Drug and Market Development

• Cardiovascular disease is still the world’s leading cause of death, even after a couple of decades of declining death rates. Expenditures for cardiovascular drugs account for about one-fifth of total expenditures for all types of drugs. As the population ages, the market will continue to grow, ensuring continued interest and activity in the research and development of new drugs for the treatment of cardiovascular disease.

• Cardiovascular drug development proceeds in three ways. First, novel drugs that are first in their class are discovered, developed, proven in clinical trials, and launched. Second, based on the success of drugs that are first in their class, similar drugs are developed and launched. Some of these may be equivalent to the first drug, while others might be second- or third-generation drugs with real advantages over the first drug. Third, existing drugs are evaluated and proven effective in new indications. Subsequent approval for expanded indications can significantly increase market share and sales.

• Several companies have traditionally been associated with strong cardiovascular drug development. These include AstraZeneca plc, Bristol-Myers Squibb Co., Merck & Co., Inc., Pfizer, Inc., and Sanofi-Synthélabo. Numerous smaller companies also have strong cardiovascular drug pipelines.

• In the next ten years there will be significant developments in the market for more statins (lipid-lowering drugs), calcium channel blockers, oral platelet GPIIb/IIIa antagonists, other anticoagulants and antithrombotics, and drugs to prevent restenosis. Beyond ten years, genomics will strongly influence cardiovascular drug development as new drug targets will have been discovered.

• The author of this article is George B. Zavoico, Ph.D., president of Cronamere Consulting Group LLC, Greens Farms, CT.

Foundations

The decline in mortality from cardiovascular disease (CVD) that the world’s population has been experiencing for the past 20 years had its foundation in the 1960s and 1970s. Public health initiatives taught us about risk factors associated with CVD, and for the most part, we as a population have listened and learned. Total deaths due to CVD increased annually throughout the 20^th century until the late 1960s and early 1970s when deaths due to CVD in the US leveled off at about 950,000 per year. Since the American population has continued to increase, the age-adjusted death rate per 100,000 Americans has actually been declining almost every year since 1980. In the 16-year period for which data is available, the age-adjusted death rate for CVD declined from about 530 to 375 deaths per 100,000 Americans, a remarkable decrease of about 30%. Going back even further, there has been a 55% decrease in the age-adjusted death rate for CVD since 1950, when the rate was 840 per 100,000 Americans.

The dramatic decrease in deaths due to CVD is attributed to a number of factors. In addition to patient education and obvious changes in lifestyle to promote a healthy cardiovascular system, there have been many important life-saving developments in the management and prevention of CVD. These include much better diagnostic tools, faster and better-trained emergency care, advances in interventional devices and surgical techniques and, of course, new and better drugs. But despite this progress, CVD is still the leading cause of death in men and women of all races in the US. In 1996, 453,297 American men and 505,930 American women died of CVD (total deaths = 959,227). Cancer, which is the second leading cause of death in the US, caused the deaths of 539,533 American men and women. Other leading causes of death in the US are chronic obstructive pulmonary disease (ranked third, with 106,027 deaths), accidents (ranked fourth, with 93,874 deaths), and pneumonia and influenza (ranked fifth, with 83,727 deaths).

CVD is a global problem. The Russian Federation has the dubious distinction of having the highest death rate due to CVD: 1,310 per 100,000 population. Most of Eastern Europe, Argentina, Scotland, Ireland, Finland, England, and Wales have higher CVD death rates than the US. In contrast, many countries surrounding the Mediterranean Sea, including Greece, Israel, Italy, Spain, and France, have markedly lower death rates, ranging from 225 to about 350 per 100,000 population. Among the industrialized nations, Japan has the lowest death rate due to CVD: 201 per 100,000 population. CVD death rates vary widely all over the world for a variety of reasons, but when considered as a fraction of deaths from all causes, deaths from CVD account for 20–50% of all deaths in most countries. In the US, for example, 41.4% of all deaths in 1996 were due to CVD.

Cardiovascular Disease

An estimated 58,800,000 Americans, or about one-fifth of the entire US population, has one or more types of CVD (see Table 5) and all of these patients receive some type of medical therapy. Some types of CVD, such as coronary heart disease (CHD) or stroke, can occur acutely and without warning, while other types, such as hypertension and hyperlipidemia, may progress more slowly. During an acute event, patients are generally treated aggressively with drugs, intervention or surgery, or a combination of both. Survivors are shifted to chronic medical therapy during recovery to prevent recurrent or new events. Slowly progressing CVD is often detected early and can usually be managed by chronic drug therapy. Thus, cardiovascular drugs are either designed for acute medical therapy to improve clinical outcomes in the short-term or for long-term management of chronic CVD.

