Preliminary results from a U.S. Phase II clinical trial with intravenous administration of Reolysin? (Oncolytics Biotech Inc), a proprietary formulation of the human reovirus (respiratory enteric orphan virus), in combination with gemcitabine (Gemzar? Eli Lilly and Company) in patients with advanced pancreatic cancer show that the trial meets primary endpoint for first part of trial (REO 017). The trial is being conducted at the Cancer Therapy & Research Center at The University of Texas Health Science Center at San Antonio (CTRC). The Principal Investigator is Dr. Monica Mita of the CTRC.

The American Cancer Society estimates that in 2010 43,140 Americans were diagnosed with pancreatic cancer and 36,800 Americans died from the disease, making this type of cancer the fourth leading cause of cancer death for both men and women in the United States.

Reolysin? is developed by Calgary-based biotechnology company Oncolytics Biotech Inc which focuses on the development oncolytic viruses as potential cancer therapeutics.

The trial drug, a proprietary formulation of the human reovirus, has demonstrated to replicate specifically in tumour cells bearing an activated Ras pathway. Activating mutations of Ras and upstream elements of Ras may play a role in more than two thirds of all human cancers. Based on preliminary studies, researchers believe that Reolysin? may represent a novel treatment for Ras activated tumour cells and some cellular proliferative disorders.

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Killing cancer-cells
Reoviruses infect the human respiratory and intestinal tracts, usually without disease symptoms. They were first recognised in 1959 when they were wrongly classified as echoviruses (Picornaviridae). There are >150 species in the family Reoviridae. They are a diverse group, infecting invertebrates, vertebrates and plants, but are unified by their most unique feature – the composition of their genome. Reoviruses are found naturally in sewage and water supplies. By age 12, half of all children show evidence of reovirus exposure and by adulthood, most people have been exposed. However, the disease is non-pathogenic, meaning there are typically no symptoms from infections. The link to its cancer-killing ability was established after the reovirus was discovered to reproduce well in various cancer cell lines.

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Tumors bearing an activated Ras pathway are deficient in their ability to activate the anti-viral response mediated by the host cellular protein, PKR. Since PKR is responsible for preventing reovirus replication, tumour cells lacking the activity of PKR are susceptible to reovirus replication. As normal cells do not possess Ras activations, these cells are able to stop reovirus infection through normal PKR activity. In tumor cells with an activated Ras pathway, reovirus is able to freely replicate and eventually kill the host tumor cells. As cell death occurs, progeny virus particles are then free to infect surrounding cancer cells. This cycle of infection, replication and cell death is believed to be repeated until there are no longer any tumor cells carrying an activated Ras pathway available.

Researchers at Oncolytics have also discovered that tumor antigens generated by this viral oncolysis may be instrumental in educating the immune system to recognize and kill tumour cells. The activation of the Ras pathway can be mimicked in non-cancerous cells by treating these cells with the chemical 2-aminopurine (2-AP) which prevents the activation of PKR.

Trial Results
“When we opened the study we anticipated positive results based on preclinical models and on the high frequency of Ras pathway abnormalities in pancreatic cancer,” said Dr. Monica Mita. “We are, however, impressed by the fact that the study met the endpoint so early. We are eager to complete the study and to proceed to the next step of development for this combination.”

The trial is a single arm, open-label, Phase II study of Reolysin? given intravenously with gemcitabine every three weeks. The study’s primary objective is to determine the clinical benefit rate (complete response (CR) + partial response (PR) + stable disease (SD)) of Reolysin? in combination with gemcitabine in patients with advanced or metastatic pancreatic adenocarcinoma with measurable disease who have not received any prior chemotherapy or biotherapy. The secondary objectives are to determine progression-free survival, and the safety and tolerability of Reolysin? when administered in combination with gemcitabine. Seventeen evaluable patients with pancreatic cancer were expected to be treated in the first stage and if three or more patients received clinical benefit, the study would then proceed to the next stage. This endpoint was met after six evaluable patients were enrolled. All patients treated reported symptomatic improvement. Three of six patients showed SD for 12 weeks or greater. In addition, one patient had stable disease at nine weeks of treatment, but was taken off of the study for alternative treatment, and one patient had a PR of less than 12 weeks duration, and then died from a medical issue unrelated to treatment. The Company now intends to complete enrollment in the first stage of the study and then continue with further studies.

“This study is supportive of the decision to conduct the randomized Phase II study being sponsored by the NCI examining Reolysin in combination with carboplatin/paclitaxel,” said Dr. Brad Thompson, President and CEO of Oncolytics.

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