[This is a good overview of the antiplatelet market, which figures to be one of the mega-blockbuster drug categories for many years to come. Among the leading new-drug contenders are LLY, AZN, SGP, and MDCO.]
Troubles with drug-coated stents, popular heart devices implanted to prop open clogged coronary arteries, are intensifying an emerging battle in the burgeoning $6 billion market for a type of medicine that prevents blood clots.
Eli Lilly & Co., AstraZeneca PLC and Schering-Plough Corp. all have new blood-thinning drugs in or nearing late-stage development that are poised to take on Plavix, the blockbuster sold by Bristol-Myers Squibb Co. and Sanofi-Aventis SA. Plavix is a dominant player in the market for therapies that prevent the platelets -- cells in the blood responsible for coagulation -- from clumping together, and it ranks as the world's second best-selling drug (after Pfizer Inc.'s Lipitor).
None of Plavix's major potential competitors is yet on the market. Each is hoping to compete by outdoing Plavix in one way or another -- by more effectively blocking platelets, or involving less bleeding, or offering a product that flushes out of the body more quickly.
The challenges to Plavix are gathering strength as physicians increasingly use the medication in an effort to prevent the rare but serious risk of blood clots forming in drug-coated stents months or years after the devices are implanted. While current regulatory recommendations call for use of Plavix for three to six months depending on the brand of stent, recently issued guidelines from professional societies urge doctors to prescribe the medicine to patients with recently implanted drug-coated stents for at least a year and often longer.
In January, Plavix prescriptions jumped 20% over year-ago numbers, says Catherine Arnold, pharmaceutical industry analyst at Credit Suisse, up from 12% growth during the first half of last year. "It's a big market that's been growing at double-digit rates, and it's been a monopoly," she says. In addition to use in stent patients, the pill is prescribed for patients with histories of recent heart attacks or strokes, poor leg circulation, and a group of heart conditions known as Acute Coronary Syndrome. Some analysts project the market for Plavix and drugs like it will nearly double to $11 billion by 2011.
Plavix, though, comes with worrisome issues: It can cause excessive bleeding, costs up to $6 a pill at retail and takes about five days to clear out of the body, during which time surgical procedures and dental care can be messy and dangerous[as Bill Clinton found out]. Yet stopping treatment for up to a week can heighten the risk of clots forming, especially in stent patients. Bristol-Myers says the drug reduces more significant events like heart attacks than it causes major bleeding.
"There's a balance that has to be struck between the efficacy and the risk of these drugs, and the problem becomes major when you talk about extending therapy from weeks and months to years," says James Ferguson, a cardiologist at the Texas Heart Institute in Houston and an associate professor at Baylor University. "Anything you can do to reduce long-term risk would be a real winner if it doesn't compromise efficacy."
Erin O'Connell Peiffer of Eldersburg, Md. , a 45-year-old stay-at-home mother with heart disease, has been on Plavix and aspirin, another anti-platelet drug, since undergoing a double-bypass surgery in 2001. She worries about costs -- she pays $126.16 out of pocket for a 30-day supply -- but she is especially troubled by frequent nosebleeds, bruising that happens if she's "hit by a feather," and concerns about bleeding if she needs surgery.
After kicking a soccer ball recently with her nine-year-old daughter, she was surprised to see her legs covered with bruises. "Most were about the size of a quarter and were initially an angry purple or black shade and took about ten days to fade away," she says. "If drug companies are looking at something that would give me the same protection without the bleeding, I'd be all for taking it."
Closest to market among the contenders is Lilly's prasugrel, which investors view as the company's most important pill in development [#msg-14220330]. The Indianapolis concern, which is co-developing the drug with Daiichi Sankyo Inc. of Japan, plans to file for U.S. approval later this year. If it gets a green light, prasugrel could be on the market as early as the second half of 2008. Credit Suisse estimates prasugrel could eventually realize up to $3.9 billion in annual sales.
Like Plavix, prasugrel works by binding to a receptor that inhibits platelets' clotting function until the body replenishes the platelets -- about every five days. Prasugrel's potential upside, Lilly says, is that it could act faster than Plavix, block platelets more effectively, and help patients who are resistant to Plavix.