Identification of risk factors for CVD provided the rationale for development of preventive therapy administered to patients who are asymptomatic for CVD. Identification of cigarette smoking as a significant risk factor has spawned an entire industry of medications to help stop smoking. High serum cholesterol is also a powerful risk factor, and millions of asymptomatic people are taking some type of lipid-lowering medication. Millions more are taking aspirin daily after a meta-analysis of 25 clinical trials (Antiplatelet Trialists’ Collaboration) showed that antiplatelet therapy, especially with aspirin, conferred a significant 25% overall reduction in the risk of developing a recurrent adverse vascular event. Even though this benefit was restricted to patients who had already experienced a stroke, transient ischemic attack (TIA), myocardial infarction (MI), or angina, many people who never had any symptoms of CVD take aspirin daily in the hope of preventing a primary vascular event. However, it has not yet been firmly established that aspirin is an effective prophylactic for primary prevention. Indeed, daily aspirin is associated with a slight increase in the risk of gastrointestinal bleeding and ulceration and hemorrhagic stroke.

The combination of effective new drugs for acute care and prophylaxis in CVD, coupled with the high incidence of these diseases, keeps cardiovascular therapeutics firmly entrenched as the largest therapeutic category in terms of sales. In 1998, IMS Health estimated that pharmaceutical sales in the world’s twelve largest markets reached $185.4 billion. Total estimated sales of cardiovascular drugs were $36.9 billion, about $7 billion more than drugs for alimentary and metabolic diseases, the second-ranked therapeutic category. Thus, sales of cardiovascular drugs contributed almost 20% of the total pharmaceutical market. IMS Health also calculated that cardiovascular drug sales grew at an annual rate of 7%.

Cardiovascular Drug Classes

Cardiovascular drugs can be classified by their mechanism of action or indication (see Table 6). Several classes of cardiovascular drugs, however, are indicated for more than one type of CVD. Angiotensin converting enzyme (ACE) inhibitors, for example, were first approved for the treatment of hypertension, but have since been proven useful in the treatment of congestive heart failure (CHF) and in the prevention of recurrent cardiac events in patients recovering from their first MI.

Several cardiovascular drugs still in widespread use were launched decades ago. These include digoxin [Glaxo Wellcome’s (Hertfordshire, UK) Lanoxin^® and many generics], a positive inotropic agent and cardiac glycoside for the treatment of CHF; unfractionated heparin (generics) and warfarin [DuPont Pharmaceuticals’ (Wilmington, DE) Coumadin^® and generics], both anticoagulants for the treatment of thrombotic disorders; and spironolactone [G.D. Searle’s (Skokie, IL) Aldactone^® and generics], an aldosterone antagonist and potassium-sparing diuretic used in the treatment of hypertension. Several drugs that were first in their class were introduced in the 1970s and 1980s, and it is probably no coincidence that it was during this period that mortality from CVD began to decline.

• The first ACE inhibitor, Squibb’s (now Bristol-Myers Squibb; Princeton, NJ) Capoten^® (captopril), was launched in the late 1970s. Captopril is now available from generic manufacturers.

• The first thrombolytic agents, Abbott Laboratories’ (Abbott Park, IL) Abbokinase^® (urokinase) and Astra’s (now AstraZeneca; London, UK) Streptase^® and Pharmacia’s (now Pharmacia & Upjohn; Kalamazoo, MI) Kabikinase^® (both streptokinase) were launched in 1977.

• The utility of antiplatelet agents was acknowledged in 1980 when the FDA approved the use of aspirin for the prevention of death and nonfatal stroke in patients who have had an ischemic stroke or TIAs. In 1985, the FDA expanded the indications for aspirin by approving its use for the prevention of death and nonfatal MI in patients with a previous MI or unstable angina.

• The first antilipemic agent of the HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor class, Merck’s (Whitehouse, NJ) Mevacor^® (lovastatin), was launched in 1987.

The efficacy and clinical benefit derived from these new classes of drugs were dramatically better than any existing drugs at the time. Consequently, many other drugs of the same class were developed and launched, some with improved efficacy, safety, or pharmacokinetics, or with new formulations that enabled once-daily dosing. Moreover, the tremendous clinical benefit of these new therapeutic approaches spawned discovery and development programs that focused on related targets. For example, angiotensin II receptor antagonists, launched by the mid-1990s, are a direct result of the success of ACE inhibitors. Platelet GPIIb/IIIa antagonists, also first launched in the mid-1990s, are a more effective way to inhibit platelet activation and aggregation, a therapeutic approach proven by aspirin.

Advances made over the past ten years can be characterized in three ways. First, the development and launch of drugs that were first in their class. Second, the development and launch of more drugs of an existing class with the belief that the newer ‘second- or third-generation’ drugs would have some advantages that would enable them to grab a significant share of the market. Advantages might be real improvements in pharmacokinetics, efficacy, or safety, or more efficient business practices such as the deployment of a larger and better trained and experienced sales force or, as has become more common recently, more direct-to-consumer or direct-to-physician advertising. Third, the clinical testing and approval of drugs of an existing class for other indications, thereby expanding their market and increasing their potential for greater sales.

