Ribozyme Pharmaceuticals Inc. said Tuesday its Phase II trial of Angiozyme in metastatic breast cancer failed to achieve a clinically significant response rate.

In addition, the Boulder, Colo.-based company said it stopped dosing in a Phase II trial of Heptazyme, another ribozyme-based drug, after an animal in a study lost its vision.

Ribozyme’s stock (NASDAQ:RZYM) dropped 32.4 percent Tuesday, or 67 cents, to close at $1.40.

Despite Angiozyme’s failure as a monotherapy in the Phase II trial, the company said the drug candidate for the first time did demonstrate biological activity in humans.

“While we did have some clinical setbacks, overall we are very excited about the fact we have demonstrated positive results in humans,” Ribozyme President and CEO Howard Robin said in a conference call.

Ribozyme is focused on the development of ribozyme-based therapeutics and diagnostic tools. Ribozymes are synthetically engineered to act as molecular scissors capable of cutting target RNA to block gene expression and thereby the production of unwanted proteins.

Robin said during the call he “would not like to see people give up on important therapy because of some temporary setbacks.”

He later told BioWorld Today that the stock drop was “an emotional reaction to a selective piece of data.” He also said that the results of the Angiozyme study in metastatic breast cancer do “not mean that ribozymes don’t work.”

The Phase II study of Angiozyme was in Stage IV breast cancer, and it was being tested as a monotherapy. Angiozyme is a ribozyme that targets the high-affinity receptor for vascular endothelial growth factor (VEGFR-1), designed as an angiogenesis inhibitor. While the response rate was not “clinically meaningful,” the study did demonstrate a statistically significant reduction in the levels of soluble VEGFR-1, which also was a goal of the study, the company said.

Cathy Robins, director of corporate communications at Ribozyme, said although the outcome was not the desired one, it was important to study Angiozyme as a monotherapy to gauge the impact of the drug.

Ribozyme also is conducting a Phase II trial of Angiozyme as a combination therapy in conjunction with the Saltz regimen for metastatic colorectal cancer. The Saltz regimen consists of a standard chemotherapy regimen of CPT-11, 5-FU and leucovorin. Enrollment of 80 patients was completed, and the company expects to have results by year’s end. However, Robin described the results to date as “very encouraging.”

Ribozyme is partnered with Chiron Corp., of Emeryville, Calif., for the development of Angiozyme. The companies share costs 50-50 in the co-development agreement entered in August 1994. (See BioWorld Today, Aug. 5, 1994.)

The Heptazyme Phase II trial began in October and included about 40 patients with chronic hepatitis C. Heptazyme is a direct antiviral therapeutic specifically engineered to prevent replication of HCV, and has shown potent antiviral activity in preclinical models, the company said. The study is designed to evaluate Heptazyme safety and efficacy when administered alone and in combination with interferon.

Robin said that although the company decided it was “appropriate” to stop dosing in the trial when the vision loss was discovered, there has been no direct correlation between the vision loss and Heptazyme. Ribozyme is waiting for a response from the FDA as to if and when it can continue the trial, he said.

The company intends to find a company to partner with on Heptazyme, he said.

Still, Robin said that there was a “knockdown of virus” in 10 percent of the patients based on evaluation of 32 patients.

“We’re very excited about starting the cohort with interferon,” he said, although pending the FDA’s response and any additional study that may be required, he could not say when that part of the study might be initiated.

Ribozyme also is conducting a Phase I dose-escalation trial of another candidate, Herzyme, in patients with HER2-overexpressing cancers. Ribozyme is collaborating with Elan Corp. plc, of Dublin, Ireland, in a venture named Medizyme Pharmaceuticals. The trial is employing Elan’s Medipad device to deliver Herzyme subcutaneously.

Ribozyme had $28 million in cash at the end of the first quarter, and its net loss last year was $60.6 million, though Robin said the burn rate is expected to be significantly reduced this year.

“We certainly do have to raise more money, and we have to maintain a positive cash position,” he said.

In what he called a financial “gap-filler,” Ribozyme entered the diagnostics arena in March when it entered an agreement with Fujirebio Inc., of Tokyo, to develop and commercialize ribozyme-based clinical diagnostic products. Ribozyme is set to receive licensing fees, research funding, milestone payments and royalties, as well as retaining certain manufacturing rights. Robin said that he expects milestone payments this year. (See BioWorld Today, March 5, 2002.)

“We are moving forward in improving the detection limits and improving the technology in the diagnostics area,” Robin said. “When we get to certain levels we get certain milestones, and we certainly expect to meet those levels this year.”

Additionally, Ribozyme is collaborating with Geron Corp., of Menlo Park, Calif., to develop its lead telomerase inhibitor, GRN163.

Ribozyme has spun out and licensed technology to Atugen AG, of Berlin, a company focused on target validation. With Archemix Corp., of Cambridge, Mass., Ribozyme has a licensing agreement to use allosteric ribozymes in drug discovery and optimization and environmental monitoring. Ribozyme holds equity positions in both companies.