Clinical Trials Roundup—Week of 4/12

CardioRex Reduced Fatty Plaques in Study

Forbes Medi-Tech Inc. (Vancouver, BC, Canada) announced the results of recent animal studies with CardioRex—the company's proprietary, sterol-based cholesterol-lowering agent. Details of the study have been published in the current issue of Circulation, a journal of the American Heart Association. The major finding of this study was that CardioRex reduced the formation of atherosclerotic lesions (fatty plaques) in the blood vessel wall by 50% as compared to the control animals.

Further to earlier studies that show CardioRex's cholesterol-lowering and plaque reduction effects, this study tested other blood parameters in order to better understand these antiatherogenic properties. CardioRex increased HDL cholesterol levels by 14% and decreased fibrinogen, a blood-clotting factor, by 19%. The study also supports earlier research data that Cardiorex effectively reduces blood cholesterol levels and decreases the incidence heart-related disease.

For more information: Forbes Medi-Tech Inc., Suite 2000, 1066 West Hastings Street, Vancouver, B.C., Canada, V6E 3X2. Tel: 604-689-5899. Fax: 604-689-7641. Email: info@forbesmedi-tech.com.

ImClone's C225 Shows Anti-Tumor Activity; Other Anti-Cancer Agents In Trials

At the annual meeting of the American Association for Cancer Research (AACR) in Philadelphia, ImClone Systems Inc. (New York) announced findings from two preclinical studies of their lead cancer therapeutic, C225, demonstrating anti-tumor activity in animal models of human pancreatic carcinoma. C225, a monoclonal antibody, is an inhibitor of the epidermal growth factor receptor (EGFr) which is associated with cancer cell growth in a number of solid tumors.

In addition to C225, ImClone's other late stage clinical development program is an anti-cancer vaccine, BEC2. In May 1998, ImClone and its corporate partner Merck KgaA (Darmstadt, Germany) initiated a Phase III multinational clinical trial in limited disease small cell lung cancer patients. Also in preclinical development, ImClone is evaluating the therapeutic potential of its anti FLK-1/KDR monoclonal antibody as an anti-angiogenic agent, especially against tumors known to secrete vascular endothelial growth factor.

For more information: Samuel D. Waksal, President and CEO, ImClone Systems, 180 Varick St., 7th Fl., New York, NY 10014. Tel: 212-645-1405. Fax: 212-645-2054.

Sugen Begins Trial of SU6668, Reports on Other Angiogenesis Inhibitors in Trial

Also at the AACR annual meeting, Sugen (South San Francisco, CA) announced that it has dosed its first patient with an oral formulation of SU6668, a broad-spectrum tyrosine kinase inhibitor that combines both anti-angiogenic and anti-tumor properties. The Phase I dose-escalating trial of the oral formulation of SU6668 is taking place at UCLA's Jonsson Comprehensive Cancer Center in patients with advanced cancers who have failed all other treatment options. A Phase I study using an intravenous (IV) formulation of SU6668 is also taking place at the Royal Marsden Hospital in association with the Cancer Research Campaign Center for Cancer Therapeutics at the Institute of Cancer Research, Sutton, Surrey, UK.

Researchers also presented the following preclinical data on Sugen's other angiogenesis inhibitors:

• In a study led by Abhijit Guha at the University of Toronto, Princess Margaret Hospital, administration of SU5416 resulted in 54.8% tumor shrinkage, decreased tumor vascularity, decreased tumor proliferation and increased apoptosis in neurogenic sarcomas (nerve tissue tumors) in mice.
• In a study led by W. K. Alfred Yung at the M.D. Anderson Cancer Center in Houston, analogs (chemically related structures) of SU5416 and SU6668 were shown to inhibit cell growth and the formation of matrix metalloproteases (MMPs) in human glioma cell lines. Certain MMPs are believed to be associated with tumor growth, metastases and angiogenesis.
• In a study led by G. Tim Bowden of the University of Arizona Cancer Center, SU5402 (an analog of SU5416 and SU6668) was shown to inhibit the formation of MMPs in prostate cancer cells.

For more information: Stephen Evans-Freke, Chairman and CEO, Sugen Inc., 230 E. Grand Ave., South San Francisco, CA 94080-4811. Tel: 650-553-8300. Fax: 650-553-8301.

AVAX Completes Successful Phase II Trial of Cancer Vaccine

Post-surgical treatment with the autologous cell vaccine (AC Vaccine), M-Vax, appears to extend survival and reduce relapse rates in melanoma patients whose disease had metastasized to two nodal sites, according to the results of a Phase II clinical trial. The findings of the study, which was sponsored by AVAX Technologies Inc. (Kansas City, MO), were presented at the annual meeting of the AACR, and suggest that vaccines may play an important role in the treatment of one of the most fatal forms of cancer.

