A U.S. Government Accountability Office study reported that 80 percent of the drugs withdrawn from the market are removed due to side effects on women. For example, in 2013—20 years after the drug first became available—the recommended dosage of a popular sedative for women was cut in half after it was realized that women process the drug more slowly than men and were experiencing serious side effects as a result. This problem is amplified by the fact that many medicines were only ever tested on men during clinical studies. This poses a distinct danger that females are receiving optimal care and that treatments specifically benefiting women are going undiscovered.
The Office of Research on Women’s Health, a division of the National Institutes of Health, includes as part of its mandate a focus on engaging, recruiting and retaining women when planning, designing and conducting clinical research. However, there is still work to do. In an effort to reduce the gender bias that is leaving women exposed to critical health risks, the Research for All Act—which would require federally funded research to perform studies on both male and female animals, cells and tissue—was first introduced into Congress in 2014 and reintroduced in 2015.
Oncolytic viral therapy offers one arena in which improved, targeted treatments for women may result from their participation in clinical studies. Oncolytics Biotech recently reported preliminary data from a Phase 2 study of its lead product, Reolysin , a proprietary formulation of the human reovirus, in advanced or metastatic colorectal cancer, in combination with other cancer drugs. In the study, female patients had an objective response rate of 63.2 percent versus 23.8 percent in the control arm—a result with a level of significance higher than that observed among the men in the study. The company intends to follow up this study with an additional study in female metastatic colorectal patients. In a separate Phase 2 study of Reolysin and other cancer drugs in patients with non-small cell lung cancer, once again, female patients did better than in the standard treatment arms than male patients.
The reovirus is a form of oncolytic virus. It is a non-enveloped virus with a double-stranded, segmented RNA genome. The reovirus preferentially replicates in cancer cells that have an “activated Ras pathway,” which is caused by mutations in genes including KRAS, BRAF and EGFR. The reovirus leaves normal cells unharmed. This makes it intrinsically tumor-selective without the need for any genetic manipulation.
The reovirus is a virus with no known associated disease. It replicates in the cytoplasm and therefore does not integrate into the cell’s DNA. The reovirus is found commonly in nature and has been isolated from untreated sewage, river and stagnant waters. Exposure to the reovirus is common in humans, with half of all children by the age of 12 having been exposed and up to 100 percent testing positive by adulthood.
Tumors bearing an activated Ras pathway cannot activate a viral response. Studies have shown that the reovirus actively replicates in transformed cell lines with an active Ras signaling pathway, eventually killing the host cell and freeing the viral progeny contained within, which in turn go on to infect and kill more tumor cells. When normal cells are infected with the reovirus, the normal viral response can neutralize the virus. Approximately two-thirds of cancer cells have an activated Ras signaling pathway.
Clinical trials of Reolysin are now underway to evaluate its use as a treatment for a wide variety of cancers. Much research remains to be done on the ability of Reolysin to impact specific cancers; however, two factors seem to contribute to the possibility that metastatic disease would be receptive to treatment with reovirus. First, Reolysin appears to distribute preferentially to organs where metastasis is common, including the lungs, liver, lymph nodes, and the peritoneal cavity, so the agent can concentrate in those regions of the body. And second, a growing body of literature suggests Ras pathway activation is common in metastatic lesions.
There is growing recognition of the importance of developing immunotherapies such as Reolysin to specifically treat women. Earlier this year, for example, Oncology published a feature spotlighting new strategies for the treatment of gynecological malignancies using immunotherapy. The recent Oncolytics study results, however, indicate that specific therapies for women might arise in cancers that impact both sexes.
Various immune-based therapies have demonstrated a profile where patients derive tumor response and overall survival benefit with limited or no impact on progression free survival; Reolysin appears to be demonstrating a similar profile in female patients with advanced or metastatic colorectal cancer. It is also interesting to see a gender linkage to progression free survival and overall survival in the preliminary data from the non-small cell lung cancer study.
These recent study results led weight to the crucial possibility that there could exist important treatments for women that are within researchers’ grasp. This raises the question whether researchers have overlooked gender-specific data because the overall data were not sufficient to move forward in the clinical development process, and whether there exist other therapies that may have potential if administered in a more personalized approach.
Ensuring that women-specific treatments become reality means addressing the imbalance in the male-to-female ratio within studies.
Brad Thompson, PhD is president and CEO of Oncolytics Biotech Inc., a Calgary-based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics.
Filed Under: Drug Discovery