High Blood Pressure / Hypertension

Hypertension: Emerging Therapies

By Cardiologist on May 11th, 2011

The current marketplace for antihypertensive therapies is crowded, but it remains highly lucrative, and the competition for market share is still high. An emerging therapy that successfully penetrates this market could enjoy worldwide sales in the billion-dollar, “blockbuster” range. However, the recent launch of some new agents and combinations of agents, together with the discontinuation of agents in several novel classes, has left the developmental landscape for antihypertensives rather barren. New agents in existing antihypertensive classes, such as angiotensin-converting enzyme inhibitors (ACEIs), calcium-channel blockers (CCBs), and angiotensin II receptor antagonists (AIIRAs), face the greatest challenges to market entry. These classes already have many well-established agents, and many ACEIs and CCBs are available generically, thus making the barrier to entry for new branded agents even higher. One of the few compounds in an established drug class still in development is Kotobuki Seiyaku’s AURA pratosartan (KT3-671), which is in Phase III trials for hypertension in Japan. Similarly, the market is now served by many single-pill combinations of established drugs (see TABLE. Emerging Therapies in Development for Hypertension). Several combinations of CCBs and ACEIs, such as AstraZeneca/Sanofi-Aventis’s felodipine/ramipril and Vita-Invest’s nitrendip-ine/enalapril, have already enjoyed limited European launches.

Calcium-Channel Blockers

Overview. Although CCBs are a well-established class of antihypertensive drug, some development has continued within the class, especially in Japan, where their use is much higher than in the other six major pharmaceutical markets (United States, France, Germany, Italy, Spain, and United Kingdom). Of note is the 2003 approval of azelnidipine (Sankyo’s Calblock). Another CCB in development is clevidipine, a short-acting, intravenous CCB in Phase III development. This compound was originally being developed by AstraZeneca and had reached Phase II trials, but in 2002, AstraZeneca handed over worldwide development and commercialization rights to the Medicines Company. Otsuka recently confirmed that it has discontinued development of pranidipine (Acalas), for which the company had filed for approval in Japan.

Mechanism Of Action. CCBs induce vasodilation by inhibiting the entry of calcium ions, via L-type calcium channels, into vascular smooth-muscle cells (vascular smooth-muscle cells), which in turn lowers blood pressure.

Graded Extended-Release Diltiazem. DOV Pharmaceutical is developing an extended-release formulation of diltiazem (DOV diltiazem)  for the treatment of angina and hypertension. Only Phase I trials have been reported, but in July 2004, DOV and the FDA reached an agreement on the development necessary to allow DOV to submit a new drug application (NDA).

TABLE. Emerging Therapies in Development for Hypertension

^aPR = Preregistered.

DOV was originally codeveloping the drug with Biovail, but this agreement was terminated in April 2003. Biovail does retain some rights to the compound and has agreed to carry out DOV’s next scheduled Phase I trial of DOV diltiazem.

Although diltiazem itself is already launched, the DOV formulation uses a novel method of delivery, which combines a unique dissolution profile with evening dosing. In this way, diltiazem‘s efficacy is improved because the blood levels of the drug are matched to the patient’s requirement for hypertensive control over a 24-hour period.

Several large-scale clinical trials have demonstrated diltiazem‘s efficacy. For example, the Nordic Diltiazem Study (NORDIL) compared diltiazem (100-360 mg) with beta blockers, diuretics, or both in 10,881 patients aged 54-74 with diastolic blood pressure > 100 mm Hg (Hansson L, 2000). Investigators found that systolic blood pressure reductions were significantly lower in the diuretic and beta-blocker ( — 23.3) groups compared with the diltiazem group ( — 20.3) (p < 0.001), but both treatment approaches were equally effective in preventing the primary end point of stroke, MI, or cardiovascular death. A trend toward a lower incidence of fatal plus nonfatal stroke was seen in the diltiazem-treated group.

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