M-Vax is one of AVAX's AC Vaccines that is made from the patient's own cancer cells. The vaccine is made by modifying the tumor cells with a molecule called a "hapten." This process, known as "haptenization," alters the tumor cells and makes them appear foreign to the patient's immune system. When the hapten-modified cells are injected into patients, they stimulate the immune system to recognize the cancer cells and destroy them.

For more information: Jeffrey M. Jonas, President and CEO, AVAX Technologies Inc., 4520 Main St., Ste. 930, Kansas City, MO 64111. Tel: 816-960-1333. Fax: 816-960-1334.

GelTex Completes Phase II Trials of Cholestagel

GelTex Pharmaceuticals Inc. (Waltham, MA) announced findings from two Phase II clinical trials evaluating the efficacy of Cholestagel at reducing LDL-cholesterol levels when used in combination with either simvastatin (Zocor) or atorvastatin (Lipitor), the two most widely prescribed HMG-CoA reductase inhibitors ("statin" drugs). In the trials, the reduction in LDL cholesterol observed during the co-administration of Cholestagel and the statin was statistically superior to that observed with either Cholestagel or the statin alone.

The Phase II combination study with simvastatin was conducted in 13 U.S. and two Canadian medical centers, and evaluated 260 patients over a six-week treatment period. Cholestagel, in doses of 2.3g and 3.8g, was administered as monotherapy, and in combination with simvastatin in doses of 10mg and 20mg. The Phase II atorvastatin combination study was conducted in three U.S. medical centers, evaluating 94 patients over a four-week treatment period. Cholestagel (3.8g) was administered as monotherapy and in combination with atorvastatin (10mg).

For more information: Mark Skaletsky, President and CEO, GelTex Pharmaceuticals, 9 Fourth Ave., Waltham, MA 02154. Tel: 781-290-5888. Fax: 781-290-5890.

Study Shows IntraDose Injectable Gel Improves Efficacy of Cisplatin

At the AACR annual meeting, researchers suggested that the combination of systemic chemotherapy using cisplatin, a widely used anticancer drug, and local chemotherapy with a delayed-release version of the same drug may be more effective than systemic chemotherapy alone in controlling primary and metastatic (distant) disease and in improving survival. In the studies, conducted by Matrix Pharmaceutical Inc. (Fremont, CA), mice treated with intraperitoneal (i.p.) injections of cisplatin and direct injections of Matrix's IntraDose (cisplatin/epinephrine) Injectable Gel into their primary tumor lived longer with less metastatic disease and had significantly better control of the primary tumor than animals treated with i.p. (systemic) cisplatin alone.

MPI 5020, a locally injected gel containing the anticancer agent fluorouracil, is designed to enhance the cytotoxic effects of radiation therapy. MPI 5020 is in a Phase I/II trial in recurrent and metastatic breast cancer. The company is also developing FMdC, a systemically-administered new chemical entity currently under evaluation in a Phase II trial in non-small cell lung cancer.

For more information: Richard D. Leavitt, Sr. VP, Medical and Regulatory Affairs, Matrix Pharmaceutical, 34700 Campus Dr., Fremont, CA 94555. Tel: 510-742-9900. Fax: 510-742-8510.

Combination of Targretin and Tamoxifen Causes Breast Tumor Regression

At the AACR annual meeting, Ligand Pharmaceuticals Inc. (San Diego) presented results of a pre-clinical study showing Targretin (bexarotene), when added to tamoxifen therapy, caused complete or partial regression in 94% of tamoxifen-resistant primary breast tumors. In addition, the combination of Targretin and tamoxifen resulted in a 38% decrease in the total number of mammary tumors per animal. The combination regimen also significantly decreased primary tumor burden by 68%.

Targretin, also known as LGD1069 (bexarotene), a synthetic retinoid analogue discovered by Ligand scientists, selectively activates a subclass of retinoid receptors called Retinoid X Receptors (RXR), which play an important role in the control of cellular functions.

For more information: William W. Lamph, Associate Director, Retinoid Research, Ligand Pharmaceuticals Inc., 10275 Science Center Dr., San Diego, CA 92121-1117. Tel: 619-550-7500. Fax: 619-550-7506.

