BiDil is a fixed dose, combination therapy consisting of 37.5 mg of hydralazine hydrochloride and 20 mg of isosorbide dinitrate per tab taken three times daily. Although hydralazine and isosorbide dinitrate are both approved for use in several cardiovascular indications, their use together in a fixed dose format for the treatment of CHF is unique and merits an innovation score of 65. Nitric oxide is important in myocardial remodeling. BiDil may exert its therapeutic effect as both a source and preserver of nitric oxide in the heart.

Estimates of the prevalence of congestive heart failure range from 3 to 5 million Americans. We use an incidence of 400, 000 new diagnoses per annum; this translates into a burden of illness variable value of 35. Congestive heart failure results from an impairment in pump function in which the heart fails to maintain the circulation of blood adequately. In the New York Heart Association’s functional classification of CHF, class III is characterized by a marked limitation in normal physical activity. Class IV is defined by symptoms at rest or with any physical activity.

If approved, we expect significant demand/diffusion of this emerging technology. The integration of BiDil into the CHF therapeutic armamentarium will create an increase in the pharmacologic treatment cost per patient per year. BiDil will be added to existing patient specific therapeutic regimens. We have assigned the demand/diffusion variable a value of 30 and an overall BioHorizon Emerging Health Technology Impact Score of 53. If FDA approval occurs, we intend to recommend early assessment activities.

Technology Details
Target Disease / Indication: Congestive Heart Failure
Technology Classification: Drug
Body System: Cardiovascular System
Program Area: Medicine/Cardiology
Regulatory Status: Phase 3
BioHorizon Impact Score: 53/100 – Moderate

Prasugrel is an oral antiplatelet drug that may prevent platelet activation by blocking adenosine diphosphate receptors on the platelet surface. When activated, these receptors allow for a protein in the blood known as fibrin to link platelets together, creating a ‘plug’ or ‘clump’ of platelets that can produce a critical vessel blockage and cause a heart attack. Other anti-platelet treatments currently available include ASA, the thienopyridines-clopidogrel (Plavix), and ticlopidine as well as the glycoprotein IIb/IIIa inhibitors abciximab and tirafibrin. We have assigned prasugrel 50/100 for innovation as a new drug in an existing class of oral antiplatelet drugs.

BioHorizon believes that demand/diffusion parameters for oral anti-platelet drugs are increasing. Bristol Myers Squibb, the manufacturers of Plavix™, recently reported a 23% increase in U.S. prescriptions and a nine month total sales figure of in excess of 900 million dollars. Depending on the forthcoming efficacy and adverse event data, prasugrel could compete in this market. We have assigned this technology a demand/diffusion score of 20/100.

The overall BioHorizon Emerging Health Technology Impact Score is 47/100, currently placing prasugrel in our Moderate Impact Technology category. No preliminary assessment activities are recommended for health services clients at this time.

Technology Details
Target Disease / Indication: Acute Coronary Syndrome
Technology Classification: Drug
Body System: Cardiovascular System
Program Area: Medicine/Cardiology
Regulatory Status: Phase 3
BioHorizon Impact Score: 47/100 – Moderate Impact

Zocor is a so-called ‘statin’ lipid lowering agent that exerts its action by inhibiting an enzyme known as HMG-CoA., which plays a critical role in cholesterol synthesis. The clinical benefit of Zocor in reducing death due to CHD, MI, and decreasing the need for invasive coronary procedures in patients with elevated cholesterol levels is well established. Unlike Zocor, Zetia works by inhibiting the absorption of dietary cholesterol from the small intestine. Data demonstrating Zetia’s ability to significantly decrease morbidity and mortality from coronary artery disease has not been produced.

According to the American Heart Association, in excess of 100 million Americans presently have total blood cholesterol levels above 200 mg/dl. In addition, fewer than 50% of patients who would benefit from cholesterol lowering treatments are actually receiving them. Some analysts expect Vytorin to eventually attain annual sales of up to $8 billion.

