By Randall Osborne
Providing a financial boost for its just-begun pivotal Phase III clinical trial of an oral compound for stable angina, CV Therapeutics Inc. has closed a $12.9 million private placement with Biotech Target S.A., an affiliate of BB Biotech A.G., of Switzerland.
CV Therapeutics, of Palo Alto, Calif., will have 8.4 million shares outstanding after the placement of 1.4 million shares at $9.25 per share with BB Biotech, a new investor. The placement gives BB Biotech 16.6 percent of CV Therapeutics' shares.
Ranolazine, the company's drug in the Phase III trial, lets the heart burn glucose rather than fat for energy, lowering its demand for oxygen without reducing heart rate, blood pressure or pumping ability in stable, or chronic, angina, which is regular pain associated with heart disease.
About seven million patients in the U.S. suffer from angina. Of those, about 15 percent at some point become unstable and undergo chest pain at irregular intervals.
Michael Sterns, director of business development for CV Therapeutics, said ranolazine is meant for stable patients — especially for the core group that does not respond to the usual therapies: nitrates, beta blockers and calcium channel blockers.
Three to six percent of patients make up the core group of stable angina patients who are not well controlled by conventional drugs, Sterns said. "They're not surgical candidates, because they are often older patients with multi-vessel disease. There's really nothing else to do.
"As you move out from this inner circle [of three to six percent], you pick up the people with congestive heart failure," Sterns continued. "They have a hard time with beta blockers and calcium channel blockers," which suppress the heart. "They can't stand any more pump compromises."
Another market would be angina patients with asthma or other pulmonary problems, for whom beta blockers are not recommended.
Andrew Wolff, vice president of clinical research for CV Therapeutics, said the Phase III trial is expected to enroll 108 subjects at 14 or more sites and will last one year. Patients in the placebo-controlled, double-blind study are being given alternating ranolazine dosage levels of 500 mg, 1,000 mg and 1,500 mg, along with the placebo. The endpoint is angina-limited exercise duration, as measured on a treadmill.
The treadmill test is "the FDA gold standard" for trials of angina drugs, Wolff said. "We hope to get at least 30 seconds more on one of the ranolazine doses."
Each patient is shown a five-level pain scale before stepping onto the treadmill. Level zero is no pain. Level 1 is "something's happening," Wolff said. "Level 2 is, 'Yes, this is angina. This is not heartburn.' Level 3 is, 'I would stop now, if I were out on the street or playing golf. I would take nitroglycerin.'"
Level 4 is extreme pain, possibly signaling a heart attack, Wolff said. "This should only happen to somebody by accident," he added.
Researchers will measure how long each patient walks the treadmill before pain starts, how long the walking and pain continue before the patient must stop, and how much myocardial ischemia (reduction of blood flow) shows up on an electrocardiogram to which the patient is attached during the test.
In earlier trials, Wolff said, ranolazine (piperazine acetamide) showed its effectiveness in letting the oxygen-starved heart use glucose rather than fat for energy. "Fats are more energy-rich, but you need to use more oxygen to get the energy out," he said. "You get more energy out of the glucose per atom of oxygen that you use. That's the key, that ratio."
A second, larger Phase III trial will be conducted in the second half of next year, Wolff said, and will conclude by the end of 1999. The company hopes to file a new drug application with the FDA in the year 2000, he said.
As of June 30, CV Therapeutics had $26.85 million in cash and recorded a net loss of $5.12 million for the first six months of 1997. The company's stock (NASDAQ:CVTX) closed Wednesday at $10.937, down $0.563, or 4.896 percent. *