Staff Writer

OncoGenex Technologies Inc. said encouraging data were reported from a Phase II trial of OGX-011 in combination with docetaxel in patients with metastatic breast cancer.

Data were presented by the National Cancer Institute of Canada - Clinical Trials Group at the annual meeting of the American Association for Cancer Research in Los Angeles. OGX-011 is designed to specifically inhibit the production of the cell-survival protein clusterin, which is associated with treatment resistance in many cancers and in response to various treatments.

Five of the 15 patients treated showed a partial response, and nine patients showed disease stabilization. In those nine, tumor reduction ranged from 1 percent to 23 percent, and disease stabilization was sustained for a median of 9.3 months.

Only one patient advanced to progressive disease. While patient monitoring is ongoing, the median progression-free survival for all patients was eight months, and the median time for survival had not yet been reached.

OncoGenex, of Vancouver, British Columbia, plans to release additional Phase II data from its OCX-011 programs in prostate cancer and non-small-cell lung cancer later this year.

In other news from the AACR meeting, which ends today:

• Adherex Technologies Inc., of Research Triangle Park, N.C., presented preclinical data on ADH-1 in combination with chemotherapy. In vitro, ADH-1 showed synergistic effect with paclitaxel in ovarian cell lines. In vivo, the combination of ADH-1 and paclitaxel had antitumor activity significantly superior to the untreated group and the groups treated with single-agent ADH-1 alone or paclitaxel alone. Also, in vitro, ADH-1 prevented N-cadherin-mediated cell scattering and migration, and induced apoptosis. In vivo, ADH-1 prevented tumor growth and metastasis.

• Adnexus Therapeutics Inc., of Waltham, Mass., presented data showing CT-322, a specific VEGFR-2-blocking protein agent, had activity in preclinical tumor models comparable to the pan-specific tyrosine kinase receptor inhibitors sunitinib and sorafenib. CT-322 is a monospecific blocker of the tyrosine kinase receptor, VEGFR-2, and blocks its activation by all known extracellular ligands: VEGF-A, VEGF-C and VEGF-D.

• AEterna Zentaris Inc., of Quebec City, presented in vivo data for its growth hormone-releasing hormone antagonist, JMR-132, in breast cancer. With docetaxel, it induced regression of MX-1 human experimental breast cancers. The effect was shown in doxorubicin-resistant cancers.

• Alnylam Pharmaceuticals Inc., of Cambridge, Mass., said it advanced a systemically delivered RNAi therapeutic, ALN-VSP01, for the treatment of liver cancer and potentially other solid tumors as a new development program. ALN-VSP01 is an RNAi therapeutic designed to target vascular endothelial growth factor and kinesin spindle protein. Alnylam expects to submit an investigational new drug application for that program in 2008. Data presented showed the ability of RNAi therapeutics to silence both VEGF and KSP expression in the liver and to stop cancer cell proliferation by targeting KSP. ALN-VSP01 is made with a liposomal formulation technology, manufactured by partner Inex Pharmaceuticals Corp., of Vancouver, British Columbia.

• Anadys Pharmaceuticals Inc., of San Diego, presented data from an in vitro study showing that the active metabolite of ANA773 promotes natural killer cell-mediated anti-tumor response by inducing cytokine secretion, cytolysis of tumor cells and enhanced antibody-dependent cellular cytotoxicity. The study found that the active metabolite of ANA773, an oral Toll-like receptor 7 agonist prodrug, induced the secretion of interferon-alpha and various other cytokines from human peripheral blood mononuclear cells cultured in vitro.

• Avalon Pharmaceuticals Inc., of Germantown, Md., reported on an AVN944 biomarker study that used its AvalonRx technology to identify gene signatures that may be useful for patient stratification. AVN944 is an orally available inhibitor of inosine monophosphate dehydrogenase 1 and 2. The biomarker study may help identify patients most likely to benefit from AVN944 therapy.

• AVEO Pharmaceuticals Inc., of Cambridge, Mass., presented encouraging preclinical data on AV-412, a next-generation oral tyrosine kinase inhibitor of EGFR/HER2, using its EGFR mutant and drug-resistant lung cancer tumor models. Results showed AV-412 is greater than 10 times more potent than erlotinib (Tarceva) in genetically engineered lung tumor models with the EGFR L858R mutation, producing rapid and complete tumor regression at a daily dose of 1 mg/kg. Additionally, AV-412 is active against tumors carrying the EGFR kinase-resistance mutation EGFR L858R/T790M.

• Barbara Ann Karmanos Cancer Institute, of Detroit, said its researchers presented data showing the copper-binding antibiotic Clioquinol, typically prescribed for Alzheimer's disease, appears to have an antitumor effect in mice bearing human prostate cancer cells. Research began after the discovery that certain tumor tissues had high levels of copper.

• Cell Genesys Inc., of South San Francisco, reported immune-response data from two previously conducted Phase II trials of GVAX immunotherapy for prostate cancer. Evaluation of antibody responses in patients with advanced disease showed GVAX cell-based immunotherapy induced antibody responses to a broad array of prostate cancer-associated antigens, including some not previously known to be associated with prostate cancer. In addition, the antibody responses to this non-patient-specific product were predominantly patient-specific and unique from patient to patient.

