The antihypertensive market accounted for approximately $30 billion in worldwide sales in 2003. The market is growing rapidly as the number of adults with hypertension in 2025 predicted to reach 1.56 billion, 60% higher than the 0.972 billion in 2005. The increasing use of multiple drug therapy and the falling use of older drug classes in the absence of specific compelling indications will continue to drive sales of the largest therapeutic classes and will provide a growing market for new entrants. The global market leader, Norvasc, and the fastest growing class, angiotensin II receptor blockers (ARBs), will both face generic competition during this period due to patent expirations. This will result in switching from older therapeutic classes and provide a window of opportunity for new therapeutic classes. Seven ARBs are currently available in the United States: losartan potassium (Cozaar®, Merck), valsartan (Diovan®, Novartis), irbesartan (Avapro®, Sanofi / Bristol-Myers Squibb), candesartan cilexetil (Atacand®, AstraZeneca), telmisartan (Micardis®, Boehringer Ingelheim), eprosartan (Teveten®, Biovail Pharmaceuticals), and olmesartan medoxomil (Benicar(tm), Sankyo Pharma Inc/Forest). None of the ARBs are available generically, however patent expirations are expected after 2009.

There are a several late-stage drugs in the antihypertensives pipeline. Of the major drugs in development, Novartis’ SPP100 renin inhibitor drug shows the most promise for reaching the blockbuster status of Pfizer’s Norvasc, the current market leader. SPP100 is the first-in-class Renin inhibitor being developed for the treatment of hypertension. Renin is the key enzyme at the top of the Renin Angiotensin System (RAS), one of the key regulators of blood pressure. Inhibition of Renin, articulated as Plasma Renin Activity (PRA), is believed to be very important in end-organ protection (e.g. heart and kidney). PRA is an independent and direct surrogate marker for several cardio-renal diseases, such as myocardial infarction and chronic renal disease. Studies have shown that a Renin Inhibitor lowers PRA efficiently while other therapeutic classes actually increase PRA levels.

We have updated and added 8 drug revenue models within the Systemic Hypertension market.

BACKGROUND

Hypertension, known as the "silent killer" since it shows few, if any, symptoms, is a major risk factor for other cardiovascular diseases such as stroke, heart attacks and congestive heart failure. Defined as a systolic blood pressure greater than or equal to 140mmHg and a diastolic blood pressure of greater than or equal to 90mmHg, hypertension is the most prevalent of all cardiovascular diseases in the developed world. In fact, some 20-30% of adults in developed countries have high blood pressure.

Antihypertensives are medications used to treat high blood pressure (systemic hypertension). People taking antihypertensives are also encouraged to make healthy lifestyle changes, such as quitting smoking, losing weight and getting regular exercise. The main classes of medications for hypertension are calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, angiotensin II receptor blockers (ARBs) and thiazide diuretics. The choice of medication is dependent on the individual's characteristics. There are numerous effective antihypertensive drugs, and many protocols for combining those drugs have been devised.

DRUGS IN DEVELOPMENT – Mid Term Outlook

Penwest Pharmaceutical’s PW2010 (Phase III)
On December 2, 2004, Penwest Pharmaceuticals announced that in its efficacy trial of the low dose strength of PW2101, a beta blocker intended for the treatment of hypertension and angina, PW2101 did not meet the study's primary endpoint. The results, while positive, were not statistically significant at a p-value of 0.05. However, the low dose strength did meet some of the trial's key secondary endpoints. Based on the overall statistics found in both trials, the low dose strength of PW2101 is clinically active. Penwest intends to submit the Phase III PW2101 data to the FDA in the first quarter of 2005 and expects to have discussions with the FDA on its approvability and labeling for the low dose of PW2101.

Novartis’ SPP100 (Phase III)
On November 19, 2003 Novartis presented at their R&D Day in New York the outcome of a randomized, double blind, placebo controlled, parallel study of SPP100 versus Irbesartan, a potent angiotensin receptor blocker, covering 650 patients over a period of 8 weeks. The study results indicate that SPP100 significantly reduced blood pressure in patients with essential hypertension at all doses tested and was either as good as, or statistically better, than Irbesartan in lowering Diastolic Blood Pressure. Based on these results, Novartis announced to start Phase III development in 2004.

