By Karen Pihl-Carey

Shown to be an effective agent in tumor reduction, IntraDose Injectable Gel will be the subject of a new drug application (NDA) to be filed this year by its developer, Matrix Pharmaceutical Inc.

In two Phase III studies in 178 patients with late-stage recurrent or refractory head and neck cancer, IntraDose not only met its primary endpoint of tumor response, but it demonstrated high benefits to patients in pain control and relief of symptoms, among other benefits. The data were presented Monday at the 36th annual meeting of the American Society of Clinical Oncology (ASCO) in New Orleans.

"You're getting a very high response rate to late-stage disease, with a side effect profile that's very, very tolerable for patients, and we're excited about that," said David Ludvigson, chief operating officer of Fremont, Calif.-based Matrix.

"These are very late-stage patients," he added. "They've all had multiple courses of prior therapy - surgery, radiation, chemotherapies - and so it's a very difficult patient population."

Matrix expects to submit the NDA by the end of this year. Under IntraDose's fast-track designation, the FDA will have six months to make a decision once it accepts the NDA, meaning an approval could be made as early as mid-2001.

Investors did not respond favorably to the news, on a day when biotech stocks were down in general. The company's stock (NASDAQ:MATX) closed Monday at $10, down $1.50, or 13.04 percent.

Combined results of the two trials show that 29 percent of patients taking IntraDose achieved an objective tumor response vs. 2 percent of patients on placebo. This is statistically significant (p<.001 about percent of the patients achieved a complete response. class="text">Before the trial began, patients and their physicians each individually determined a patient benefit goal - pain control, relief of obstructive symptoms, improved mobility, improved physical appearance, wound control, or ability to hear, smell or see. The two trials demonstrated that 27 percent of the IntraDose-treated patients achieved the benefit goal, compared with 12 percent of those patients on placebo, again a statistically significant difference (p<.046 class="text">"Most importantly, there was a high correlation in the people who had a tumor response who also achieved their patient benefit goal," Ludvigson told BioWorld Today.

Almost half - 47 percent - of patients with a tumor response also achieved their predetermined benefit goal, compared to 15 percent of those without a tumor response.

The first study included 86 patients and was conducted in North America, while the second study enrolled 92 patients and was conducted outside North America. Patients were randomized to receive IntraDose or placebo (collagen gel) in a 2-to-1 ratio. They were given up to six intratumoral injections within an eight-week period. Responses had to be sustained for 28 or more days.

Side effects of IntraDose included injection site reactions, such as pain, but the systemic side effects normally associated with systemic cisplatin therapy were infrequent.

"There was some pain that was experienced, and also some necrosis of the tumor tissue," Ludvigson said. "There was some minor nausea and vomiting, but nothing similar to what you would see with patients who receive systemic cisplatin."

Early in the trial, four patients did experience cerebrovascular side effects, but none of these side effects occurred after modified protocols excluded patients with tumors invading or in close proximity of the carotid artery, the company said.

Ludvigson said there are about 164,000 people who have head and neck cancer in the U.S., with about 42,000 new cases each year. Matrix expects to file to market IntraDose in Europe following the U.S. filing later this year.

"We plan to sell and market the product in the U.S. and to partner the marketing and sales outside the U.S.," he said.

IntraDose is a collagen-based gel that incorporates cisplatin and epinephrine. It is injected directly into the tumor site. It has shown a benefit in multiple types of tumors other than head and neck cancer, including recurrent breast cancer, malignant melanoma, esophageal cancer and primary liver cancer, Ludvigson said.

Matrix presented results this week at ASCO of an ongoing Phase II study of 38 patients with primary liver cancer - or hepatocellular carcinoma (HCC) - being treated with IntraDose. The endpoints of the study are tumor response and patient survival. About 55 percent of patients have experienced a response to therapy, Matrix said. Of the 21 responders, nine had complete responses and 12 remain in remission. Median survival time from the date of study entry is 23 months for patients who responded to the therapy, and 13 months for the non-responders.

"This early result is quite significant, as patients in this study possess unresectable HCC - IntraDose may be as effective as the gold standard in this study population," stated a research note put out by analyst Peter Ginsberg, of U.S. Bancorp Piper Jaffray in Minneapolis.

Matrix expects to report final results from the HCC trial in 2001.

Aside from IntraDose, the company is developing the anticancer compound FMdC, which is in Phase I and Phase II trials. And its radiopotentiator, MPI 5020, has completed a Phase I trial.