By Karen Pihl-Carey

Although Chiron Corp.¿s FGF-2 failed to meet its primary endpoint in a Phase II trial in symptomatic coronary artery patients, the drug may still have some value in reducing chest pain.

At the American College of Cardiology¿s 49th Annual Scientific Session, researchers presented the study in which recombinant fibroblast growth factor-2 (FGF-2) was tested in patients who were not candidates for angioplasty or bypass surgery. The primary endpoint was the improvement of exercise time at a 90-day analysis.

¿That analysis did not show statistical significance. The patients who received the drug in the active treatment arm exercised a little longer than patients who received placebo, but the changes were comparatively modest,¿ said Bruce Scharschmidt, vice president of clinical development at Chiron, of Emeryville, Calif. ¿However, when we looked at our most important secondary endpoint, we saw some very encouraging signals.¿

Researchers noticed a reduction of angina, or chest pain, as measured by both patients and their physicians. Despite that finding, the company¿s stock (NASDAQ:CHIR) still fell 24 percent Monday to close at $45.75, down $14.187.

¿This is a pretty young field,¿ Scharschmidt told BioWorld Today. ¿This is the biggest trial yet conducted in the field of angiogenesis.¿ He said the trial had a goal of confirming safety and finding evidence of efficacy in order to ¿find endpoints that would be most appropriate to think about for pivotal trials.¿

The reduction of angina could very well be the primary endpoint in a subsequent trial, Scharschmidt said, but Chiron must evaluate the patients at a 180-day mark, as well as look at preclinical studies and the results of a Phase II trial of FGF-2 in peripheral artery disease. All of these results are expected in the second half of the year.

In the Phase II study for coronary artery disease, 337 patients received one of three doses ¿ 0.3, 3 and 30 micrograms/kg ¿ administered as a single intracoronary infusion, or a placebo.

An exercise tolerance test administered at the beginning of the study and at the 90-day mark evaluated the primary endpoint of the double-blind study.

¿We simply looked at the total time on treadmill,¿ Scharschmidt said. ¿About half the patients, or a little less, stopped because of progressive angina. The next largest reasons were patients who became fatigued and couldn¿t go on, or just patients who requested to stop.¿

Scharschmidt said that six patients enrolled in the study died, but that they had been treated in all dose groups and their deaths did not seem to be related to the therapy. An independent safety monitoring board came to the same conclusion, he said.

¿With these patients, the annual mortality might be somewhere in the range of 5 [percent] to 10 percent,¿ he said. ¿In this particular trial we had six deaths out of 337 patients. That¿s less than 2 percent.¿

VEGF-2 Reaches Statistical Significance

Researchers at St. Elizabeth¿s Medical Center in Boston found that VEGF-2 demonstrated statistically significant results in a study evaluating the gene therapy in patients with coronary artery disease.

In a 30-patient study, researchers looked at the safety and effects of increasing doses of vascular endothelial growth factor-2 (VEGF-2) in patients with stable and refractory exertional angina who were not candidates for revascularization procedures. The primary endpoints included changes in angina class and exercise tolerance testing at 12 weeks.

Three groups of 10 patients each received 200 mcg, 800 mcg or 2 mg of VEGF-2 as a naked DNA plasmid via direct injection into the myocardium. Eighty percent of the patients were male, with a mean age of 59.

Researchers found that 70 percent of patients experienced a reduction equal to or greater than two angina classes. A statistically significant increase was observed in exercise tolerance, while statistically significant reductions were observed in sublingual use of nitroglycerin and in frequency of angina episodes per week.

The most common adverse events were pain, fever and nausea. A 59-year-old man, who had undergone a triple coronary bypass graft in 1993, died of cardiac arrest one day following treatment.

Lead investigator Jeffrey Isner, chief of cardiovascular research at St. Elizabeth¿s, said the man was one of five deceased people who had participated in any of the four Phase I/II VEGF-2 studies for the treatments of advanced coronary artery disease and peripheral artery disease. One of those patients was on placebo. Isner said the number of deaths does not exceed anticipated rates in such patient groups and investigators do not believe they are associated with the therapy.

VEGF-2 is part of Rockville, Md.-based Human Genome Sciences Inc.¿s product portfolio. The company¿s stock (NASDAQ:HGSI) closed Monday at $152.562, down $19.937, or 11.56 percent.

In other news at the conference:

¿ Alexion Pharmaceuticals Inc., of New Haven, Conn., and Yale University School of Medicine, also of New Haven, discovered that patients with acute coronary syndrome have severe inflammation in their coronary arteries. Alexion said its two C5 complement inhibitors, 5G1.1-SC and 5G1.1, specifically block the production of harmful complement components.

¿ AVI BioPharma, of Portland, Ore., said data from a study of its antisense compound, Resten-NG, showed the drug prevented balloon-induced restenosis in rabbits with atherosclerotic vascular disease resulting from a high-cholesterol diet.

¿ Genentech Inc., of South San Francisco, said it plans to collaborate with other major pharmaceutical manufacturers to test the new, single-bolus thrombolytic, TNKase (tenecteplase), in combination with leading antithrombotic agents in the treatment of acute myocardial infarction (AMI). The testing will take place in four clinical trials involving about 9,000 patients. One study will be a multicenter, international trial, studying TNKase in combination with enoxaparin sodium (Clexane/Lovenox) and the antiplatelet drug abciximab (ReoPro) in the treatment of AMI. TNKase is under regulatory review in the U.S. and Europe.

¿ Texas Biotechnology Corp., of Houston, said Phase III results showed Novastan injections significantly improved patient outcomes in the primary endpoint and provided anticoagulation with no increase in bleeding as compared to the control group. The drug was tested in patients with heparin-induced thrombocytopenia (HIT). The primary endpoint called for the evaluation of all-cause death, all-cause amputation or new thrombosis over a 37-day period. Historical control patients with HIT (those with a drop in platelets but not thrombosis at baseline) had a 68 percent greater risk of experiencing death, amputation or new thrombosis, while patients with HITTS (those with thrombosis at baseline) exhibited a 75 percent greater risk. Statistical significance in favor of Novastan was achieved in both study arms. The company received an approvable letter for the drug last month. (See BioWorld Today, Feb. 23, 2000, p. 1.)

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