CD&D s

The initial reluctance of CV Therapeutics (CVT; Palo Alto, California) to be bought out by Astellas Pharma (Tokyo) paid off with the report last month that CVT and Gilead Sciences (Foster City, California) have entered into a definitive agreement in which Gilead will pay $1.4 billion in cash for the cardiovascular drug developer.

That's $400 million higher than Astellas offered in its year-long pursuit of the CVT and amounts to a $20-per-share offer, compared to the $16 offered by Astellas. The terms represent a 25% premium to the previous CVT closing price, but also a 76% premium to its price before Astellas's $16 bid was made public.

For Gilead, primarily known as an anti-infectives drugmaker, the deal makes it a larger player in the cardio market. It will gain two key marketed CVT products, chronic angina drug Ranexa (ranolazine extended-release tablets), and pharmacologic stress agent for cardiac imaging Lexiscan (regadenoson).

Ranexa may have been the big draw. Approved by the FDA in 2006, it has been something of an underperformer, perhaps due to labeling that limited its use to second-line angina. However, after gaining a special protocol assessment from the FDA, CVT conducted additional trials and in late 2008 won a new label that includes use in first-line chronic angina, arrhythmia reduction, and small reductions in HbA1c in patients with diabetes, and fewer safety precautions.

During a conference call, Kevin Young, Gilead executive VP for commercial operations, called Ranexa a "phenomenal product with a huge potential." Gilead's initial focus will be to move the drug into the market for refractory chronic angina, a category that includes about 1 million people, he said.

John Milligan, Gilead president/COO, noted that 10 million people in the U.S. have chronic angina, and Ranexa's market share is only 75,000 of those. Referring to Ranexa as an "under resourced product," Milligan said Gilead's experience in sales and medical education can boost the relaunch of Ranexa.

The addition of Ranexa also provides could provide some marketing synergy with Gilead's Phase III resistant hypertension drug darusentan, which has been given the blockbuster potential title by some, with data expected in the second quarter.

Analyst consensus favored the deal, but the market viewed it cautiously, with shares of Gilead afterwards rising 29 cents to close at $43.75. Shares of CVT fared better, bouncing 29%, or $4.70, to close at $20.70.

A case of little or no drug benefit

People over 80 suffering from a certain type of heart failure do not appear to benefit from most commonly prescribed heart medications, according to a study conducted at the Cedars-Sinai Heart Institute (Los Angeles) and published in the March 15 issue of The American Journal of Cardiology.

"The American population continues to live longer lives, often surviving with heart failure and other chronic conditions, but patients in this age range are typically excluded from medical research. Our review of 142 patient cases found that medications had little if any beneficial effect on five-year survival or rehospitalization for heart problems among elderly patients who have heart failure but an ejection fraction of at least 50%," said Cedars-Sinai Heart Institute cardiologist Ernst Schwarz, MD, PhD, senior author.

The authors noted that while the study found no proven benefit for drug therapy in this group, cardiovascular drugs are often prescribed at both financial and physiologic cost. They urge special caution in prescribing digoxin and diuretics medications that are often used to treat congestive heart failure and other cardiac conditions because the study showed a trend toward increased mortality.

The average age of patients in this study was 87 years at the time of initial hospitalization with heart failure; 31% of the subjects were men. Sixty-nine percent died during the five-year follow-up, and none of the drug therapies statins, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, beta blockers, diuretics, calcium channel blockers, nitrates, and digoxin appeared to make a significant difference in which patients survived and which did not.

"The risk of adverse drug effects in the geriatric population is high. Because older patients may be taking multiple medications for a variety of medical conditions, and because drugs may affect older people differently than they do younger people, it is important for physicians to prescribe heart medications judiciously and account for a different and often more severe side effect spectrum" said Schwarz, professor of medicine at Cedars-Sinai, medical director of the Cardiac Support Program and co-director of the Heart Transplant Program at the Cedars-Sinai Heart Institute.

AF/AFl drug licensed to Bristol-Myers Squibb

Nissan Chemical Industries (Chiyoda-ku, Tokyo) and Teijin Pharma (Chiyoda-ku) have signed a license agreement with Bristol-Myers Squibb (BMS; New York) in early March regarding the new drug NTC-801 invented by Nissan Chemical and jointly developed by Nissan Chemical and Teijin Pharma for treating and preventing cases of atrial fibrillation (AF) and atrial flutter (AFl). The ex-Japan license with BMS covers both NTC-801 and its backup compounds. NTC-801 is currently in phase I clinical trials in Japan.