• ChemGenex Pharmaceuticals Ltd., of Melbourne, Australia, presented preclinical data on its lead compound, Ceflatonin (homoharringtonine, or HHT), demonstrating its oral bioavailability and further describing its mechanism of action. Ceflatonin is in Phase II/III trials for chronic myeloid leukemia patients who are resistant to tyrosine kinase inhibitors. The product, previously identified as an inhibitor of protein synthesis, regulates the binding of transcription factors in a more specific manner than the non-specific protein synthesis inhibitor cycloheximide. Separately, it said a preclinical agent (CXS299) up-regulates the expression of the tumor suppressor p53 and circumvents resistance to cisplatin.

• Cougar Biotechnology Inc., of Los Angeles, presented positive Phase I and II data on its prostate cancer drug candidate, CB7630 (abiraterone acetate). Data showed inhibition of androgen synthesis resulted in a high response rate in castration-refractory prostate cancer. To date, 38 patients had been treated in the Phase I/II trial. Of 30 evaluable patients, 18 experienced confirmed declines in prostate-specific antigen levels of greater than 50 percent, with 10 of the 30 patients experiencing PSA declines of greater than 90 percent. Abiraterone is an oral, irreversible CYP450c17 enzyme inhibitor.

• Curis Inc., of Cambridge, Mass., disclosed that its April 2005 discovery collaboration agreement with Genentech Inc., of South San Francisco, is focused on developing drug candidates that target the Wnt signaling pathway. Abnormal activation of Wnt signaling is present in various cancers. They have discovered a class of Wnt antagonists that, in preclinical studies, inhibit the Wnt pathway by acting upstream of beta-catenin. Separately, they found that antagonizing the Hedgehog pathway results in a growth delay of a subset of primary human pancreatic cancer xenografts.

• Cyclacel Pharmaceuticals Inc., of Berkeley Heights, N.J., said a preclinical combination study of seliciclib, an orally available cyclin-dependent kinase inhibitor, with the epidermal growth factor receptor inhibitor erlotinib (Tarceva) demonstrated the drugs act synergistically in suppressing tumor growth in models of non-small-cell lung cancer. The combination reduced EGFR signaling and synergistically induced death by apoptosis in cancer cells.

• EntreMed Inc., of Rockville, Md., presented preclinical data showing that oral administration of ENMD-1198 was well tolerated and produced significant dose-dependent antitumor activity in a preclinical breast tumor model. Histologic staining and evaluation of tumor sections from the model demonstrated a decrease in HIF-1 alpha, tumor cell growth (PCNA) and angiogenesis (CD31). ENMD-1198 is a new chemical entity based on a modified chemical structure of 2-methoxyestradiol (2ME2). Separately, ENMD-1198 demonstrated antitumor activity against vinca alkaloid-sensitive and resistant leukemia cell lines.

• ExonHit Therapeutics SA, of Paris, said a panel of gene expression biomarkers effectively identified breast cancer patients at an early stage (I/II). An 85 percent sensitivity and 87 percent specificity were obtained from a group of 188 patients and controls. The panel provided similar results when applied to an independent cohort of 60 women. A prospective clinical study that will include 1,875 individuals began in September, with collaborator bioMerieux, of Paris.

• GenVec Inc., of Gaithersburg, Md., presented data showing its molecularly targeted adenovectors selectively delivered genes to cancer cells in the peritoneal cavity in several animal models. Those data demonstrated the ability of targeted vectors to penetrate tumor tissue and trigger protein expression in a dose-dependent manner. The preclinical research suggests that tumor-selective adenovectors can preferentially deliver the TNF-alpha gene, and holds promise as a treatment for ovarian cancer. GenVec's lead product, TNFerade, is an adenovector containing the gene for TNF-alpha.

• GlaxoSmithKline plc, of London, said its cervical cancer candidate vaccine, Cervarix, demonstrated 100 percent efficacy in preventing precancerous lesions due to cancer-causing human papillomavirus types 16 and 18 for up to 5.5 years. Data came from an extended follow-up trial. The vaccine also showed 68 percent vaccine efficacy against precancerous lesions (CIN2+) and 38 percent vaccine efficacy against abnormal pap smears, regardless of the type of cancer-causing virus detected. The study provided further preliminary evidence of cross-protection against incident infection with cancer-causing virus types 45 and 31 that also extended up to 5.5 years after vaccination. GSK has filed for approval of the vaccine with the FDA.

• Immunomedics Inc., of Morris Plains, N.J., reported that the antigen targeted by its humanized PAM4 antibody is expressed in early stage pancreatic cancer specimens, a stage before the tumor becomes invasive. Researchers found that more than 89 percent of 56 specimens of early pancreatic cancer tested positive for the PAM4 antibody. Likewise, 87 percent of 48 specimens of invasive adenocarcinoma of the pancreas showed positive labeling with PAM4. PAM4 is an antibody that recognizes a specific biomarker (MUC1) made almost exclusively by pancreatic cancer. Immunomedics also presented positive preclinical data on its Rap-hRS7 immunotoxin for prostate and lung cancers. Rap-hRS7 was constructed by fusing an amphibian RNase to hRS7, a humanized antibody targeting epithelial glycoprotein-1.