But it may not improve on the bleeding risk that hangs over Plavix. "With any of the stronger anticlotting drugs, we would anticipate a higher bleeding risk," says Christopher Cannon, a cardiologist at Brigham and Women's Hospital, Boston, who led a midstage study of AstraZeneca's compound.
That drug, called AZD6140, is being tested in an 18,000-patient study that London-based AstraZeneca hopes will lead to its filing for regulatory approval in 2009. The drug's blood-thinning properties appear to be reversible in about 36 hours because it detaches from the platelet receptor at low concentrations in the body. That would be a boon, for instance, for patients needing surgery, but patients may need to take the pill twice a day to maintain protection against clots.
Schering-Plough's compound, known as SCH 530348, works by binding selectively to a different receptor on platelets than the other molecules, and the company hopes that will give the drug a bleeding advantage. It could also reduce inflammation in the arteries that can cause vessels to become more prone to blockages. In early studies, the drug was found to work in most patients in one hour -- much more quickly than some competitors.
An indication of SCH 530348's promise came Saturday when researchers presented results of a phase II, or midstage, clinical trial at the American College of Cardiology conference in New Orleans[#msg-18181453]. The trial was designed to look at the safety of using the Schering drug on top of Plavix and aspirin in patients undergoing angioplasty, many of whom got drug-eluting stents. The new agent showed no increase in bleeding, while appearing to decrease the number of cardiovascular events in patients treated.
The drug recently received so-called fast-track review status at the Food and Drug Administration that will hasten its evaluation once the company files an application. The company expects the drug to enter large phase three studies this year, putting it on the market as early as 2010.
Fred Hassan, Schering-Plough's chairman and chief executive, says the product is now the most important in the company's pipeline, with over $1 billion in sales potential due to the large unmet medical need, a novel method of action and the possibility to be administered as a standalone therapy. "This is a product we're following and nurturing," he said. "If this is a transformational opportunity, it could be the breakout we've been looking for that has the same impact on this company that the cholesterol business had a few years ago."
The U.S. unit of Eisai Co. of Japan and the Medicines Co., Parsippany, N.J., are testing new anticlotting drugs as well.[MDCO’s drug is called Cangrelor and, like AZN’ AZD6140, is reversible: #msg-12358790.]
There's no assurance that these drugs will make it to the market. The field is littered with high-profile failures that didn't achieve a safe balance between clotting and bleeding. Moreover, Plavix is scheduled to lose patent protection as soon as 2011 -- shortly after many of the new medicines are expected to become available, and sales were already cannibalized last year by the short-term entrance of generic competition. To compete with cheaper generic pills, drugs like prasugrel will likely have to prove they offer an advantage worth a premium price.
Meanwhile, Bristol-Myers and Sanofi are not giving up on Plavix. At the cardiology conference, long-term data on Plavix from two separate patient registries is being presented in hopes of showing longer-term outcomes in real-world settings.
Bernadette Connaughton, Bristol-Myers's senior vice president for cardiovascular and metabolics, says, "There's a lot of work to be done between now and 2011" and the company is confident that the drug will remain competitive because of its broad array of indications and proven record in 50 million patients. <<
[The above is my characterization, not SGP’s, but it gets the point across that TRA-SCH 530348, as the drug is known, has blockbuster potential beyond anything in SGP’s pipeline from the potential to be added to the antiplatelet SoC consisting of Plavix and aspirin. The phase-3 program will include ~30,000 patients: 10,000 in ACS and almost 20,000 in second-MI/stroke prevention and PAD. The primary endpoint in both trials is a composite of cardiovascular death, MI, stroke, revascularization and, in the ACS trial only, rehospitalization.]