BMS will make an initial payment of $40 million when the contract is formally concluded, a total of $170 million for reaching milestones in development and a total of $175 million for reaching milestones in sales, as well as pay royalties on sales.
The agreement is aimed at hastening NTC-801's development for the global market. Nissan Chemical has been researching new medical compounds based on its proprietary precision organic synthesis technology, which has resulted in the commercial launch of calcium antagonist and superstatin cholesterol-reducing drugs.

NTC-801 suppresses AF with a novel mechanism acetylcholine-activated potassium current (IKACh) inhibition unlike antiarrhythmic drugs currently undergoing clinical use. Since atrial fibrillation only exists in the atrium, NTC-801 selectively acts on the atrium and does not create dangerous adverse reactions, such as inducing ventricular proarrhythmia or depression of cardiac function, as seen with certain antiarrhythmic drugs.

NTC-801 is envisioned as a drug that could redefine the existing class of AF drugs, according to the companies developing it.

Teijin Pharma is building a pipeline for drugs used to treat respiratory organs, bones and joints, and metabolic and circulatory organs. The company is expanding its presence in these fields by aggressively introducing new products through solo and collaborative efforts. The agreement will also present Teijin Pharma with the opportunity to collaborate with BMS in drug development in Japan.

A must-see atherosclerosis model: zebrafish

Scientists at the University of California, San Diego School of Medicine have done to laboratory zebrafish exactly what many people still do to themselves added excess cholesterol to their diet. Because young zebrafish are transparent, researchers were able literally to see the development of plaques in the zebrafish blood vessels.

The study was led by Yury Miller, MD, PhD, associate professor of medicine at UC San Diego School of Medicine, who said the zebrafish study offers a "promising method to screen for new drugs and cardiovascular imaging agents."

Extreme hyperlipidemia, or the presence of excess fat and cholesterol molecules in the bloodstream, has been induced in mice and rabbits in the past, but microscopic examination of plaque build-up was only possible post-mortem.

Miller and colleagues fed a high-cholesterol diet (HCD) to zebrafish, supplementing the HCD with a red fluorescent lipid. They also used fish with endothelial cells - the thin layer of cells that line the interior surface of blood vessels - that were tagged with green fluorescent protein. Fish macrophages were tagged with red fluorescent protein, illuminating these immune cells which regulate chronic inflammation and indicate the development of atherosclerosis.

"Because zebrafish are transparent for the first 30 days of life, we can see in the living fish that the blood vessels glow green, while the fat deposits in vascular plaques are red," said Miller. He added that, interestingly, the zebrafish on a high-cholesterol diet did grow little fat fish stomachs.

The scientists used confocal microscopy, able to detect the fluorescent cells, in order to monitor vascular lipid accumulation and view the thickening of the endothelial lining in the living zebrafish. In other experiments, zebrafish in which the macrophages expressed red fluorescent protein were given HCD. This resulted in the pathologic accumulation of fluorescent macrophages along the endothelial cells of the vascular wall, as happens in human atherosclerotic plaques.

To explore the potential of zebrafish for atherosclerosis-related drug screening, the researchers administered the drug ezetimibe, marketed as Zetia, by adding it to the fish tank water. Ezetimibe is used to lower plasma cholesterol levels by lowering cholesterol absorption in the intestine. After treating the HCD-fed zebrafish with ezetimibe, the scientists saw that the drug significantly diminished the thickening of the vascular wall and improved its barrier function.

The study was published online March 5th in advance of print in the April issue of the American Heart Association's (Dallas) Circulation Research.

First-in-man study of heparin antagonist PMX-6005

PolyMedix (Radnor, Pennsylvania) reported completing its first-in-man clinical study with the heparin antagonist drug PMX-60056. It said that this ascending single-dose intravenous pharmacokinetic and safety study met the necessary Phase I goals of defining both a limiting single dose for ten-minute infusions and also the plasma distribution/elimination kinetics for the drug in the absence of heparin. Pending regulatory clearance, PolyMedix said it expects to proceed with a Phase IB proof-of-concept clinical study.

