By Mary Welch

By the end of the year, NeuroVir Therapeutics Inc. expects to have two products that use modified herpes simplex viruses (HSV) in Phase II and I/II trials for glioblastoma and colorectal cancer that has metastasized to the liver.

"We've put two products in the clinic in three operating years for less than $8 million," said Peter Ulrich, president and CEO of NeuroVir. "That's a record not many companies have equaled, I believe. It points to our efficiency as well as the fact that we're fortunate to have a pervasive platform technology. We may also be one of the only - if not the only - company that is developing replication-competent HSV-based products for these two indications."

Founded in Vancouver, British Columbia, NeuroVir will relocate its operations to San Diego later this year. The company was formed as a result of a licensing agreement with Aviron, of Mountain View, Calif.

"Aviron focuses on infectious diseases and had developed this intellectual property for herpes that is very broad," Ulrich said. "Aviron's scientific collaborators had a relationship with scientists at the University of British Columbia, who were doing some experiments on modified oncolytic herpes viruses where they eradicated brain tumors in rat models. Aviron realized that to best develop the oncology application of its technology, it would be preferable to transfer the technology to another or a new company."

Three founding scientists - Michael Hayden, Max Cynader and Frank Tufaro - started the company and Aviron transferred its technology for equity in the new start-up. Currently it owns 15.7 percent of the company. Seed financing came through Haywood Securities, of Vancouver, and private investors. Additional funding has since come from Haywood as well as First Marathon Securities, of Toronto. So far, the company has raised about C$13.5 million (US$9 million).

NeuroVir, now with 23 employees, believes that modifying HSV offers a lot of benefits.

"Herpes infects a large percentage of the population, is well characterized and has a demonstrated ability to infect certain cells, spread from cell to cell and kill them," Ulrich said. "NeuroVir takes the cancer cell-killing properties of the herpes virus and through molecular modification, directs their aggressiveness toward solid tumors. The virus retains its ability to kill cancer cells but is neutralized, through molecular modification, in its ability to cause diseases."

NeuroVir has three applications for its platform technology. The first is a simple oncolytic method of action. The modified herpes virus is administered into the tumor, where it replicates and kills it. It has the selective ability to spread from tumor cell to tumor cell even in the presence of anti-HSV antibodies.

"One of the benefits of this technology is that it can be given by multiple routes of administration, including direct tumor injection, hepatic artery infusion, peritoneal cavity injection and intravenous injection," Ulrich said.

The second way takes advantage of the fact the HSV is a physically large DNA virus, which enables scientists to insert large therapeutic genes or multiple genes. Such gene insertion offers the possibility of augmenting the rapid, potent and selective tumor-killing capabilities of HSV with gene expression. Potentially complementary gene approaches include immunomodulatory, anti- angiogenic, chemosensitizing and protective genes.

The third application is called Amplicon HSV, in which the viral genes are eliminated but the viral exterior proteins are retained and the vector can be used as a "moving van for genes," Ulrich said.

"When you use the Amplicon virus, you can insert even larger amounts of genetic material into HSV," he said. Applications of Amplicon HSV to treat cancer and neurodegenerative diseases are in the discovery stage.

The privately held company has two product candidates in the clinic. G207 is a tumor-killing HSV designed to treat central nervous system malignancies such as primary cancers of the brain and metastases of other cancers to the brain. A Phase I study of 21 patients with glioblastoma was started in Feb. 1998 and completed in June. Phase II trials should start by year's end, Ulrich said.

The company recently received the go-ahead from the FDA to start a Phase I/II trial of its second candidate, NV1020, for patients with colorectal cancer that has metastasized to the liver. The trial will be conducted at New York's Memorial Sloan-Kettering Cancer Center, where preclinical data in animals showed an 84 percent reduction in the number of metastatic nodules with a single HSV infusion.

"This is a really neat platform technology that is causing a lot of enthusiasm," Ulrich said. "The National Cancer Institute studies demonstrated that HSV could kill most solid tumors, although not blood cancers. But, there is great potential for treating brain, colorectal, liver, bladder, lung, head and neck, ovarian, gastric and prostate. Investigators also have demonstrated true synergy with radiation and chemotherapy."

NeuroVir has embarked on its third fund-raising effort and anticipates a $10 million private placement in early fall. "This placement predominately will be used to fund the clinical trials," Ulrich said. "The first two rounds involved institutions and private individuals and we're looking for the same mix here but also plan to add some traditional venture investors."

Ulrich said he is confident of reaching this latest financial goal because "HSV therapy has the potential to become the fourth leg on the stool of cancer treatment, joining surgery, chemotherapy and radiation."