Given that Vytorin is comprised of two already approved drugs, a positive FDA decision is anticipated. Combination therapies are almost always less expensive than the cost of their constituents purchased separately, so potentially Vytorin would not drive up cost of per patient treatment. However, Vytorin will most certainly be more costly than the individual statin drugs that in some cases it is likely to replace. Clinicians might choose Vytorin when they are striving for more aggressive lipid control or when patients are inadequately controlled on a statin alone. Both of these scenarios would see the cost of treatment significantly increase on a per patient basis and forms the underlying rationale for our recommendation that clients should begin preliminary assessment activities for Vytorin in anticipation of FDA approval.

Technology Details
Target Disease / Indication: Hyperlipidemia
Technology Classification: Drug
Body System: Cardiovascular System
Program Area: Medicine/Cardiology
Regulatory Status: Phase III
BioHorizon Impact Score: 81/100 – High

The Cordis Carotid System is comprised of the Precise® Nitinol Self-Expanding Stent and the Angioguard™ Emboli Capture Guidewire. These products are currently approved outside the U.S for use in carotid arteries. The Angioguard is delivered beyond the lesion, where it opens into a tiny perforated basket designed to catch plaque particles dislodged during the angioplasty and stent procedure, while allowing continuous blood flow. Once the stent is implanted to hold the artery open, the protective basket is closed and removed. Cordis has positioned its Carotid System as a minimally invasive alternative to carotid endarterectomy in high-risk patients with carotid artery disease.

Carotid artery disease refers to a buildup of atherosclerotic plaque (fatty material) in the neck’s carotid arteries that supply blood to the brain. In some patients, pieces of this plaque may break off or embolize and cause a stroke. According to CDC surveillance data, stroke is the third leading cause of death in the U.S after heart disease and cancer. Some estimates place the number of carotid endarterectomies performed annually in the U.S in the 100,000 range.

Clients with significant CVT surgery exposure should review carotid endarterectomy volume. Some preliminary clinical epidemiology detailing numbers of procedures on high risk patients is suggested at this time. Biohorizon recommends consultation with CVT surgeons concerning plans for device use if final FDA approval is obtained.

Technology Details
Target Disease / Indication: Carotid Artery Disease
Technology Classification: Device
Body System: Cardiovascular System
Program Area: Surgery/CVT Surgery
Regulatory Status: Investigational
BioHorizon Impact Score: 45/100 – Moderate

Ranexa is believed to exert its effect on the heart by partial inhibition of fatty acid oxidation (pFOX inhibition). Pre-clinical studies have suggested that pFOX inhibition alters heart myocardial cell metabolism in such a way as to increase its efficiency and, in effect, to require less oxygen to do a given amount of work.

Angina as a disease occurs when an imbalance exists between the heart’s energy demands and the coronary vasculature’s ability to deliver oxygen. Chronic angina is usually associated with coronary artery disease (CAD) and is characterized by repeated, often debilitating episodes of chest pain. The American Heart Association reports that 6.8 million Americans suffer more than 700 million angina attacks per year in the United States. Current anti-anginal therapies include beta-blockers, calcium channel blockers, and nitroglycerin.

CV Therappeutics has yet to complete or publicly release the results of the pivotal Phase III trials required for FDA approval of Ranexa. However, given the high incidence and prevalence of chronic angina in North America, innovative technologies effective in treating this condition have the potential to significantly alter, if not transform, the anti-anginal landscape. Bearing this in mind, Biohorizon has designated Ranexa as a High Impact Technology but is recommending no preliminary assessment activities until more clinical trial data become available.

Technology Details
Target Disease / Indication: Chronic Angina
Technology Classification: Drug
Body System: Cardiovascular System
Program Area: Medicine/Cardiology
Regulatory Status: Phase III
BioHorizon Impact Score: 75/100 – High

Torecetrapib is a cholesterol ester transfer protein (CETP) inhibitor. CETPs play a role in the conversion of HDL cholesterol into LDL cholesterol. It is thought that interfering with the activity of CETP increases HDL levels. There are a number of chemical CETP inhibitors in the pre-clinical stage of development. At least one other CETP inhibitor, JTT-705, has been tested in human clinical trials.