Significant New Drug Approvals of the Past Ten Years

The last decade has seen a tremendous expansion in the availability and use of cardiovascular agents. Two major new drug classes were introduced in the 1990s. Centocor, Inc. (Malvern, PA) developed and launched ReoPro^® (abciximab), the first platelet GPIIb/IIIa antagonist. ReoPro is a chimeric monoclonal antibody fragment directed against the platelet fibrinogen receptor, glycoprotein (GP) IIb/IIIa. It was launched in 1995 for patients undergoing balloon angioplasty (percutaneous transluminal coronary angioplasty, or PTCA) who are at high risk for acute arterial occlusion. In 1997, ReoPro was approved as an adjunct to prevent ischemic complications in patients undergoing a variety of percutaneous coronary interventions and in patients with unstable angina not responding to other medical therapy prior to a planned percutaneous intervention. A Phase III clinical trial, GUSTO IV, has begun that will evaluate ReoPro in the medical management of unstable angina and, in combination with low-dose thrombolytic agents, acute MI. ReoPro has also been evaluated in a Phase II clinical trial for the treatment of ischemic stroke. Centocor and Eli Lilly & Co. (Indianapolis, IN) co-market ReoPro; in 1998, sales were $365 million. Johnson & Johnson (New Brunswick, NJ) acquired Centocor for $4.9 billion in 1999.

Merck & Co. and DuPont Pharmaceuticals developed and launched Cozaar^® (losartan), the first angiotensin II receptor antagonist for the treatment of hypertension, when the two companies had a joint venture called the DuPont Merck Pharmaceutical Co. Several other angiotensin II receptor antagonists have been launched since Cozaar’s introduction in 1995. These are Diovan^® (valsartan) from Novartis (Basel, Switzerland), Aprovel^®/Avapro^®/Karvea^® (irbesartan) from Sanofi-Synthélabo (Paris, France) and Bristol-Myers Squibb, Atacand^® (candesartan) from AstraZeneca, Tevesten^® (eprosartan) from SmithKline Beecham plc (Middlesex, UK), and Micardis^® (telmisartan) from Boehringer Ingelheim GmbH (Ingelheim, Germany). Wyeth-Ayerst Laboratories (Philadelphia, PA), a division of American Home Products (Madison, NJ), was developing an angiotensin II receptor antagonist called Verdia^® (tasosartan), but it withdrew the NDA in 1998 because of potential liver toxicity. Verdia may have been the exception in this class of drugs that are generally associated with fewer adverse events than ACE inhibitors. Increased safety, coupled with a greater average reduction in blood pressure, led some to predict that this class of drugs will replace ACE inhibitors as the treatment of choice in patients with hypertension.

Sanofi (before its merger with Synthélabo) developed a thienopyridine inhibitor of platelet aggregation called ticlopidine, which would become the company’s biggest selling product. Ticlopidine, launched in France as Ticlid^® (Panaldine^® in Japan) in 1978 (1992 in the US), reduces the risk of thrombotic stroke in patients who have already had a stroke or TIAs. Unfortunately, ticlopidine is associated with several adverse side effects; particularly neutropenia, gastrointestinal upset, and skin rashes. Sanofi very slightly modified ticlopidine’s chemical structure and came up with a second generation thienopyridine platelet inhibitor called clopidogrel, which was safer and more potent. In partnership with Bristol-Myers Squibb, clopidogrel was evaluated in a very large clinical trial called CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events), which enrolled 19,185 patients with a recent ischemic stroke or MI, or symptomatic peripheral arterial disease. Patients were administered clopidogrel or aspirin daily for one to three years. Clopidogrel produced an additional 8.7% reduction in the risk of ischemic stroke, MI, or vascular death compared to aspirin. Based on the CAPRIE data, aspirin and clopidogrel are predicted to prevent 19 and 24 major vascular events, respectively, for every 1,000 patients treated for one year. Clopidogrel was launched as Plavix^® or Iscover^® in 1998.

By the time Warner-Lambert (Morris Plains, NJ) and Pfizer (New York, NY) launched their HMG CoA reductase inhibitor Lipitor^® (atorvastatin) in 1997, several other drugs of this class were already available. These were Merck’s Mevacor^® (lovastatin) and Zocor^® (simvastatin), Bristol-Myers Squibb’s Pravachol^® (pravastatin), and Novartis’ Lescol^® (fluvastatin). Bayer’s (Leverkusen, Germany) Baycol^® (cerivastatin) was launched after Lipitor. Lipitor was introduced into a market that was worth $7.7 billion in 1997, but despite the competition, Lipitor rapidly acquired a significant market share. This was because Lipitor was the first ‘superstatin’, a second-generation HMG CoA reductase inhibitor that produced a significantly greater decrease in serum low density lipoproteins (LDL) and triglycerides than any of the other statins. By 1998, Lipitor’s worldwide sales were $2.2 billion and it was receiving 42% of all new statin prescriptions in the US. Since the launch of Lipitor, all other statins have lost market share.

