CD&D

A combination of disappointing data and urging by a panel of physicians against blockbuster cholesterol drug Vytorin dented two pharma giants, as the annual meeting of the American College of Cardiology (Washington) got under way in Chicago.

However, that news was considered a positive sign for one area of biotech, those companies hoping to get in on the $35 billion cholesterol market.

Another study, however, out of the University of Michigan (Ann Arbor) reported the halt of a trial that showed positive results for a two-drug combination in one table to control blood pressure.

Among the myriad scientific posters presented at the annual meeting, results from the Ezetimibe aNd simvastatin in Hypercholesterolemia enhANces atherosclerosis rEgression (ENHANCE) trial garnered the most attention. Data from the study, initially reported in January, showed that Vytorin demonstrated no significant difference in change in carotid artery wall thickness, as measured by ultrasound, over two years, compared to simvastatin treatment alone.

But data presented at the ACC meeting prompted a review by a panel of physicians, who urged doctors to reconsider prescribing Vytorin, unless patients had failed other treatments, and recommended a return to statin therapy.

That news sent shares of Schering (Kenilworth, New Jersey) down 25%, or $4.94, to close at $14.52, while Merck (Whitehouse, New Jersey) fell $6.78, or 15%, close at $37.73.

Though data showed that Vytorin, a 2-in-1 product that combines Zetia (ezetimibe) and Zocor (simvastatin), significantly lowered LDL more than simvastatin alone, the drug failed to show statistical significance in four secondary endpoints: percentage of patients manifesting regression in the average carotid artery intima-media thickness (CA IMT); the proportion of patients developing new carotid artery plaques >1.3 mm; the changes in the average maximum CA IMT; and changes in the average CA IMT, plus in the average common femoral artery.

Merck executives said the likely cause of the failure related to the behavior of IMT in the trial population, comprised of 720 patients with heterozygous familial hypercholesterolemia, a rare genetic condition that produce very high LDL levels.

Sales of Vytorin, which totaled about $1.5 billion in 4Q07, were predicted to take a hit following the ACC panel — meanwhile, potentially boosting patented statins like Pfizer's (New York) Lipitor (atorvastatin) and AstraZeneca's (London) Crestor (rosuvastatin), along with generic statins. But it might also clear the way for some other drugs coming down the development pipeline, such as Genzyme's (Cambridge, Massachusetts) lipid-lowering agent Mipomersen.

Analyst Mark Schoenebaum of Bear Stearns,wrote in a research note that the "window is opening wider for Genzyme's Phase III drug" in light of Vytorin's troubles.

In January, Genzyme acquired rights to Mipomersen from Isis Pharmaceuticals (Carlsbad, California), in a potential $1.9 billion deal, which included a hefty $325 million up-front payment. That product is in a large Phase III trial in homozygous familial hypercholesterolemia, with results expected in 2009 and 2010.

Genzyme's drug is one of the closest to market, but several other firms are working in the cholesterol space, including Abbott (Abbott Park, Illiniois) which presented Phase III data at ACC showing that its ABT-335 combined with two commonly prescribed statins, atorvastatin and simvastatin, significantly improved LDL cholesterol, as well as triglycerides and HDL cholesterol, compared to corresponding monotherapies. ABT-335, also known as TriLipix, is a fenofibric acid molecule.

2-drug tablet challenges 1-pill protocol

In a late-breaking trials session at the ACC conference, an international blood pressure (BP) study comparing two single-pill drug combinations yielded results prompting study halt, and the researchers said their findings could alter the way high blood pressure is treated worldwide.

The randomized study showed that both drug combinations helped people who had high BP and other cardiovascular risk factors reduced their BP down to recommended levels — despite the fact that two-thirds of them had been unable to achieve good BP control with other medications before they entered the study.

Importantly, the study revealed that the patients taking one of the combinations had 20% fewer heart-related events than the patients taking the other one. Those events included cardiovascular deaths, heart attacks, strokes, hospitalizations for unstable angina and treatments to re-open blocked heart arteries.