There are many large-scale clinical trials that demonstrate that the lowering of low-density lipoproteins (LDL cholesterol) with statins has significant effects on a variety of clinical outcomes. While it is generally accepted in the medical literature that low levels of HDL cholesterol increase the risk of coronary artery disease, the data supporting the beneficial effects of elevating HDL cholesterol is epidemiologic in nature. Pfizer will have to demonstrate the safety and efficacy of torcetrapib with respect to some hard cardiovascular endpoints, similar to what has been done with the statins, before this innovative therapy can have a substantial impact on the estimated 100 million Americans with abnormal cholesterol levels.

It appears as though Pfizer continues to devote considerable resources to the development of torcetrapib. Pfizer reportedly paid $1.3 billion to acquire the company that developed torcetrapib and has earmarked $800 million for ongoing clinical trials. Combining Lipitor and torcetrapib in a single treatment for dyslipidemia could significantly increase per patient cost. Biohorizon currently designates torcetrapib a Moderate Impact Technology and recommends no assessment activities at this time.

Technology Details
Target Disease / Indication
Low HDL/Coronary Artery Disease

Technology Classification
Drug

Body System
Cardiovascular System

Program Area
Medicine/Cardiology

Regulatory Status
Phase I

BioHorizon Impact Score
64/100 – Moderate

FM-VP4 is a member of a new class of cholesterol lowering drugs, described as water and lipid soluble cholesterol absorption inhibitors or ‘phytostanol analogues’. The company has indicated that they plan to pursue this as an adjunctive therapy to statins in the treatment of hyperlipidemia and noted that the potential market for combination therapies in the treatment of high cholesterol may reach $4.7 billion dollars by 2011.

According to the American Heart Association, in excess of 100 million Americans presently have total blood cholesterol levels above 200 mg/dl. In addition, fewer than 50% of patients who would benefit from cholesterol lowering treatments are actually receiving them.

Although currently classified as a Moderate Impact Technology, FM-VP4, or any other adjunctive therapy (i.e. in addition to standard statin therapy) for the management of hyperlipidemia could potentially fulfill the Biohorizon criteria for a High Impact Health Technology. If approved, FM-VP4 could become standard therapy for patients not adequately controlled on statins alone. In this case, the addition of FM-VP4 to the standard statin therapeutic regimen would significantly increase the cost of treatment on a per patient basis. However, FM-VP4 has yet to enter pivotal Phase III trials. Due to the considerable time and uncertainty associated with this process, Biohorizon does not recommend assessment activities at this time.

Technology Details
Target Disease / Indication
Hyperlipidemia

Technology Classification
Drug

Body System
Cardiovascular System

Program Area
Medicine/Cardiology

Regulatory Status
Phase II

BioHorizon Impact Score
62/100 – Moderate

Enoximone is a small organic molecule that selectively inhibits type-III phosphodiesterase (PDE-III). PDE-III is an enzyme that is present in the heart and plays an important regulatory role in cardiac function. PDE-III inhibitors block the action of this enzyme, increasing the force of contraction of the heart and increasing the rate of relaxation, thereby increasing cardiac output. Enoximone also causes vasodilation, an increase in the diameter of blood vessels, through its effects on smooth muscle cells that surround blood vessels, which results in lower pressure against which the heart must pump. Positive inotropy and vasodilation can both be therapeutically useful in the treatment of heart failure.

Chronic heart failure (CHF) generally occurs in patients with a long history of uncontrolled high blood pressure or in patients that have suffered a heart attack or some other heart-damaging event. It is estimated that half of all patients with this disorder die within five years of diagnosis. CHF therapeutics are a $14 billion market that is expected to grow to more than $22 billion in 2008.