Norvasc^® (amlodipine), a second-generation calcium channel blocker of the dihydropyridine class, has become the world’s best selling drug for the treatment of hypertension since its launch by Pfizer in 1990. Norvasc, with sales of $2.575 billion in 1998, is a more selective calcium channel blocker in vascular smooth muscle cells than cardiac cells; hence, it has little or no negative inotropic effect. It provides reliable control of hypertension and angina with once-daily dosing due to its long plasma half-life of 35 to 50 hours. Norvasc is also very well tolerated. Most calcium channel blockers are indicated for the treatment of hypertension, angina, or both, but Norvasc, in addition to blocking calcium channels, has antiproliferative, membrane-modifying, and antioxidant activities that may be beneficial in other CVDs. Thus, Pfizer is not letting Norvasc rest on its laurels as an antihypertensive agent. In two clinical trials, Norvasc was shown to provide clinical benefit in patients with advanced CHF and CHD. PRAISE (Prospective Randomized Amlodipine Survival Evaluation) showed that Norvasc significantly reduced the incidence of sudden deaths (21%) and pump failure deaths (6.6%) compared to placebo in patients with advanced CHF who were already taking ACE inhibitors, diuretics, and digitalis. PREVENT (Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial) showed that Norvasc reduced the incidence of fatal and nonfatal cardiovascular events by 31%, the need for angioplasty and coronary artery bypass grafting by 46%, and the hospitalization rate for severe angina by 35%.

Low molecular weight heparins (LMWHs) were developed and launched in Europe long before they were introduced in the US. At least eight LMWHs are available in Europe, but only three in the US. In 1993, Rhône-Poulenc Rorer’s (Collegeville, PA) Lovenox^® (enoxaparin) became the first LMWH approved in the US for short-term (7–14 days) prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism following hip or knee replacement surgery. The company has continued to evaluate Lovenox for other indications and to apply for and receive additional marketing approvals. In 1997, the FDA approved Lovenox for the prevention of DVT and pulmonary embolism in patients undergoing abdominal surgery. In 1998, Lovenox was approved for the following: (1) long-term prevention (3 weeks) of DVT and pulmonary embolism in patients undergoing hip or knee replacement surgery; (2) prevention of ischemic complications of unstable angina and non-Q-wave MI (with aspirin); (3) inpatient treatment (with warfarin) of acute DVT with and without pulmonary embolism; and (4) outpatient treatment (with warfarin) of acute DVT without pulmonary embolism. Lovenox is still being considered for more indications. It is in Phase III clinical trials for long term treatment of unstable angina and as adjunctive therapy in intravascular stent placement. Another potential indication is prevention of DVT in trauma patients.

When the FDA approved SmithKline Beecham’s Coreg^®/Kredex^® (carvedilol) for the treatment of symptomatic CHF in 1997, no other b-adrenoreceptor had been approved for this indication. Coreg was originally approved and launched for the treatment of hypertension in 1995. Coreg is also a a1-adrenoreceptor blocker and antioxidant. Whether these properties contribute to its efficacy in treating patients with CHF is unknown. The US Carvedilol Heart Failure Program evaluated Coreg for the treatment of CHF, but the study was terminated early when the data and safety monitoring board found that Coreg caused a 65% risk reduction in overall mortality compared to placebo in patients with ischemic and nonischemic cardiomyopathies. In 1998, Coreg had sales of $118 million.

The ‘reperfusion era’ in treating acute MI began in the late 1980s after streptokinase and other first generation thrombolytic agents showed a dramatic (nearly 50%) reduction in mortality in patients treated within one hour of the onset of symptoms. Soon thereafter, Genentech developed and launched a recombinant tissue plasminogen activator (t-PA) called Activase^®/Actilyse^®/Activacin^®/GRTPA^® (alteplase), which provided a modest but significant reduction in 30-day mortality and the incidence of nonfatal stroke compared to streptokinase. Activase became the thrombolytic agent of choice in the US, but due to its higher cost, it did not capture as much market share in Europe. Genentech pursued further indications for the drug and, in 1990, Activase was approved for the treatment of acute pulmonary embolism (streptokinase and urokinase were already approved for this indication). More significantly, Genentech discovered that patients with ischemic stroke who were treated with Activase within three hours of the onset of symptoms had a significant improvement in four different stroke assessment scales three months after treatment when compared to patients treated with placebo. There was a net benefit even though thrombolytic therapy was associated with an increased risk of intracranial hemorrhage. When Activase was approved for this indication in the US in 1997, it represented the first new therapeutic approach to the treatment of ischemic stroke in years. Unfortunately, further studies showed that Activase was no better than placebo if patients were treated more than three hours after the onset of symptoms.

