers Squibb and Pfizer to help address the unmet need for improved treatment options versus warfarin to reduce the burden of stroke in patients with nonvalvular atrial fibrillation,” said Lamberto Andreotti, CEO of Bristol-Myers Squibb, on the announcement. “With its compelling clinical profile, Eliquis represents the commitment of our partnership with Pfizer to scientific innovation and our shared vision of bringing innovative and meaningful medicines to patients.”

On Dec. 6, Health Canada approved Eliquis for the prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation. T en, on Dec. 8, the two companies announced the results of the Phase III AMPLIFY-EXT trial, which evaluated treatment with Eliquis over a one-year period compared to placebo for the prevention of recurrent venous thromboembolism in 2,486 patients who had already completed six to 12 months of anticoagulation treatment for the condition, including deep-vein thrombosis or pulmonary embolism. In the trial, extended treatment with Eliquis 2.5 milligrams and 5 milligrams twice daily, demonstrated superiority versus placebo in the reduction of the composite endpoint of symptomatic, recurrent venous thromboembolism and death from any cause (11.6 percent in the placebo group, compared with 3.8 percent and 4.2 percent in the Eliquis 2.5 milligram and 5 milligram groups, respectively).

Eliquis also was superior to placebo for the predefined secondary efficacy outcome of recurrent VTE and VTE-related death (8.8 percent in the placebo group, compared with 1.7 percent in both the Eliquis 2.5 milligrams and 5 milligrams groups). Both of these endpoints,
the primary and secondary efficacy outcomes, were statistically significant.

“Up to 10 percent of patients will experience a recurrent venous thromboembolism event after completing the currently recommended six-to-12-month treatment period, suggesting the need for additional prophylaxis,” says Dr. Giancarlo Agnelli, professor of internal medicine, University of Perugia, Italy; director of the Department of Internal and Cardiovascular Medicine and Stroke-Unit, University Hospital, Perugia, Italy; and lead investigator of the study. “In the AMPLIFYEXT trial, which added an additional year of treatment, Eliquis reduced the composite risk of recurrent venous thromboembolism and total mortality without an increase in major bleeding versus placebo.”

The day after Christmas, regulators in Japan approved Eliquis for the prevention of ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

“The approval in Japan marks the third regulatory approval for Eliquis within six weeks,” said John Young, president and managing director, Pfizer Primary Care Business Unit, on the annoucement. “We are excited by this momentum and confident that our combined cardiovascular leadership and expertise with BMS will lead to a successful introduction of this important medicine to patients and physicians in Japan.”

Then, just two days later, the two companies got the best news of all when FDA approved Eliquis to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

“The approval of Eliquis offers patients with nonvalvular atrial fibrillation a novel treatment option for reducing the risk of stroke,” said Mr. Andreotti. “Eliquis is the result of leading scientific innovation and the shared vision of our alliance to introduce a new oral anticoagulant for patients with nonvalvular atrial fibrillation in the United States.”

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