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Selected press releases - September 1st-14th 2004

Stroke prevention - good and bad news: About 700,000 Americans suffer a new or recurrent stroke each year usually due to atherosclerosis in the carotid/vertebral arteries. Recovery from stroke is unpredictable and rarely complete and consequently 15-30% of ischemic stroke victims are permanently disabled and 20% require prolonged institutional care. Stroke survivors are at high risk of suffering a further stroke - compared with the population as a whole, their risk of stroke is multiplied 15-fold.

After age, hypertension is the most powerful risk factor for stroke. Hypertension is a relatively well served therapeutic field, with a range of well-tolerated drug classes. Despite this, the majority of patients are not controlled. Results of large-scale outcome studies in the last decade suggest there is no longer a gold standard therapy for hypertension. Over recent years the angiotensin II receptor antagonists, or 'sartans', have been the fastest-growing antihypertensives with sales of losartan hitting $1.4 billion in the first half of 2004. According to the analysts DataMonitor the need for antihypertensives to do more that just lower blood pressure may confer a market advantage and effective protection against stroke represents an ovious opportunity.

In a press release circulated August 31 the established antihypertensive agent TEVETEN (eprosartan) was reported to offer effective protection against cerebrovascular and cardiovascular events in hypertensive patients with a previous stroke, over and above that offered by blood pressure reduction offering potential market opportunities for this antihypertensive.

Initial results from the landmark MOSES(1) study, presented by Professor Joachim Schrader at the XXVI Congress of the European Society of Cardiology in Munich, showed that blood pressure was equally well controlled when hypertensive patients with a history of stroke were treated with either TEVETEN-based or nitrendipine-based therapies. However, there was a significant reduction of 20% in the primary endpoint (total mortality and total cardiovascular and cerebrovascular events) in the TEVETEN group. In addition, there was a significant reduction of 25% in the recurrence of stroke and associated disease (transient ischemic attack and prolonged reversible neurological deficit, and a significant reduction of 30% in first-time cardiovascular events in patients treated with TEVETEN.

Other angiotensin-II receptor antagonists have previously demonstrated cardio- and cerebroprotective effects in patients at risk of stroke. However, earlier studies focused on patients who, although at risk, have not yet had a stroke. These studies helped to establish the value of antihypertensive treatment in primary stroke prevention, but until now there were few data on the effectiveness of these drugs in preventing recurrent stroke. MOSES is the first study to specifically compare the outcomes of alternative antihypertensive treatment in patients with a history of stroke. The calcium channel blocker nitrendipine was chosen as the comparator agent because of its success in the Syst-Eur study(2) where treatment reduced the risk of stroke by 42% in elderly patients with systolic hypertension. In the MOSES study, both nitrendipine and TEVETEN produced impressive reductions in blood pressure, with approximately 75% of patients in each group reaching the target blood pressure as determined by ambulatory blood pressure monitoring. Since both agents produced similar reductions in blood pressure, the reduced incidence of cerebrovascular and cardiovascular events in patients receiving TEVETEN indicates that these benefits are achieved independently of blood pressure reductions. [more on this story]

Not such good news for stroke sufferers was announced on Sept 9th when an FDA review of AstraZeneca's Exanta questioned the experimental drug's effectiveness as a stroke treatment and faulted the company's plan to manage possible toxic side effects.

The news, which came a day before a panel of outside experts met to discuss whether to recommend Exanta for approval by the FDA, shook widespread confidence among investors in the potential blockbuster. The company may have been "too liberal" in assessing the effectiveness of Exanta against the standard anticlotting treatment warfarin, according to FDA staff comments. Several reviewers expressed concern over AstraZeneca's decision to compare Exanta to warfarin rather than a placebo in some studies. Exanta is the first new anticoagulant pill since warfarin was introduced 60 years ago. A notoriously difficult drug to use, it is marketed by Bristol-Myers Squibb under the name Coumadin. Some industry analysts said the efficacy of the product had been considered a given and the questions about its effectiveness amounted to a setback for approval hopes.

Five clinical trials tested Exanta in nearly 18,000 patients and showed it takes effect more quickly and requires less frequent testing than warfarin, AstraZeneca officials have said. Company spokeswoman Rachel Bloom-Baglin said the studies showed a "strong, positive balance of benefit to risk." FDA officials also questioned the drug's possible toxic effects on the liver. The company's risk plan for the product did not address some possible concerns, including risks of delayed liver toxicity after short-term use, heart failure or excessive bleeding caused by Exanta, the reviewers said. Hamish Cameron, AstraZeneca's vice president of cardiovascular, said the company had been open about the liver problem. "We're happy to do more," Cameron said.

Exanta is a pivotal product for AstraZeneca, which needs to make up for declining sales of its ulcer pill Losec/Prilosec, now facing generic competition. The drug is already approved in Europe to prevent blood clotting after orthopedic surgery, but analysts estimate nearly 80% in sales could lie in stroke prevention. Hence the decision to not approve Exanta announced the following day sent shares in AstraZeneca already down by 4% following the FDA review down still further. Despite the Committee members' recognition of the need for a new oral therapy to complement warfarin in the treatment of thrombotic disorders, the Committee advised that the indications for the prevention of strokes in patients with atrial fibrillation (AF), for the prevention of blood clots in patients undergoing knee replacement surgery, and for the long term secondary prevention of blood clots following standard treatment of a clot, should not be recommended on present data.

Sir Tom McKillop, Chief Executive of AstraZeneca, said "We are disappointed with the outcome of the Advisory Committee, particularly for patients who need an effective alternative therapy to warfarin, the only existing oral anticoagulant. We will now continue our discussions with the FDA on a way forward for Exanta." [more on this story]

• News on asthma therapeutics presented at the European Respiratory Society [more]

• Stroke prevention - good and bad news [more]

• News from the European Association for the Study of Diabetes [more]

• Long-awaited FDA decisions on pain therapeutics [more]

Pharma NewsBytes features selected press releases recently featured on DailyUpdates and offers the reader a leisurely stroll through the past few weeks of activity from within the pharmaceutical industry.