• Innovive Pharmaceuticals Inc., of New York, presented additional clinical and preclinical data on INNO-406, an oral, dual Bcr-Abl and Lyn-kinase inhibitor for Gleevec-resistant or intolerant chronic myelogenous leukemia. It said Phase I data to date demonstrated clinical activity, safety and tolerability. Data showed a 55-fold reduction in Bcr-Abl transcript levels.

• Lorus Therapeutics Inc., of Toronto, presented research showing a new dosing schedule of GTI-2040 and docetaxel resulted in greatly enhanced synergy. GTI-2040 is an antisense drug that specifically targets the R2 component of ribonucleotide reductase. Lorus also said it screened a series of siRNAs to select a lead drug candidate, siRNA-1284, which has demonstrated antiproliferative and antitumor activity both in vitro and in vivo.

• Medarex Inc., of Princeton, N.J., presented preclinical data demonstrating antitumor activity from two separate studies exploring the efficacy and safety of anti-CD19 and anti-CD70 antibody-drug conjugates in animal models. A fully human anti-CD19 antibody drug conjugate demonstrated in vivo antitumor efficacy leading to regression of subcutaneous tumors and systemic tumors in leukemia xenograft models. Efficacy also was seen in low-dose treatment of lymphoma and renal cancer xenografts with human anti-CD70 antibody toxin conjugates.

• MethylGene Inc., of Montreal, disclosed biomarker data for its histone deacetylase inhibitor, MGCD0103, demonstrating that the transcription of metallothionein-3 (MT3) was induced by MGCD0103 in a dose-dependent and time-dependent manner in a variety of human cancer cells in vitro, and in human peripheral white blood cells obtained from patients. Therefore, it said, MT3 may be a novel biomarker for pharmacodynamic effects for MGCD0103 in clinical studies. It also showed interleukin-6 specifically was induced in cells from acute myelogenous leukemia patients treated with MGCD0103 alone or in combination with Vidaza. There appeared to be a correlation between induction of IL-6 and clinical responsiveness.

• Myriad Genetics Inc., of Sal Lake City, presented studies that characterize the mode of action of its investigational new drug, Azixa, as a vascular-disrupting agent. Azixa previously was shown to be an inducer of apoptosis, and a potent inhibitor of human tumor cell growth and survival in cell culture, regardless of the multiple-drug-resistance stature of the tumors. Key to this activity is its ability to inhibit the formation of microtubules. Azixa is being evaluated in two Phase II trials, one in patients with primary brain cancer and the other in melanoma that has spread to the brain.

• Novacea Inc., of South San Francisco, said a preclinical study showed AQ4N, an anticancer prodrug, rapidly penetrated the hypoxic, or oxygen-starved, regions of tumors that normally are difficult to reach with conventional cancer therapies. Additionally, the study showed that when used in combination with mitoxantrone, tumor growth delay in rodent breast cancer models was achieved when compared to either agents used alone. Novacea also said the journal Clinical Cancer Research published data from a preclinical study showing AQ4N significantly delayed tumor growth, progression and survival in multiple pancreatic tumor models.

• Oncolytics Biotech Inc., of Calgary, Alberta, said researchers found that treatment of human colon cancer cell lines with the combination of Reolysin and gemcitabine resulted in both in vitro and in vivo synergy. Tumors treated with the combination were significantly smaller by area and weight than control tumors or tumors treated with either agent alone. Reolysin is a formulation of the human reovirus.

• Peregrine Pharmaceuticals Inc., of Tustin, Calif., said preclinical data confirmed a mouse equivalent to its monoclonal antibody, bavituximab, given in combination with docetaxel, decreased the growth of common forms of prostate cancer significantly more than either agent alone. The increase in antitumor efficacy was achieved with no apparent increase in toxicity. Researchers also observed that in one tumor model, the combination significantly decreased the level of serum PSA, a biomarker for prostate cancer, and in both tumor types tested it was more effective in decreasing the density of the microvessels needed to support tumor growth and development.

• ProNAi Therapeutics Inc., of Kalamazoo, Mich., said its DNQA interference agent PNT2258 demonstrated preclinical in vivo efficacy in xenograft mice for a number of human cancers, including curative events for difficult-to-treat Burkitt's lymphoma. DNA interference entails targeting genomic DNA using sequence-specific therapeutic oligonucleotides, employing single strands of DNA to target and treat nontranscribed regions of genomes responsible for complex genetic diseases.

• Ziopharm Oncology Inc., of New York, presented preclinical data supportive of the development of an oral form of ZIO-101. It said ZIO-101 demonstrated high bioavailability when administered orally, as well as anti-angiogenic activity. Data showed administration of the organic arsenic agent dramatically reduced new blood vessel formation in a mouse model of angiogenesis.