The failure of enoximone to achieve statistical significance at the primary endpoint in this clinical trial is important. However, Myogen’s pivotal clinical trials with oral enoximone, ESSENTIAL I & II, are expected to complete their treatment phase by the end of 2004. Until these clinical trial results are released and analyzed, Biohorizon recommends no preliminary assessment activities.

Technology Details
Target Disease / Indication
Chronic Heart Failure (CHF)

Technology Classification
Drug

Body System
Cardiovascular System

Program Area
Medicine/Cardiology

Regulatory Status
Phase III

BioHorizon Impact Score
67/100 – High

Unlike traditional or ‘bare metal’ stents, the Taxus stent is coated with a substance named paclitaxel and a unique polymer. The stent props the blocked coronary artery open while the polymer gradually releases the paclitaxel into the vessel wall to stop the growth of scar tissue which causes restenosis. The pivotal Boston Scientific sponsored Taxus IV clinical trial reported an in-segment (stented vessel segment plus 5 mm beyond each end of the stent) binary restenosis (50% or greater vessel re-occlusion) rate of 7.9% in the Taxus group compared with 26.6% in the control group (P=<0.0001). The study also reported a target lesion revascularization (TLR) rate of 3.0% in the Taxus group compared with 11.3% in the control group (P=<0.0001). TLR (or retreatment) rate is one of the most accurate indicators of the performance of drug-eluting stent technology.

In excess of five million Americans are treated for coronary artery disease each year. Most of these patients (about 80%) are treated medically, however, in excess of 1million patients will require more invasive procedures like Coronary Artery Bypass Grafting (CABG) or angioplasty. Among those patients receiving stents, 15-20% will require repeat treatment for restenosis. Industry analysts value the drug-eluting stent market in the 3-4 billion dollar per annum range with some predicting a 5 billion dollar market within the next 2 years. The actual direct cost increase associated with Taxus compared to a bare metal stent is significant. Each Taxus stent will likely cost between $2500 and $3000. This represents an increase of 200-300% over the per unit cost of a bare metal stent. It is duly noted that the significant decrease in restenosis rates and therefore revascularization procedures may ultimately reduce the cost per patient treated by a given health services organization.

The Taxus Express stent is currently in our High Impact Technology category. All clients with significant cath-lab operations should commence or continue assessment activities as soon as possible.

Technology Details
Target Disease / Indication: Coronary Artery Disease
Technology Classification: Combination Drug/Device
Body System: Cardiovascular System
Program Area: Cardiology
Regulatory Status: Approved

BioHorizon Impact Score: 84/100 – High

In excess of five million Americans are treated for coronary artery disease each year. Most of these patients (about 80%) are treated medically, however, in excess of 1million patients will require more invasive procedures like Coronary Artery Bypass Grafting (CABG) or angioplasty. Among those patients receiving stents, 15-20% will require repeat treatment for restenosis. The CYPHER stent, approved for U.S. marketing in April 2003, has been used to treat approximately 500,000 patients in more than 80 countries worldwide. Industry analysts value the drug-eluting stent market in the 3-4 billion dollar per annum range. The actual direct cost increase associated with CYPHER compared to a bare metal stent is significant. Each CYPHER stent costs in the $2500 to $3000 range. This represents an increase of 200-300% over the per unit costs of a bare metal stent. It is duly noted that the significant decrease in restenosis rates and therefore revascularization procedures may ultimately reduce the cost per patient treated by a given health services organization.

The CYPHER stent is currently in our High Impact Technology category. All clients with significant cath-lab operations should commence or continue assessment activities as soon as possible.

Technology Details
Target Disease / Indication: Coronary Artery Disease
Technology Classification: Combination Drug/Device
Body System: Cardiovascular System
Program Area: Medicine/Cardiology
Regulatory Status: Approved
BioHorizon Impact Score: 86/100 – High