By GEETA ANAND and RON WINSLOW Staff Reporters of THE WALL STREET JOURNAL March 20, 2001

ORLANDO, Fla. -- The biotechnology industry's product pipeline is brimming with promising drugs for patients suffering from one of medicine's most debilitating maladies: heart failure.

Four compounds in late-stage development offer novel strategies for attacking the disease, including two aimed at patients admitted to the hospital with life-threatening symptoms of heart failure. So many people suffer from heart disease and so dire is the need for new treatments that some analysts believe at least two of the drugs could become billion-dollar-a-year blockbusters by the middle of the decade. There are other promising candidates in earlier stages of development.

"These drugs are going to put more things on the shelf for us to use, in contrast to the paltry choices we have right now," says James Young, a heart-failure expert at Ohio's Cleveland Clinic.

Current treatment options include drugs that reduce salt and body fluids and control blood pressure. For acute symptoms, standard treatment includes old-line medicines such as nitroglycerin to improve heart function. While beta blockers, used to treat chest pain and reduce blood pressure, have recently been shown to significantly reduce death rates from heart failure, the American Heart Association estimates that half of heart-failure patients die within five years of diagnosis.

Tuesday, at a big scientific meeting here of the American College of Cardiology, researchers will present details of a major study of one of the drugs intended to make inroads against this toll. Called Tezosentan, it is being developed for patients with acute heart failure by Actelion Ltd., a Swiss biotech company, in collaboration with Genentech Inc., the South San Francisco biotech concern. The companies have already announced that the results of the study are positive, and they hope the drug could be approved for marketing by late next year. Actelion and Genentech are also testing in humans a drug for chronic heart failure; as with Tezosentan, the companies hope to gain approval for the second drug, Bosentan, by late 2002.

Scios Inc. of Sunnyvale, Calif., is leading the race to the market with its drug Natrecor, also for acute heart failure. The company has completed its required human testing and anticipates marketing approval from the Food and Drug Administration by this summer. And Immunex Corp. of Seattle is testing its rheumatoid-arthritis drug Enbrel for chronic heart failure.

The seeds for these new treatments took root about a decade ago, when doctors began to notice a surprising rise in the number of patients diagnosed with heart failure. The disease is characterized in part by an enlarged heart, which becomes progressively weaker and less able to pump blood effectively. While the causes of heart failure aren't fully understood, scientists believe, ironically, that medical progress is one. Advances in heart care beginning in the 1970s have enabled many who otherwise would have died to survive heart attacks and heart-valve problems -- at a price. The body's powerful healing and inflammatory responses to a heart attack, which normally repair bodily damage and then retreat, become overactive in the presence of chronic injury to the heart, causing more damage. The new biotechnology drugs attempt to break this vicious cycle.

Acetelion's Tezosentan, which is injected intravenously, works by interfering with the action of two different types of a hormone called endothelin. The hormone is the body's most potent blood-vessel-constricting agent and is overproduced by the lining of blood vessels when the heart is damaged. The excess endothelin latches on to receptors on muscle cells in the blood-vessel wall, causing it to constrict, and forcing the heart to work much harder to pump blood. High levels of the substance are associated with higher deaths rates and worsening heart failure. Researchers are expected to describe Tuesday how Tezosentan occupies the endothelin receptors to prevent the hormones from constricting the vessel wall.

Bosentan, a pill, also targets endothelin receptors. A study proved it effective against a rare condition called primary pulmonary hypertension that also involves excess levels of endothelin and afflicts about 100,000 mostly young patients, restricting their breathing capacity. It may reach the market for that problem later this year and, the company hopes, for heart failure at the end of 2002.

Scios's Natrecor eases blood flow by bolstering the body's own supply of a hormone called B-natriuretic peptide, which causes blood vessels to dilate and relax. The genetically engineered intravenous compound also appears to boost the body's ability to excrete salt and fluids, which can help patients with acute heart failure.

A Healthy Outlook:  New drugs in development to fight heart failure

Tezosentan

Manufacturer: Actelion, Genentech Stage of development: In late-stage clinical trials, hoping for FDA approval in late 2002

Bosentan

Manufacturer: Scios Stage of development: Applied to FDA for approval; hoping for approval in July, 2001

Enbrel

Manufacturer: Immunex Stage of development: In late-stage clinical trial, hoping for FDA approval in 2003

Source: The companies

In a study of 498 patients headed by the Cleveland Clinic's Dr. Young and reported late last year, Natrecor proved better than intravenous nitroglycerin, the current standard of care, in quickly relieving symptoms of acute heart failure among patients admitted to the hospital. It was also easier to use and resulted in fewer side effects than nitroglycerin.

Dr. Young believes Natrecor may enable some patients to recover and be discharged without an overnight hospital stay. For others, it may eliminate or reduce the time needed for treatment in a hospital intensive-care unit.

Immunex takes a different approach with Enbrel, an injectable drug that works in rheumatoid-arthritis patients by reducing levels of a protein called tumor necrosis factor, one of the agents of the body's immune system. Douglas Mann, a researcher at Baylor College of Medicine in Houston, read an article 10 years ago that reported elevated levels of the inflammatory agent in heart-failure patients. His lab subsequently conducted a study that showed the damaged heart actually produces the protein at levels that instead of curing the problem "destroy the heart tissue and erode its infrastructure," he says.

Dr. Mann tested Enbrel in a group of 47 heart-failure patients. He reported substantial benefits for the medicine last month in Circulation: Journal of the American Heart Association. The pumping capacity of patients who received the highest doses improved by 25% on average compared with those who took only standard treatment, while 67% of the Enbrel patients reported an improved quality of life compared with 44% on standard therapy. Two larger trials should be finished later this year.

But these novel approaches from biotech companies also bring the challenge of price. Rachel Leheny, a biotech analyst at Lehman Brothers, anticipates the two acute heart-failure drugs from Actelion and Scios each will sell for almost $1,000 per round of treatment, while Actelion's chronic heart-failure medication could sell for $1,800. Enbrel, already priced at about $12,000 a year for rheumatoid arthritis, could cost more than $10,000, she says. Currently, the supply of Enbrel is so constrained that some arthritis patients are on a waiting list, but Immunex is building two new plants.

While companies aren't discussing pricing for now, it is certain to be an issue based in part on the already high cost of heart failure treatment. Such patients rack up costs estimated at $4,000 a year in out-patient care and $10,000 for every hospital admission. The companies argue that the cost of their drugs will be offset, at least in part, by savings in reduced hospital and other care.

Write to Geeta Anand at geeta.anand@wsj.com and Ron Winslow at ron.winslow@wsj.com