PMX-60056 is a small-molecule drug candidate designed to block the anticoagulant action of heparin and low molecular weight heparins (LMWH), clot prevention drugs which are commonly used in a number of applications.

The company said that data from this study demonstrate that single intravenous doses can be given at levels that will support the planned follow-on therapeutic proof-of-concept Phase IB clinical trial. Further clinical development is expected to continue for this drug as an agent for the rapid reversal of heparin after surgery, and for emergencies where heparin anticoagulation presents a clinical problem.

Nicholas Landekic, CEO of PolyMedix, said, "This novel reversing agent represents a potential fundamental breakthrough in safely reversing the anticoagulation produced by heparin and LMWH. PMX-60056 is the first and only small molecule in clinical development for this purpose."

Based on preclinical studies conducted by PolyMedix and its collaborators, potential advantages of PMX-60056 over protamine may include reduced bleeding complications, reduced risk of immune-mediated side effects, and the ability to neutralize LMWH.

PMX-60056 was designed to bind to the pentasaccharide region found on heparin. PMX-60056 is believed to form a stable electrostatic bond to heparin, blocking its action.

This molecular combination is believed to persist until removed from circulation by normal processes. In previous studies conducted by PolyMedix and other groups, PMX-60056 has been demonstrated to reverse the action of heparin in isolated human plasma, isolated human whole blood, and in animal studies in rats and dogs.

A total of 15 healthy subjects received a single intravenous dose of up to 0.5 mg/kg infused over a 10-minute period. The subjects were grouped into different cohorts with different dosage levels which allowed for the study of the effects of increased dosages.

Five different dose levels were administered, two of them unblinded. Once drug-related effects were identified, dosing became double-blind, with neither investigators nor subjects aware whether active drug or placebo was being administered.

The next planned study is a proof-of-concept Phase IB trial, reversing the action of heparin in healthy volunteers. Because the combination with heparin is believed to occur very rapidly, little or no free PMX-60056 is expected to occur in the plasma. Dosing will begin at levels below those associated with pharmacological effects for the free drug, and increase gradually as tolerated.

It is anticipated that the presence of heparin may prevent significant levels of free PMX-60056, and therefore that hypotension may not be a problem at doses required to reverse the anticoagulation.

In clinical use, it is expected that the only free PMX-60056 would be the excess over the amount needed to neutralize the heparin remaining in the plasma, according to the company.

In brief ...

Celera (Alameda, California) and collaborators presented data showing increased risk of myocardial infarction in carriers of the KIF6 gene variant in a case-control study of a Hispanic population from Costa Rica.

In the study, carriers of the KIF6 gene variant (58% of control subjects) had an elevated risk for non-fatal MI when compared with non-carriers, and ethnicity had no apparent effect on the association between the KIF6 variant and non-fatal MI.

The increased risk of clinical events observed in KIF6 carriers was independent of other well-known CHD risk factors, which Celera said supports the conclusion that the KIF6 gene variant is a new, independent predictor of risk for CHD. This current observational study did not measure response to statin therapy according to KIF6 status.

Schering-Plough (Kenilworth, New Jersey) said that results of a Phase II trial of SCH 530348, a novel oral thrombin receptor antagonist, demonstrated that the investigational antiplatelet compound met its primary endpoints of safety and tolerability.

It showed no increase in major and minor thrombolysis in myocardial infarction-scale bleeding when given with current standard antiplatelet therapy (aspirin and clopidogrel) for patients undergoing percutaneous coronary intervention, commonly known as balloon angioplasty with stenting. The results were published in The Lancet.

ViroMed (Seoul, South Korea) has received an approval from the FDA for a Phase I/II trial for VM202-CAD, a heart disease medicine being jointly developed with the Biologics Delivery Systems Group of Cordis, a business of Johnson & Johnson. The trial will be for patients with angina pectoris and will take place at various medical centers designated by Cordis.

• GTC Biotherapeutics (Framingham, Massachusetts) reported receiving a $1 million milestone payment from Ovation Pharmaceuticals (Deerfield, Illinois), the commercialization and development partner for ATryn (antithrombin [recombinant]) in the U.S. The milestone payment reflects the recommendation for approval by the blood products advisory committee meeting in January 2009.

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