Innovators in Cardiovascular Drug Development

Several companies stand out as having established a franchise in cardiovascular drugs, most of whom continue to be active in this therapeutic area.

AstraZeneca plc. The Astra AB and Zeneca Group plc merger in 1998 combined two strong cardiovascular drug franchises. Astra’s best-selling cardiovascular drug was Seloken^®/Toprol XL^® (metoprolol), a b-adrenergic blocker with sales of SEK 3,568 million in 1998. Seloken is indicated for the treatment of hypertension, MI, angina, CHF, and arrhythmias. The company’s vasoselective calcium antagonist Plendil^® (felodipine), indicated for hypertension and angina, had sales of SEK 2,625 million in 1998. Astra’s other cardiovascular drugs include a nitrate vasodilator called Imdur^® (isosorbide mononitrate), a long-acting ACE inhibitor called Ramace^® (ramipril) that was licensed from Hoechst, and an HMG CoA reductase inhibitor called Canef^® (fluvastatin) that was licensed from Novartis. Astra and Takeda Chemical Industries, Ltd., of Japan also jointly developed a new angiotensin II receptor antagonist called Atacand^® (candesartan). Sales of Atacand leapt from SEK 8 million in 1997 to SEK 242 million in 1998. Astra also marketed several drug combinations including felodipine and metoprolol as Logimax^®, felodipine and ramipril as Unimax^®, and felodipine and Merck’s enalapril as Lexxel^® (in the US).

Zeneca’s major cardiovascular drug Zestril^® (lisinopril) is an ACE inhibitor licensed from Merck. Zestril sales totaled £677 million in 1998. The company’s b-adrenergic blocker, Tenormin^® (atenolol), had sales of £302 million in 1998. Another b-adrenergic blocker called Inderal^® (propranolol) and a sustained-release calcium antagonist called Sular^® (nisoldipine) that was licensed from Bayer AG round out Zeneca’s line-up of cardiovascular drugs. Like Astra, Zeneca was also marketing several drug combinations, including atenolol and nifedipine as Nif-Ten^®; atenolol and chlorthalidone, a thiazide diuretic, as Tenoretic^®; and lisinopril and hydrochlorothiazide, another diuretic agent, as Zestoretic^®. AstraZeneca was obliged to divest itself of several drugs in certain European markets because of the merger, but this did not dramatically change the company’s cardiovascular drug offerings.

AstraZeneca has three cardiovascular drugs in Phase II clinical trials: (1) ZD-4522 (S-4522), an improved HMG CoA reductase inhibitor licensed in from Shionogi & Co., Ltd. (Osaka, Japan); (2) melagatran, an orally available small molecule thrombin inhibitor; and (3) AR-C 69931, an intravenously administered platelet purinoceptor antagonist indicated for the treatment of unstable angina. Further behind in development are an orally available platelet purinoceptor antagonist, more thrombin inhibitors, a factor Xa inhibitor, and an endothelin receptor antagonist.

Bristol-Myers Squibb (BMS). Pravachol^® (pravastatin), an HMG CoA reductase inhibitor indicated for primary and secondary prevention of coronary and cardiovascular events, is the company’s best selling drug. Sales in 1998 were $1.643 billion, a 14% increase from 1997. Other cardiovascular drugs in the company’s stable include Monopril^® (fosinopril), a second generation ACE inhibitor administered once-daily for the treatment of hypertension or CHF; Plavix^® (clopidogrel), an inhibitor of platelet aggregation that reduces the risk of stroke, MI, and peripheral vascular disease in patients with atherosclerosis; and Avapro^® (irbesartan), an angiotensin II receptor blocker for the treatment of hypertension. Monopril, Plavix, and Avapro generated $380 million (16% increase), $144 million, and $120 million in sales, respectively. Plavix and Avapro, both developed in collaboration with Sanofi-Synthélabo, were launched in 1998. Plavix is undergoing clinical studies for further indications. CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events) will determine whether clopidogrel in combination with aspirin is more effective than aspirin alone in the prevention of acute coronary syndromes. CLASSICS (Clopidogrel Aspirin Stent International Cooperative Study) and CREDO (Clopidogrel for Reduction of Events During Extended Observation) will evaluate clopidogrel plus aspirin in patients receiving stents and for long-term therapy, respectively.