>> Schering-Plough Announces Initiation of Two Phase III Clinical Trials for Novel Selective Antiplatelet Therapy (TRA-SCH 530348)
Wednesday April 18, 5:36 pm ET
Global Trials of Nearly 30,000 Patients to Evaluate Unique and Distinct Investigational Oral Thrombin Receptor Antagonist in Reducing Major Cardiovascular Events, Without Incremental Bleeding
KENILWORTH, N.J., April 18 /PRNewswire-FirstCall/ -- Schering-Plough Corporation today announced plans to initiate two global Phase III large-scale clinical outcomes trials for its novel selective oral antiplatelet therapy, the thrombin receptor antagonist (TRA) SCH 530348. The investigational compound inhibits the most potent stimulus of platelet activation, thrombin, which is a driver of the clotting process. This compound is being evaluated to determine whether it has the potential to provide clinical benefit without the additional bleeding liabilities often found in current therapies. TRA is being developed by Schering-Plough for the treatment and prevention of cardiac events in patients with acute coronary syndrome and those with prior myocardial infarction (MI) or stroke, as well as in patients with existing peripheral arterial disease.
The Phase III clinical development program will include two large clinical trials to evaluate the risk reduction provided by TRA-SCH 530348 plus standard antiplatelet therapy (including aspirin and clopidogrel) compared to placebo plus standard antiplatelet therapy in two patient groups -- acute coronary syndrome (ACS) patients and in secondary prevention in patients who have had a prior MI (heart attack) or stroke, as well as patients with existing peripheral arterial disease. The trials will be conducted in approximately 30 countries at more than 800 sites for each trial.
"The advance of our novel selective antiplatelet TRA to Phase III represents a significant milestone for a compound discovered by scientists at Schering-Plough Research Institute that has the potential to treat a disease with a significant unmet medical need," said Thomas P. Koestler, Ph.D., Executive Vice President and President, Schering-Plough Research Institute.
The Phase II TRA-PCI Trial recently presented at the annual Scientific Sessions of the American College of Cardiology/i2 Summit in New Orleans met its primary endpoint of demonstrating no increase in major and minor bleeding, according to the TIMI bleeding scale, when this investigational antiplatelet compound was added to standard antiplatelet therapy (including aspirin and clopidogrel) among patients undergoing percutaneous coronary intervention (PCI). While not powered to establish efficacy, the study also reported a non-statistically significant 46 percent reduction in cardiovascular events at the highest TRA dose tested compared to standard antiplatelet therapy.
The Phase III Thrombin Receptor Antagonist in Acute Coronary Syndrome (TRA-ACS) trial will be a multinational, randomized, double-blind, placebo- controlled study in approximately 10,000 patients with non ST segment elevation acute coronary syndromes (unstable angina or non-ST elevation MI). Patients will be randomized to either placebo plus standard medical care (including aspirin and clopidogrel) or to TRA once daily plus standard medical care. The Phase III TRA-ACS trial will use the oral 40 mg loading dose and the 2.5 mg maintenance dose. In the Phase II TRA-PCI trial, this dose was not statistically different from placebo in the combination of TIMI Major and Minor bleeding, and, although non-statistically significant, resulted in the greatest reduction in major adverse cardiac events (MACE).
The primary endpoint of the Phase III TRA-ACS trial is the composite of cardiovascular death, MI, rehospitalization for ACS, urgent coronary revascularization, or stroke. The key secondary endpoint is the composite of cardiovascular death, MI or stroke. Patients will be followed for a minimum of one year. This Phase III trial is being conducted by the Duke Clinical Research Institute, Durham, NC.
"Nearly 1.5 million patients with ACS who are discharged annually from hospitals in the U.S., including both primary and secondary discharge diagnoses, are underserved by current treatments," said Robert A. Harrington, M.D., Director of the Duke Clinical Research Institute and lead investigator for the Phase III TRA-ACS Trial. "We are hopeful that encouraging results of the recently-presented Phase II TRA-PCI Trial will be borne out in the broader scale population of ACS patients."
The Phase III Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2P-TIMI 50) trial will be a multinational, randomized, double-blind, placebo-controlled study in approximately 19,500 patients with prior MI or stroke, as well as patients with existing peripheral arterial disease. Patients will be randomized to either placebo plus standard medical care (including aspirin and clopidogrel) or to TRA once daily plus standard medical care. This Phase III trial will use the 2.5 mg maintenance dose.
