The Cardiovascular Pipeline: ACC 2010 Features Late-Stage Drugs

March/April 2010, Vol 3, No 2 - Pipeline
Wayne Kuznar
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Although promising late-stage drugs in the cardiovascular (CV) pipeline are few, increasing numbers of pharmaceutical manufacturers are taking a stab at oral, fixed-dose alternatives to warfarin, many of which are in phase 3 clinical trials. The following agents were featured at special sessions at the 2010 annual meeting of the American College of Cardiology (ACC).

Unique Factor X Inhibitor
Betrixaban was the subject of a late-breaking session at ACC. Betrixaban is unique among the factor Xa inhibitors, because it is not cleared by the kidneys, and it is being codeveloped with an antidote to reverse its anticoagulant effect in the event that anticoagulation needs to be turned off rapidly, said Michael D. Ezekowitz, MD, PhD, Vice President, Lankenau Institute for Medical Research, Wynnewood, PA, and Professor of Medicine, Jefferson Medical College, Philadelphia.

The onset of action of betrixaban is rapid, according to Dr Ezekowitz, and therapeutic anticoagulation is achieved in 3 to 4 hours. The drug can be taken once daily and is not metabolized via the cytochrome P450 enzyme, and therefore has lower potential for drug–drug interactions.

Betrixaban was studied in 508 patients with atrial fibrillation and at least 1 other risk factor for stroke. The patients were randomized to warfarin, with the dosage adjusted to maintain a therapeutic range (ie, international normalized ratio, 2.0-3.0), or to 40 mg, 60 mg, or 80 mg of betrixaban. The median follow-up was 4.9 months.

There was no difference in the rates of death or stroke between any betrixaban dose and warfarin. Only 1 patient had a major bleeding event with the 40-mg dose of betrixaban compared with 4 patients in the warfarin group. In addition, 5 major bleeding events occurred in patients assigned to the 60-mg and 80-mg doses of betrixaban.

Results from D-dimer testing suggest that 40 mg of betrixaban is active, said Dr Ezekowitz, adding that previous clinical experience with betrixaban demonstrated activity of 30 mg in the prophylaxis of deepvein thrombosis.

More adverse gastrointestinal (GI) events occurred in patients randomized to betrixaban, especially at higher doses, compared with warfarin, but "only 1 patient withdrew from the study because of GI side effects," Dr Ezekowitz said. The GI safety profile will be monitored in future trials.

Quick Onset/Offset Antiplatelet
Ticagrelor, an investigational antiplatelet agent with a quick onset and offset of action, fared well against clopidogrel in patients with acute coronary syndrome (ACS) who then had coronary artery bypass graft (CABG) surgery.

The PLATO (Platelet Inhibition and Patient Outcomes) CABG trial was a subset of the much larger PLATO trial, which included 18,624 patients with ACS who were randomized to ticagrelor or to clopidogrel (Plavix). In PLATO, ticagrelor was associated with a 16% reduction in the composite end point of CV death, stroke, and heart attack.

In PLATO CABG, analysis of results in the 1261 patients who had CABG showed a similar reduction in events with randomization to ticagrelor. Mortality rate was 50% less in the patients assigned to ticagrelor (46%) versus clopidogrel (9.2%), said Claes Held, MD, PhD, Associate Professor of Cardiology, Uppsala Clinical Research Center, Uppsala University, Sweden.

The fast onset/fast offset action of ticagrelor would make it attractive for use in patients who go on to CABG, in whom bleeding is a risk.

A New Drug Application for ticagrelor was submitted to the US Food and Drug Administration in November 2009.

Novel Antihypertensive
LCZ696, a first-in-class antihypertensive, lowered blood pressure more effectively than valsartan (Diovan) in a double-blind study of 1328 patients with mild-tomoderate hypertension who were treated for 8 weeks, reported Luis Miguel Ruilope, MD, Head, Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain.

LCZ696 inhibits both the angiotensin II receptor and neprilysin. The latter mechanism prolongs the life of natriuretic peptides to exert antihypertensive action.

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