Virulizin Reduces Pancreatic Tumor Size in Pre-Clinical, Clinical Trials

Pre-clinical and clinical results of Lorus Therapeutics's (Markham, ON, Canada) lead anti-cancer drug, Virulizin, were presented at the AACR annual meeting. In a preclinical study in mouse models of human pancreatic cancer, researchers found that Virulizin significantly inhibited tumor growth, reducing tumor size by up to 40% when used alone and up to 74% when used with the chemotherapeutic agent Gemcitabine. On the clinical side, 37% of patients in a Phase I/II trial achieved a stable disease and one patient achieved a complete response. The patients treated with Virulizin had a median survival of 6.7 months and a 6-month survival rate of 58 percent. They also showed significant improvement in quality of life.

Virulizin is an immunotherapeutic agent—it activates the host's own immune defenses against cancer. The agent, which activates immune system cells known as monocytes and macrophages, is isolated from the bile of cows. Earlier research had demonstrated that Virulizin had significant antitumor activity against several tumor types, including pancreatic cancer, melanoma, and AIDS-associated lymphoma.

For more information: Philippe Lacaille, President and CEO, Lorus Therapeutics Inc., 7100 Woodbine Ave., Ste. 215, Markham, Ontario L3R 5J2, Canada. Tel: 905-305-1100, ext. 234. Fax: 905-305-1584. Email: lacaille@lorusthera.com.

GVAX Shown to Reduce PSA Levels in Prostate Cancer Patients

Additional clinical data from Cell Genesys' (Foster City, CA) initial Phase I/II trial of GVAX prostate cancer vaccine is consistent with previously reported interim results demonstrating that the vaccine was safe and well tolerated and resulted in antitumor activity as measured by blood levels of prostate specific antigen (PSA). Of the 21 patients in the study, 15 (71%) had disease stabilization and a decrease in the rate of rise of PSA levels. One patient has experienced a greater than 50%decrease in PSA levels. Treatment was safe and well tolerated in the outpatient setting. In addition, analysis of the blood of patients receiving GVAX(TM) has confirmed that the vaccine induces specific antitumor immunity as evidenced by a unique pattern of antibodies directed against tumor antigens on the gene-modified prostate cancer cells comprising the vaccine.

GVAX vaccine for prostate cancer is comprised of irradiated prostate cancer cells that have been genetically modified to continually produce granulocyte-macrophage colony stimulating factor (GM-CSF), a hormone which plays a key role in augmenting the body's immune response to vaccines. Cell Genesys is also testing GVAX cancer vaccines in lung cancer and melanoma. GVAX has now been reported to show evidence of antitumor activity in all four types of cancer tested to date including prostate cancer, lung cancer, melanoma, and kidney cancer, suggesting that GVAX may be applicable to multiple types of cancer.

For more information: Dale Ando, VP, Clinical Research and Regulatory Affairs, Cell Genesys, 342 Lakeside Dr., Foster City, CA 94404. Tel: 650-425-4400. Fax: 650-425-4457.

Demegen's D2A21 Peptide Inhibits Tumor Growth in Study

At the AACR annual meeting, researchers from the University of Pittsburgh Cancer Institute (UPCI) presented results of preclinical studies using Demegen Inc.'s (Pittsburgh) patented D2A21 peptide. In the preclinical experiments conducted at UPCI, investigators used Demegen's D2A21 to treat established aggressive prostate cancers in rats. The researchers found that D2A21 inhibited tumor growth by as much as 60% as compared to untreated animals. In addition, treatment with D2A21 did not cause any significant toxicities.

Demegen's D2A21 peptide is a laboratory-synthesized small compound that destroys a cancer cell by attaching to its surface and disrupting its outer membrane. At therapeutic doses, D2A21 is designed to target and lyse (eliminate) cancer cells, sparing the normal healthy cells and tissues.

For more information: Richard Ekstrom, CEO, Demegen Inc., 1051 Brinton Rd., Pittsburgh, PA 15221. Tel: 412-241-2150. Fax: 412-241-2161. Email: info@demegen.com.

U.K. Approval of Atridox Delayed

Atrix Laboratories Inc. (Fort Collins, CO) announced that U.K. approval of Atridox antibiotic therapy for periodontal disease, which was expected by the end of March, has been delayed temporarily and is now expected in May. Atrix received product approval from the Medicines Control Agency (MCA) in the United Kingdom last November and then submitted a series of 20 "variations" to the Product License. These variations, which relate to improvements in testing and manufacturing of the product made while the Product License Application was under review, are in the last stage of review by the MCA. Final approval of the Product License should occur in May.

For more information: John Urheim, CEO, Atrix Laboratories Inc., 2579 Midpoint Dr., Fort Collins, CO 80525. Tel: 970-482-5868. Fax: 970-482-9735. Email: Jurheim@atrixlab.com.