The primary endpoint of the trial is the composite of cardiovascular death, MI, urgent coronary revascularization, or stroke. The key secondary endpoint is cardiovascular death, MI or stroke. Patients will be followed for a minimum of one year. This Phase III trial is being conducted by the Thrombolysis in Myocardial Infarction (TIMI) Study Group.
"We have long known that patients who experience a heart attack or stroke are at high risk for another serious and potentially life-threatening cardiovascular event," commented Eugene Braunwald, MD, Distinguished Hersey Professor of Medicine, Harvard Medical School; Chairman, TIMI Study Group and Chair of the Phase III TRA 2P-TIMI 50 Trial. "One of our treatment goals is to identify a medication that can reduce that risk without the high incidence of bleeding that frequently accompanies currently available therapies."
Status of Schering-Plough's TRA Clinical Development
The investigational antiplatelet TRA SCH 530348 is being developed by Schering-Plough for the prevention and treatment of atherothrombotic events in patients with acute coronary syndrome and in those with prior myocardial infarction or stroke, as well as in patients with existing peripheral arterial disease.
The U.S. Food and Drug Administration (FDA) had previously granted Fast Track designation to the compound. Fast Track designation allows FDA to expedite review of drugs and biologics for serious or life-threatening conditions that demonstrate the potential to address unmet medical needs. An important feature of Fast Track designation is that it emphasizes the critical nature of close, early communication between the FDA and the sponsor company to improve the efficiency of product development.
Thrombosis may result in partial or complete blockage of arteries in the heart, brain or periphery. This process is the underlying mechanism of most acute vascular events, including acute coronary syndromes (ACS), such as myocardial infarction (MI), and ischemic stroke, which are the leading causes of death. Platelets are activated at the site of atherosclerotic plaque rupture in arteries and release substances that initiate aggregation and clot formation, and thrombin is the most potent activator of platelets. Drugs that block platelet activation by other mechanisms, such as the thromboxane- or ADP-mediated pathways, have shown reduction in such clinical events, but events continue to occur despite these therapies. There is, thus, a need for novel agents that specifically modify the actions of thrombin, the most potent activator of platelets. TRA binds selectively to the thrombin receptor on platelets (PAR-1), and is therefore a member of a potentially new class of drugs called thrombin receptor antagonists. Importantly, Schering-Plough's TRA is being investigated to determine whether it has the potential to provide clinical benefit through inhibition of this thrombin-mediated platelet activation without the liability of increased bleeding, a tendency associated with drugs that block thromboxane or ADP pathways. Specifically, this compound is being investigated as a selective oral antiplatelet agent for patients with established vascular disease, with the intent to demonstrate incremental benefit on top of standard antiplatelet (including aspirin and clopidogrel) and other antithrombotic therapies, with no significant increase in bleeding. Clinical studies have shown no increase in bleeding time or prolongation in coagulation times (aPTT or PT) with TRA-SCH 530348.
In the Phase II TRA-PCI Trial, TRA was generally well-tolerated at each of the studied dosing regimens. The discontinuations due to any adverse events were 6 percent with TRA and 5 percent with placebo.
Adverse findings reported in preclinical animal toxicology studies have generally been at high doses and been species specific. Changes such as these are not uncommonly seen in animal toxicology studies at high doses. None of these findings is considered to predict human risk. These include reversible phospholipidosis, retinal vacuolation, hepatic thrombi, skeletal muscle degeneration and lymphoid necrosis in rats; urinary bladder, ureter, epididymidal and renal histopathology changes, sertoli cell vacuolation and phospholipidosis in mice; transient acute inflammatory changes, swollen lymph nodes, kupffer cell hyperplasia, tremors/convulsion and phospholipidosis in monkeys. These events occurred at multiples of >3 to >300 times the exposure at the human therapeutic dose.
About Schering-Plough Corporation
Schering-Plough is a global science-based health care company with leading prescription, consumer and animal health products. Through internal research and collaborations with partners, Schering-Plough discovers, develops, manufactures and markets advanced drug therapies to meet important medical needs. Schering-Plough's vision is to earn the trust of the physicians, patients and customers served by its approximately 33,500 people around the world. The company is based in Kenilworth, N.J., and its Web site is www.schering-plough.com. <<
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