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The Lancet Oncology

Friday, January 16, 2009

A Novel Targeted Multi-Mechanistic Oncolytic Poxvirus Targets Refractory Hepatocellular Carcinoma (HCC)

JX-594, a novel, first-in-class, targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell cycle abnormalities and EGFR/ ras pathway activation, may be uniquely suited to treat cancers.

The EGF pathway is a validated pathway and targeted by marketed pharmaceuticals such as cetuximab (Erbitux®, ImClone Systems Incorporated, Branchburg, NJ 08876, Bristol-Myers Squibb Company, Princeton, NJ 08543 and Merck KGaA, Darmstadt, Germany), which is indicated for the treatment of patients with metastasized colorectal cancer whose tumor expresses a protein called an Epidermal Growth Factor Receptor (EGFR), and gefitinib (Iressa®, AstraZeneca Pharmaceuticals, London, United Kingdom), which is indecated for continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum based and docetaxel chemotherapies.

In many cancers EGFR is often inappropriately activated, leading to uncontrolled cell growth. JX-594 is designed to blocks tumor growth and induce tumor regression. The compound, which is currently in Phase II trials, treats patients with advanced, primary liver cancer refractory to standard therapies. In this trial, patients are randomized to receive treatment at one of two dose levels. The 30-patient, multi-national trial is being conducted at clinical sites in the United States, South Korea and Canada.

An engineered virus
Viruses have been engineered for cancer therapy in a variety of ways. Approaches include non-replicating gene therapy vectors, cancer vaccines and oncolytic viruses, but the clinical efficacy of these approaches has been limited by multiple factors. However, a new therapeutic class of oncolytic poxviruses, which includes JX-594, has recently been developed that combines targeted and armed approaches for treating cancer. Although holding much promise for clinical treatment of many cancers, oncolytic viruses general lack of systemic delivery, and insufficient tumor cell killing, so far, limited their usefulness.

In a phase I trial, researchers have now shown that products from this therapeutic class can systemically target cancers in a highly selective and potent fashion using a multi-pronged mechanism of action. Furthermore, efficacy and safety of JX-594 was shown in patients with diverse cancer types in three Phase I trials.

Commenting on the potential of the trial, David H. Kirn, M.D., President and Chief Executive Officer of Jennerex Biotherapeutics (One Market Street, Spear Tower, Suite 2260, San Francisco, CA 94105), a clinical-stage biopharmaceutical company focused on the development and commercialization of first-in-class, breakthrough targeted oncolytic products for cancer and currently involved in the development of JX-594, said: 'We're very excited to have this trial open and enrolling with our lead product, JX-594, which has the potential to revolutionize the treatment of the more than 10,000 patients each year who develop liver cancer in the U.S. alone. The numbers of patients with liver cancer in the EU, Japan and Asia are even higher. These desperate patients represent a huge unmet medical need since few effective therapies are available for them.'

'We have already treated four patients with JX-594 in Korea and are anxious to see the efficacy of JX-594 in these late stage liver cancer patients,' said B.G. Rhee, Ph.D., Executive Vice President of Korea Green Cross Corporation (227, Kugal-ri, Kihung-up, Yong-in, Kyonggi-do 449-900, South Korea), a biotechnology company developing several vaccines and therapeutic proteins, who is developing the new compound in collaboration with Jennerex.

The primary objective for the phase II trial is to study the efficacy of treatment with JX-594 at two different dose levels in preventing tumor progression, as measured by modified RECIST criteria, at eight weeks from initiation of treatment in patients with unresectable primary hepatocellular carcinoma. In addition, safety and tolerability, as well as tumor response and progression-free survival, of JX-594 administered at the two dose levels will be evaluated. Up to 30 total patients will be treated.

A new therapeutic approach
The new compound uses a vaccinia viruses that has been engineered to target, attack and eradicate cancer. Unlike 'vectors' or 'vaccines', JX-594 replicates in cancer cells, leading to cancer cell destruction. As a result of this uniek mechanism of action, JX-594 is able to infect and eradicate other tumor cells both locally and in distant sites in the body. The cycle of JX-594 replication, cancer cell destruction, release and spread is then repeated. Normal, healthy, cells are not affected by JX-594 resulting in safety and tolerability.

Poxvirus offers an uniek Mechanism of Action
The comound is activated by genetic pathways that are critical to the vast majority of human cancers, including common solid tumors such as lung, colon, prostate, breast, pancreas and melanoma. They employ a novel primary mechanism-of-action that is effective even against cancers that are resistant to standard therapies such as chemotherapy, small molecule tyrosine kinase inhibitors, antibodies and radiotherapy. Simultaneously, a therapeutic cascade is initiated by product replication resulting in tumor vasculature shutdown and anti-tumoral immune attack.

The poxvirus strain backbone of JX-594 has been used safely in millions of people as part of a worldwide vaccination program. This strain naturally targets cancer cells due to common genetic defects in cancer cells. JX-594 was engineered to enhance this natural safety and cancer-selectivity by deleting its thymidine kinase (TK) gene, thus making it dependent on the cellular TK expressed at persistently high levels in cancer cells. To enhance product efficacy, JX-594 is also engineered to express the GM-CSF (hGM-CSF) protein. GM-CSF complements the cancer cell lysis work of the product candidate, leading to a cascade of events resulting in tumor necrosis, tumor vasculature shutdown and an anti-tumoral immune attack.

Based on the results so far, researcher believe that JX-594 holds promise as an i.v.-delivered, targeted virotherapeutic.

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