BMS is now developing omapatrilat (Vanlev™), a dual function inhibitor of NEP and ACE [drugs with this activity are also called vasopeptidase inhibitors], for the treatment of hypertension and CHF. NEP is an enzyme that degrades several natriuretic peptides that play a role in sodium balance, induce vasodilation and inhibit cell proliferation. Preclinical and clinical evidence suggests that inhibition of both enzymes provides synergistic benefit compared to inhibition of either enzyme alone. Clinical data indicates that omapatrilat may lower systolic and diastolic blood pressure more than an ACE inhibitor alone. Omapatrilat is in Phase II and III clinical trials for CHF and hypertension, respectively, and the company hopes to have filed for regulatory approval by the end of 1999. BMS is also developing an endothelin antagonist for the treatment of CHF and is studying a triple function inhibitor of NEP, ACE, and endothelin converting enzyme (ECE).

Merck & Co. launched the first HMG CoA reductase inhibitor, Mevacor, in 1987, and then another, called Zocor^® (simvastatin), in 1991. Together, these drugs generated $4.694 billion in revenues in 1998. The company markets two ACE inhibitors, Vasotec^® (enalapril) and Prinivil^® (lisinopril), and has combined both with hydrochlorothiazide, a diuretic agent (Vaseretic^® and Prinzide^®, respectively). Merck, through a joint venture with E.I. du Pont de Nemours & Co. known as DuPont Merck Pharmaceutical Co., developed and launched the first angiotensin II receptor antagonist Cozaar in 1995 (Merck sold its share of the joint venture to DuPont in 1998). Merck also combined losartan, the active ingredient of Cozaar, with hydrochlorothiazide (Hyzaar^®), which was also launched in 1995. The company’s ACE inhibitors and angiotensin II receptor antagonists together generated another $4.214 billion in revenue in 1998. In 1998,

Merck launched Aggrastat^® (tirofiban), one of the first short-acting, nonpeptide platelet GP IIb/IIIa antagonists for intravenous infusion. Aggrastat is indicated for the prevention of ischemic events in patients with unstable angina or non-Q-wave MI, including patients scheduled for interventional procedures such as balloon angioplasty or coronary bypass surgery.

Merck is working to expand the indications for Cozaar and Hyzaar. Four clinical trials are underway to determine whether Cozaar can prolong survival and prevent cardiovascular and renal adverse events in patients with hypertension. Merck also hoped that Cozaar would prove to be superior to ACE inhibitors in comparative clinical trials of the treatment of CHF. The results of these trials would provide the basis for approval of the drug for CHF by the FDA. Cozaar has already been approved for the treatment of CHF in at least fifteen countries. Unfortunately for Merck, the results of ELITE-II (Evaluation of Losartan in the Elderly-II), revealed in November 1999, showed that Cozaar and captopril were equivalent in efficacy in treating patients with CHF. The mortality rate was 18% in the Cozaar group and 16% in the captopril group, a difference that was not significant. Consequently, Merck announced that it will not seek approval from the FDA for CHF and will request that the drug not be used as first-line therapy for CHF in countries where it has already been approved for this indication. However, there were fewer adverse events in patients administered Cozaar, so the drug may be useful in patients with CHF who cannot tolerate ACE inhibitors. Merck’s cardiovascular drug pipeline, however, has thinned out. The company reportedly has small molecule, orally active platelet GP IIb/IIIa antagonists and selective thrombin inhibitors in preclinical development.

Pfizer, Inc. Norvasc, described above, is Pfizer’s best-selling drug and the lead product in a strong cardiovascular drug franchise. Pfizer also developed and launched Procardia^® (nifedipine), one of the first calcium channel blockers, but Procardia sales have been declining as Norvasc has become more widely used. Procardia generated $714 million in sales in 1998. Cardura^® (doxazosin), an a1-adrenergic blocker, is another of Pfizer’s antihypertensive agents. Cardura, which had sales of $688 million in 1998, is also indicated for benign prostatic hyperplasia. In addition to the antihypertensive drugs, Pfizer markets Lipitor, an HMG CoA reductase inhibitor described previously, through an alliance established with the drug’s original developer, the Warner-Lambert Co.

Pfizer is working to expand the indications of its best selling cardiovascular drugs. At least five more clinical trials with Norvasc have begun. PRAISE-2 is a follow-on trial to PRAISE that will further evaluate Norvasc in the treatment of patients with non-ischemic CHF. The other trials will directly compare Norvasc, alone or in combination with an ACE inhibitor, to other forms of therapy, including ACE inhibitors and diuretics, in reducing the incidence of fatal coronary artery disease and nonfatal MI in patients with hypertension or coronary artery disease. Another clinical trial will evaluate Norvasc in the treatment of renal disease. Pfizer and Warner-Lambert have initiated TNT (Treating to New Targets), a five-year trial to determine if lowering LDL cholesterol levels to even lower target levels with higher doses of Lipitor will provide additional benefits.