On December 20, 2004 Novartis provided an update on SPP100. Phase IIb/III data confirmed efficacy as a monotherapy and suggested benefits of combination with ARBs. Details of the data were not provided. Phase III trials are ongoing in the U.S., EU and Japan. The company expects additional Phase III data in the third quarter of 2005. The first regulatory submission is planned for early 2006.

DRUGS IN DEVELOPMENT – Long Term Outlook

Alteon’s Alagebrium (Phase II)
Alagebrium targets the AMPA-type glutamate receptor. On May 19, 2004 Alteon announced detailed results from a retrospective analysis of the Phase IIb trial of alagebrium (formerly ALT-711), a hypertensive agent for decreasing systolic blood pressure (SBP). The data demonstrated that hypertensive patients treated with alagebrium, had a significant reduction in SBP as gauged by ambulatory blood pressure measurement (ABPM). The results were obtained in patients that are normally difficult to treat with anti-hypertensive drugs while these patients maintained their current blood pressure medications. On December 20, 2004 Alteon announced that its ongoing Phase IIb SPECTRA (Systolic Pressure Efficacy and Safety Trial of Alagebrium) trial is on target to complete enrollment during the first half of 2005, with data expected to be reported during the second half of 2005.

Sepracor’s (S)-Amlodipine (Phase II)
Since its release in 1992, amlodipine, a vasoselective dihydropyridine calcium channel blocker (ccb), has become a frequent component of antihypertensive regimens in adults. The (S)-amlodipine isomer is currently in Phase II stage trials for hypertension. Very little is known about the trials.

Myogen’s Darusentan (Phase II)
Darusentan is a selective endothelin receptor antagonist (eta) being developed as an oral therapy for patients with uncontrolled hypertension. Endothelin is a small peptide hormone that is believed to play a critical role in the control of blood flow and cell growth. On November 3, 2004 Myogen announced a progress update on darusentan for the treatment of hypertension. Patient enrollment for the Phase IIb trial is progressing in line with expectations and is expected to be completed mid 2005.

Forest Laboratories’ Lercanidipine (Phase II)
Lercanidipine (Zanidip) is calcium channel blocker (ccb) that inhibits the influx of calcium ions through L-type calcium channels in cell membranes. In August of 2002, Forest received an approvable letter from the FDA seeking additional data related to the proposed dosing regimen. In response to the request Forest conducted an eight week Phase II pilot study in which approximately 60 patients were dosed once daily with lercanidipine in an experimental modified release formulation. On November 3, 2004 Forest Laboratories provided an update on the study. The results indicated that this modified release version of lercanidipine was associated with a clinically relevant reduction in blood pressure, but failed to meet all the goals of the trial.

Medicure’s MC-4323 (Phase II)
On August 11, 2004 Medicure announced that it had initiated a Phase II/III trial to evaluate MC-4232 for the treatment of diabetic patients with hypertension. The trial is expected to be completed in the spring of 2005.

REVENUE MODEL UPDATES

We have updated and added 8 drug revenue models within the Systemic Hypertension market:

Norvasc-Pfizer-Approved
We project peak U.S. revenues for Norvasc for Hypertension of $2.14 billion in 2006.

PW2101-Penwest Pharmaceuticals-Phase III
We project peak U.S. revenues for PW2101 for Hypertension of $656.2 million in 2012.

SPP100-Novartis-Phase III
We project peak U.S. revenues for SPP100 for Hypertension of $2.19 billion in 2013.

Alagebrium-Alteon-Phase II
We project peak U.S. revenues for Alagebrium for Hypertension of $590.6 million in 2012.

Amlodipine-Sepracor-Phase II
We project peak U.S. revenues for Amlodipine for Hypertension of $622.1 million in 2011.

Darusentan-Myogen-Phase II
We project peak U.S. revenues for Darusentan for Hypertension of $584.2 million in 2014.

Lercanidipine-Forest Laboratories-Phase II
We project peak U.S. revenues for Lercanidipine for Hypertension of $438.2 million in 2014.

MC-4323-Medicure-Phase II
We project peak U.S. revenues for MC-4323 for Hypertension of $292.1 million in 2014.