"These results demonstrate the superiority of an ACE/CCB pill fixed-dose combination treatment strategy for reducing cardiovascular morbidity and mortality, and provides evidence that should modify future guidelines for the treatment of hypertension," said Kenneth Jamerson, MD, the leader of the study, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH). Jamerson is a professor of internal medicine at the University of Michigan Medical School and a member of the U-M Cardiovascular Center (Ann Arbor).

The study was funded by Novartis (Basel, Switzerland), which acknowledge thdat it is among the companies that offer two-drug combination tablets for blood pressure treatment and saying that single-tablet combinations of drugs are seen as easier for patients to take than multiple pills.

ACCOMPLISH showed that just six months of treatment with either drug combination was enough to bring the blood pressure of 73% of patients into an acceptable range. However, by the end of the trial, BP control rates were 80%, with mean systolic blood pressure less than 130 mmHg. The researchers said this represents exceptional blood pressure control when contrasted to the current control rate of about 30% in the U.S.

All patients in the study received no more than 40 milligrams of benazepril in each dose; amlodipine doses began at 5 mg and could be increased to 10 mg, while hydrochlorothiazide doses began at 12.5 mg and could be increased to 25 mg.

In all, 10,700 study participants took a single tablet that includes two medications. One group received a tablet containing benazepril, which is a type of drug called an ACE inhibitor, and amlodipine, which belongs to a class of drugs known as calcium channel blockers or CCBs. The other pill combined benazepril and hydrochloro-thiazide, a type of diuretic or "water pill." The 20% reduction in cardiovascular events was observed with the ACE/CCB combination tablet.

Currently, national guidelines for the treatment of BP call for patients who need medication to start out on a single pill, usually a diuretic, and to add other drugs only as needed to bring pressure down.

Eric Velazquesz, MD, a member of the ACCOMPOLISH executive committe, said that the trial results "shake the foundations of current recommendations and define a new standard ... in helping clinicians in meeting the daily challenges of hypertension management."

Other pharma news

•Boehringer Ingelheim (Ingelheim, Germany), reported results from the 25,620-patient ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study, showing that telmisartan, an angiotensin II receptor blocker, is as protective as ramipril, as ACE inhibitor, in reducing the risk of cardiovascular death, myocardial infarction, stroke and hospitalization for congestive heart failure in a cross-section of high-risk patients. Cardiovascular events occurred in 16.7% of patients receiving telmisartan vs. 16.5% in the ramipril arm.

•Centocor (Horsham, Pennsylvania) and Eli Lilly (Indianapolis), saw data presented that showed that high loading doses of clopidogrel, an oral compound that inhibits blood clots, can eliminate the need for intravenous abciximab, a cath-lab drug on which the companies have collaborated, which also interferes with platelets, but through a different pathway. That study, which involves patients undergoing percutaneous coronary intervention following heart attack, was conducted by researchers at the Deutsches Herzaentrum, Technical University (Munich, Germany).

•The Medicines Co. (Parsippany, New Jersey) said that Angiomax (bivalirudin) resulted in improved net adverse clinical outcomes and reduced the risk of major bleeding despite the sex, age, diabetes status or renal function of heart attack patients, compared to a more complex treatment regimen, 30 days following primary angioplasty. The company said the latest findings from the HORIZONS-AMI trial are consistent with earlier data demonstrating Angiomax's superior clinical outcomes and fewer cardiac deaths vs. unfractionated heparin plus a platelet glycoprotein IIb/IIIa inhibitor in patients presenting with STEMI. Angiomax is a direct thrombin inhibitor designed to deactivate circulating and clot-bound thrombin and thrombin-mediated platelet activation.

•CV Therapeutics (Palo Alto, California), reported that ranolazine significantly shortened the QT interval of patients with LQT3, a hereditary form of long QT syndrome caused by a genetic mutation in the late sodium channel that results in heart rhythm problems. Data also showed that Ranolazine resulted in shortened cardiac relaxation time.

•Synvista Therapeutics (Montvale, New Jersey), reported data from a study of diabetic mice with the haptoglobin 2-2 genotype showing that impairment in the clearance of the haptoglobin-hemoglobin complex might result in a modification of HDL structure and defective reverse cholesterol transport. Synvista said those data suggest that haptoglobin testing in people with diabetes could ensure more successful treatment to prevent cardiovascular events, such as heart attack and stroke.