Pfizer has also developed a highly selective potassium channel blocker called Tikosyn^® (dofetilide) for the maintenance of normal sinus rhythm in patients with atrial fibrillation or atrial flutter of greater than one week duration who have been converted to normal sinus rhythm. The FDA approved Tikosyn in October 1999. The company has also initiated a discovery and development program for a small molecule direct thrombin inhibitor.

Sanofi-Synthélabo is a French company formed by the merger of Sanofi and Synthélabo in 1999. Both companies had strong cardiovascular drug portfolios. The company’s best selling cardiovascular drugs are Ticlid^®/Panaldine^® (ticlopidine), an inhibitor of platelet aggregation with sales of Fr 5.563 billion in 1998; Cordarone^® (amiodarone), an antiarrhythmic agent with sales of Fr 2.601 billion; and Fraxiparine^® (nadroparin), a LMWH indicated for the treatment and prophylaxis of venous thrombosis with sales of Fr 1.606 billion. Like some other LMWHs, Fraxiparine was shown to be efficacious in the treatment of patients with unstable angina, clearing the way for expanded indications. Sanofi-Synthélabo is also marketing Aprovel^®/Avapro^®/Karvea^® (irbesartan) and Plavix^®/Iscover^® (clopidogrel), with sales of Fr 1.182 billion and Fr 893 million, respectively. Both drugs were developed in collaboration with Bristol-Myers Squibb. Late in 1998, the company launched CoAprovel^®, a combination of irbesartan and hydrochlorothiazide. Other cardiovascular drugs include Tildiem^® (diltiazem), a calcium antagonist for the treatment of hypertension and angina (Fr 1.056 million); Primacor^®/Corotrope^® (milrinone), an inotropic agent and vasodilator for the treatment of CHF (1998 sales of Fr 762 million); Aspégic and derivatives (lysine acetylsalicylate and combinations) for the prevention of stroke and MI (Fr 681 million); Kerlone^® (betaxolol), a b-adrenergic blocker for the treatment of hypertension and angina (Fr 418 million); and Lipanor^®/Modalim^® (ciprofibrate), a lipid-lowering agent of the fibrate class (Fr 368 million).

The company continues to invest in cardiovascular drug development. Novastan^® (argatroban), a direct thrombin inhibitor, is under registration in Europe for the treatment of heparin-induced thrombocytopenia and in Phase II as an adjunctive agent in thrombolysis for treatment of an acute MI. The synthetic pentasaccharide SR 90107, an inhibitor of coagulation factor Xa that is in Phase III for the prevention and treatment of thrombosis, is being developed together with Organon (West Orange, NJ), the pharmaceutical division of Akzo Nobel N.V. (Arnhem, The Netherlands). A related pentasaccharide (SR 34006) is in Phase IIa for the same indication, but SR 34006 has a longer half-life that will enable once-weekly injections. Dronedarone (SR 33589), an antiarrhythmic agent with similar efficacy but better tolerability than amiodarone, is in Phase IIb. The company also has two platelet GP IIb/IIIa antagonists and a synthetic oligosaccharide with anti-factor Xa and antithrombin activity in preclinical development.

Small Companies to Watch

Many new cardiovascular drugs will certainly emerge from the major pharmaceutical companies in the next ten years, but several small biotechnology or biopharmaceutical companies engaged in cardiovascular drug development also have promising pipelines with novel drugs. Several of these companies and their most advanced drug candidates or drug development programs are listed in Table 8 [cardiovascular drug development programs that have not progressed beyond the research phase are not included].

Cardiovascular Drug Development in the Next Ten Years

Cardiovascular drugs launched in the next five to ten years will largely be class extensions and new indications for existing drugs, although several first-in-class cardiovascular drugs are in late stage clinical trials. Developments to watch include:

• Statins. Look for the approval and launch of new ‘superstatins’. Recent clinical trial data show that higher than currently approved doses of Baycol reduced cholesterol and LDL to levels comparable to those found with Lipitor. The data are currently under review by the US FDA. AstraZeneca’s superstatin, ZD4522, is in Phase II clinical trials. If either prove to be equivalent in efficacy to Lipitor, the statin market will become even more competitive.

• Calcium channel blockers. Following on the tremendous success of Norvasc, look for the approval and launch of more long-acting lipophilic calcium channel blockers of the dihydropyridine class. Several have already been launched in various markets, including Zanidip^®/Zanedip^® (lercanidipine) by Recordati SpA (Milan, Italy) and licensees, Hypoca^®/Vasextan^® by Yamanouchi Pharmaceutical Co., Ltd. (Tokyo, Japan), and Motens^® (lacidipine) by Boehringer Ingelheim GmbH. A new class of calcium channel blocker was launched in 1997 only to be withdrawn from the market in 1998. This was Roche’s Posicor^® (mibefradil), the first combination T-type and L-type calcium channel blocker (other calcium channel blockers are selective L-type calcium channel blockers). Posicor was approved for the treatment of hypertension and angina, but it was found to have unacceptable drug interactions that increased the incidence of adverse events, including mortality.

