September 22, 2010
FDA's three-month postponement of a decision on AstraZeneca PLC 's NDA for Brilinta (ticagrelor) may signal more trouble for the long-term viability of the product rather than any concern about its actual approvability.
The extension of the user fee date to Dec. 16, which the company announced Sept. 15, gives FDA and AstraZeneca more time to negotiate the wording of the new clotbusting drug's label, particularly how it should be used in patients also given aspirin. While the pivotal clinical trial showed Brilinta was superior to Bristol-Myers Squibb/Sanofi-Aventis' Plavix (clopidogrel), North American patients in the trial – "about 10 percent of the total" – actually did worse.
During the July meeting of the Cardiovascular and Renal Drugs Advisory Committee, which eventually voted 7-1 to approve the drug, speculation centered on the higher doses of aspirin taken by U.S. patients in the trial compared to those in Europe. The committee recommended AstraZeneca conduct another study testing that hypothesis, which the company is planning ("Low-Dose Aspirin Label Could Pose High Commercial Hurdle For Brilinta," "The Pink Sheet," Aug. 9, 2010).
Still, enthusiasm for a drug that analysts believe will be the British drug giant's next big blockbuster remains high. "We've heard very positive reviews from cardiologists," said Nikhil Mehta, director of cardiovascular disorders research at Decision Resources, a market advisory firm. "We think the environment will be challenging, but we're still predicting billion dollar sales for that drug by 2014."
The pivotal trial, dubbed PLATO, showed Brilinta reduced deaths and repeat heart attacks and strokes in the year after first events by 16 percent compared to Bristol-Myers Squibb Co. Plavix (clopidogrel), which has dominated the market for platelet-inhibiting drugs for over a decade. It loses its patent protection next year, and that deadline makes the three-month delay for Brilinta critical as payers race to develop treatment protocols that address clopidogrel's shortcomings while caring for patients at a fraction of the cost that newer agents might.
The Efficacy Advantage
Brilinta will likely carry a critical labeling advantage when going into this difficult market. "Ticagrelor is the first drug that reduces mortality, and that was because it didn't increase life-threatening bleeding," said Gregg Stone, a cardiologist at Columbia University's Center for Interventional Vascular Therapy and a consultant for each company with a drug in this class. "When you've got a big study that shows a reduction in mortality, that's the bottom line."
A subsequent analysis of data from the PLATO trial released last month at a European cardiology meeting indicated Brilinta is also superior in patients with inadequate levels of the liver enzyme that breaks down Plavix, which is a pro-drug and must be metabolized before it gets to work. In March, FDA added a "black box" warning to the Plavix label aimed at patients with two mutations of the CYP2C19 gene that produces the enzyme.
Plavix was approved in 1997; its pivotal clinical trial, called CURE, showed it reduced the number of repeat heart attacks and strokes, but didn't reduce overall mortality.
More Potent, Less Permanent
Brilinta also benefits from using a different mechanism of action than either Plavix or Effient (prasugrel), Eli Lilly & Co. 's entry in the field. PLATO researchers said Brilinta also showed superior performance in patients without the genetic mutation that inhibited Plavix metabolism.
Lilly thought it could seize substantial market share from Plavix, which racked up $9.1 billion in global sales in 2009, according to IMS Health, by engineering a drug made solely of the Plavix metabolite. That would sidestep the liver enzyme problem that affects anywhere from 2% to 14% of patients, according to the FDA.
Effient's pivotal trial, dubbed TRITON-TIMI 38, also showed a significant improvement in reduced mortality, heart attacks and strokes over Plavix. But a significant increase in life-threatening bleeding risks, especially in the frail elderly, has dampened physicians' enthusiasm for the new drug, which, like Brilinta, is a much more potent platelet inhibitor. Approved in July 2009, Effient sales in the second quarter totaled just $22.9 million.
Once Brilinta enters the market, it will face the same challenge as Effient – opposition from payers who want to avoid seeing it substituted for soon-to-be-generic Plavix. One major factor in its favor is its mechanism of action. Plavix and its chemical cousin Effient permanently bind to the platelet, inhibiting its clumping action for the platelet's entire seven-day lifespan.
Brilinta, on the other hand, creates an impermanent bond that lasts less than a day. That can be an important consideration for physicians and emergency room personnel treating heart attack or stroke patients. They don't know upon presentation if that patient is going to wind up in the catheter lab for angioplasty, which can lead to insertion of stents, or undergo a major bypass operation.
If a patient has been given an immediate dose of Plavix, physicians often wait several days before operating out of fear of bleeding complications. President Clinton had to wait four days for Plavix to clear before undergoing his bypass operation, for instance.
"The irreversibility of both of those drugs (Plavix and Effient) has a downside," said Steven Nissen of the Cleveland Clinic. "Brilinta lasts just 12 to 18 hours and is given twice a day. It has the advantage because if you give it upfront, you can stop the drug and operate the next day if the patient needs it."
Payers Exploring "Start And Switch" Strategy
But that still leaves open an alternative for cost-conscious hospitals and payers. Will patients really have to stay on Brilinta, even if it has been shown to be a superior alternative? Payers are already scrambling to develop tests that can keep patients on the soon-to-be-generic Plavix instead of Effient.
Pharmacy benefit manager Medco Health Solutions is sponsoring the Genotype-Guided Comparison of Clopidogrel and Prasugrel Outcomes Study or GeCCO, which is now under way. It is comparing the two drugs in 14,600 patients who have no problems metabolizing Plavix. The trial, which will be completed in October 2011, could be used to limit Effient to non-responders if the two arms of the trial show equal results.
Bad genes aren't the only reason why people don't respond to Plavix. About a third of patients do not respond to the drug, not just the 2% to 14% with an improper liver gene allele. Some don't respond because of drug-drug interactions or the presence of other risk factors.
Even as the first clinical diagnostic ( Nanosphere 's Verigene CYP2C19) has been submitted for FDA review, data just presented at the European Society for Cardiology annual meeting question the role genetic testing could play in antiplatelet therapy and support the feeling among some cardiologists that such testing does not add clinical value ("Debate On Antiplatelet Gene Testing Continues; First Point-Of-Care Test Filed," The Pink Sheet," Sept. 13. 2010).
Payers are hoping new tests like Accumetrics' VerifyNow P2Y12, which is a platelet function assay, not a gene test, will identify who those patients are. They want to be able to switch those patients to Plavix when it goes generic. To help them out, Accumetrics is sponsoring a trial, Gauging Responsiveness with A VerifyNow Assay-Impact On Thrombosis And Safety or GRAVITAS, that adjusts the Plavix dose based on their level of platelet inhibition. It is scheduled for completion this month with results released early next year.
"All these trials are going to shape the market going forward by generating a lot of pressure from payers," said Decision Resources' Mehta. "A drug like Brilinta will do particular well because it was shown to be much more effective with less liability than prasugrel. But a few months down the line, some of these patients may have a platelet function test or a gene function test and if they respond normally to Plavix, they may get switched to the generic."
"Hospitals are already developing algorithms for whom to treat with each drug," said Nissen. "It will be much more difficult by 2012 because Plavix will be pennies per pill. Some are advocating starting with ticagrelor and then switching to clopidogrel. The question will be how you overlap the drugs."
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