Viracta’s viral gene activation therapy represents a platform for a highly targeted approach to treat a range of viral-associated cancers and other serious diseases. The Company’s initial focus is to apply the approach to address malignancies associated with the Epstein-Barr Virus (EBV), and to expand into additional applications.
The treatment approach has been termed a “kick-and-kill” strategy as it combines use of an epigenetic modifier drug, tractinostat, to induce expression of latent viral genes (the “kick”) and activate herpes virus-family’s thymidine kinase. This enables conversion of an orally administered antiviral pro-drug, such as valganciclovir (marketed by Roche/Genentech as Valcyte®), to its active form to selectively eradicate cells harboring the virus (the “kill”).
Tractinostat (formerly VRx-3996) is an orally administered class-1 histone deacetylase-selective inhibitor that is potent inducer of targeted viral genes. Tractinostat exhibited clinical characteristics that uniquely position it for Viracta’s viral gene activation therapy approach.
As represented in the diagrams, below, the approach provides a robust mechanism to selectively kill EBV+ cancer cells.
In non-dividing EBV+ cells, the approach inhibits viral replication but does not kill host cells. In replicating immune system cells, as only about 1 in 1-2 million immune cells harbor the virus, immunosuppressive effects do not appear consequential.
This therapy has been demonstrated to be highly effective in the laboratory and in a proof-of-principle clinical trials in which a prototype viral activation therapy drug demonstrated a high tumor response rate in patients with advanced EBV-related lymphoid cancers.
Notably, Viracta’s viral gene activation therapy and tractinostat have been shown to be well tolerated in cancer patients and not to suppress patients’ immune systems. This positions the approach for use concurrently with, or in advance of emerging immuno-oncology therapies, such as immune checkpoint inhibitors or adoptive cell therapy approaches.
It has long been understood that a range of viral pathogens can cause or serve as co-factors in the development of human cancers. Up to 20% of cancers are associated with infectious disease. Thus Viracta’s lead program is in clinical development for the treatment of advanced cancers in patients that are Epstein-Barr Virus positive.
EBV is widely present in almost 95 percent of adults and tends to persist asymptomatically, showing no symptoms. It is also the cause of infectious mononucleosis, often called the kissing disease. In certain cases, such as in immuno-suppressed patients, EBV can drive the formation of cancers.
EBV and it’s malignancies are often difficult to treat as the virus maintains a dormant, or latent state in affected cells, making it resistant to antiviral drugs. This has also made the development of vaccines and broadly effective immunotherapies difficult. The virus also drives multiple pro-oncogenic mechanisms such as viral proteins mimicking pro-growth signaling that drive aberrant cell division. It also produces immuno-suppressive signals that help the virus and affected cells evade detection by the immune system. Lastly, the EBV inhibits the programming of cell death pathways or tumor suppressor proteins that enable transformed cells to survive. The following schematic shows the life cycle of the EBV virus, including the variability in the viral gene expression that makes treatments difficult.
Denis Parsons Burkitt first described a cancer of the lymphatic system that is now known as Burkitt’s lymphoma and identified its association with EBV. The virus’ role in cancers is now understood to be much broader. It is estimated that there are 200,000 new cases and over 140,000 deaths each year due to EBV-associated cancers.
Uniquely, the Epstein Barr Virus was the first virus to be directly implicated in human cancer. Denis Parsons Burkitt first described a cancer of the lymphatic system that is now known as Burkitt’s lymphoma and identified its association with EBV. The virus’ role in cancers is now understood to be much broader. It is estimated that there are 200,000 new cases and over 140,000 deaths each year due to EBV-associated cancers. And due to the virus’ pleiotropic affects, EBV often result in cancers that are highly refractory to available treatments. This a significant unmet medical need that Viracta’s viral gene activation therapy is uniquely suited to address.
EBV is associated with a range of lymphoid malignancies. While first found in Burkitt’s lymphoma patients, EBV also plays roles in a subset of patients with Non-Hodgkin’s lymphoma, including patients with aggressive forms of Diffuse Large B Cell Lymphoma (DLBCL). EBV is also involved in about one-third of Hodgkin’s Disease patients. It is found in nearly all cases of patients with aggressive NK/T cell lymphomas. Among immuno-suppressed patients, such as solid organ or hematopoietic cell transplant patients, nearly all patients with post-transplant lymphoma or post-transplant lymphoproliferative disorders are associated with EBV. This is also the case with most HIV- or AIDS-associated lymphoma patients.
Post-Transplant Lymphoproliferative Disorder (PTLD) is a serious and life-threatening condition for solid organ and hematopoietic cell transplant patients. In PTLD, immuno-suppressive drugs that enable the human body to receive a transplant also keeps the immune system from controlling the proliferation of EBV-infected lymphoid cells. This results in an aggressive lymphoma. While the reduction or removal of immuno-suppressive drugs can reduce or control PTLD in cases, this can directly put the transplant graft at risk and be life-threatening. Additionally, the viral gene activation therapy may eliminate cells that harbor other pathogens, such as CMV and HHV6, that cause life-threatening side effects to PTLD patients.
NPC is an aggressive head and neck cancer that, while relatively uncommon in the US, is common in certain regions of Asia, particularly in areas of Southern China. It is a leading cause of cancer death among men in Taiwan. EBV is found in the vast majority of NPC cancers.
GC is a major healthcare concern especially in many parts of Asia and is the fourth most common cause of cancer death in the world. Certain GC sub-types, including lymphoepithelial-like GC are predominantly EBV positive.
Breast cancer is one of the leading causes of cancer worldwide. Triple negative breast cancer (TNBC) in particular is a form that tests negative for hormone epidermal growth factor receptor 2 (HER-2), estrogen receptors (ER), and progesterone receptors (PR). Since the tumor cells lack the necessary receptors, the common treatments of hormone therapy and drugs that target ER, PR and HER-2 are ineffective in the treatment of TNBC. EBV is found in a significant portion of breast cancers, particularly TNBC and is associated with the difficulty to treat this disease.