• Oral platelet GPIIb/IIIa antagonists. The efficacy and safety, as well as commercial success, of ReoPro provided the rationale for the development of orally active GPIIb/IIIa antagonists. Unfortunately, the first drugs of this type to enter Phase III clinical trials, G.D. Searle’s xemilofiban and orbofiban and Roche’s and Genentech’s Xubix^® (sibrafiban), failed to show greater benefit in patients with acute coronary syndromes and development was discontinued. Other orally available GPIIb/IIIa platelet antagonists in late-stage clinical trials include DuPont’s roxifiban, Boehringer Ingelheim’s fradafiban and lefradafiban, COR Therapeutics’ (South San Francisco, CA) cromafiban, SmithKline Beecham’s lotrafiban, and Merck KgaA’s and Yamanouchi’s gantofiban.

• Other anticoagulants and antithrombotics. Two direct thrombin inhibitors, Hoechst Marion Roussel’s (Frankfurt, Germany) Refludan^® (lepirudin) and Rhône-Poulenc Rorer’s Revasc^® (desirudin), were recently launched. Other direct thrombin inhibitors have been launched in regional markets or are awaiting approval. Mitsubishi Chemical Corp.’s (Tokyo, Japan) Slonnon^®/Novastan^® was launched in Japan and is awaiting approval in the US (licensed to Texas Biotechnology Corp.; Houston, TX) and Europe (licensed to Sanofi-Synthélabo). The Medicines Company’s (Cambridge, MA) Angiomax™ (bivalirudin), previously known as hirulog, is also awaiting approval. Numerous other companies are also developing direct thrombin inhibitors. A variety of other novel anticoagulants and antithrombotics are in various stages of development. Several companies are developing factor Xa inhibitors. Synthetic pentasaccharides from Sanofi-Synthélabo (described above), DX-9065a from Daiichi Pharmaceutical Co., Ltd. (Fort Lee, NJ) and ZD-4927 from AstraZeneca have entered clinical trials and are farthest along in development. Specific and selective factor VIIa, factor IXa, factor VIIIa, tissue factor, and von Willebrand’s factor are in early stages of development at a number of companies.

• Drugs to prevent restenosis. Late restenosis six months after PTCA or stent deployment is a confounding adverse event that affects 20–50% of patients undergoing these procedures. A variety of different types of drugs have been evaluated for the prevention of restenosis and, until recently, none have demonstrated any efficacy. There are now several promising drugs in various stages of development for this indication. They include Kissei Pharmaceutical Co. (Nagano, Japan) and SmithKline Beecham’s tranilast, an antiallergic drug that suppresses the release of certain cytokines; Otsuka Pharmaceutical Co., Ltd.’s (Tokyo, Japan) Pletal^® (cilostazol), a selective type III phosphodiesterase inhibitor that was recently approved for the treatment of intermittent claudication; Hoechst Marion Roussel’s probucol, a lipophilic antioxidant with antiproliferative activity; Centocor’s ReoPro (described previously); and Pfizer’s Norvasc (described previously).

Summary

The scope of this article is limited to a brief review of drug development for the treatment of CVDs in the past few decades and what new types of drugs may be approved and launched in the next ten years. It is important to note, however, that cardiovascular medicine is a rapidly changing field that involves more than just the development of new drugs. Dramatic advances in interventional devices such as balloons and stents for acute coronary syndromes and peripheral vascular disease, as well as new surgical approaches have provided enormous benefit to patients. Many of these new procedures would be too dangerous to perform without appropriate peri- and post-procedural drug therapy, and the development of certain new drugs has markedly lowered the risk and increased the success rates of these procedures. Adjunctive drug therapy is a rapidly growing market as the search for the optimal drug therapy for each of these new procedures continues.

If one looks even farther down the road then one must begin to consider the impact genomics will have on cardiovascular drug development. Searches by several companies to discover and characterize genes that may predispose an individual to CVD are beginning to bear fruit. But before a drug candidate can emerge from such a discovery effort, the gene product must be identified and characterized. Only then can one develop high-throughput screening assays or begin other types of rational drug design to find or synthesize potentially active compounds. The development of new and better cardiovascular drugs is driven by the huge market potential for these drugs, one that will continue to grow as a fraction of the elderly in the population increases.

For more information about D&MD Newsletter, please contact Jonathan Gerson at 508-616-5550 x444, 508-616-5544 (fax) or via email at jgerson@drugandmarket.com. Drug & Market Development Publications, One Research Drive, P.O. Box 5194, Westborough, MA 01581-5194.

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