Annamycin is an anthracycline intended for the treatment of relapsed or refractory AML. The therapy of combining two chemotherapeutic drugs, which always includes an anthracycline, in inducing a remission of leukemic cells (called “induction therapy”) has not improved since it was first used in the 1970s and we estimate that this induction therapy has the same cure rate of about 20% as at that time. Currently, the only viable long term option for acute leukemia patients is a bone marrow transplant, which is successful in a significant number of patients. However, in order to qualify for a bone marrow transplant, patients must first undergo induction therapy.
Metabolic Inhibitors
MBI is engaged in developing new drugs to exploit the metabolic differences between tumor cells and normal cells. MBI’s lead compound is targeted specifically for metabolically active brain cancers, taking advantage of the differential utilization of glucose by cancerous tissue versus normal brain tissue. MBI believes that targeting this difference in metabolism is the key technology making its product competitive and applicable to many other cancers.
Our current lead metabolism candidates have shown activity against brain tumor cell lines in in vitro testing and, more importantly, in an orthotopic brain tumor (implanted in the brain) animal model. One candidate has been shown to outperform Schering-Plough’s Temodar®, the frontline FDA approved drug, which is considered the standard of care for the treatment of brain tumors. The market for Temodar® has reached nearly $1 billion in annual revenue. We believe that WP1122 and similar compounds address a significant unmet need in the treatment of brain tumors and should be applicable to other difficult-to-treat, glucose dependent tumors, such as pancreatic cancer.
The same principle that drives tumor cells to over-consume glucose allows PET scanning to highlight the size and location of tumors by imaging radiolabeled glucose decoys that are taken up by tumor cells in substantially higher concentrations than normal cells. PET scanning is less effective in brain scans because such decoys have difficulty crossing the blood brain barrier. For this reason, our compounds may also lead to a significant improvement in diagnostic imaging of the brain.
Need For Improved Brain Cancer Drugs
MBI’s technology has the potential to target a wide variety of solid tumors, which eventually become resistant to all treatments, and thereby provide a large and important opportunity for novel drugs. Notwithstanding this potential, MBI is focused on the treatment of central nervous system malignancies and especially glioblastoma. Although less prevalent than some larger categories of solid tumors, cancers of the central nervous system are particularly aggressive and resistant to treatment. The prognosis for such patients can be particularly grim and the treatment options available to their physicians are among the most limited of any cancer.
The National Cancer Institute has estimated 22,850 new cases of brain and other nervous system cancers will occur in the United States in 2015, resulting in 15,320 deaths. Despite the severity and poor prognosis of these tumors, there are few FDA-approved drugs on the market. The market leader is temozolomide (Temodar®, Merck), which is prescribed for glioblastoma and refractory anaplastic astrocytoma. Notwithstanding the rare nature of brain cancer, Merck (who acquired Schering-Plough, the maker of Temodar) reported sales of $882 million worth of the drug in 2012. The patent for Temodar expired August 31, 2013.
The market for drugs to treat brain cancer is clearly open for new entries. MBI is developing a drug that attacks a different target than Temodar® and has shown efficacy in animal models. MBI’s products could be stand-alone treatments or provided in combination with other drugs, surgery and radiotherapy.
Targeting the Metabolism of Cancer
As far back as 1930, science recognized that many cancer cells have a unique metabolism, distinct from that of normal cells. Dubbed the “Warburg Effect” by its discoverer, “tumors rely preferentially on glycolysis for the metabolism of glucose, even in the presence of abundant oxygen for energy (adenosine triphosphate (ATP)) production.” This alternative form of energy production makes cancer cells as much as 17 times more dependent on glucose than normal cells.
The fundamental mechanism for imaging actively growing tumors using positron emission tomography (PET scans) is the Warburg Effect. As shown in these images at the left, a radio labeled glucose decoy called F18DG accumulates disproportionately in tumors because of their dramatically increased rate of glucose uptake and accumulation.
For decades, researchers have theorized that if you could block a tumor’s access to glucose, you could essentially starve the tumor out of existence. Previous attempts at targeting the metabolism of tumor cells have failed due to the rapid metabolism and short half-life (minutes) of the drugs being investigated. Efforts to target tumor metabolism in the brain were further thwarted by the inability to get glycolytic inhibitors into the brain in sufficient (therapeutic) amounts due to the presence of what is called the “blood brain barrier”.
We believe WP1122 and similar molecules provide the potential to develop a technology platform for enabling increased cellular uptake, increased drug half-life and, importantly, an increased ability to cross the blood brain barrier, enabling greater uptake in the brain. Our approach was inspired by the same principle that distinguishes morphine from heroin. Heroin is chemically the diacetyl ester of morphine. While morphine has a limited ability to cross the blood brain barrier (making it a good candidate for pain killing without impairing mental function), its diacetyl form, heroin, has the ability to accumulate in the brain by 10 to 100 fold more than morphine. Once across the blood brain barrier, the acetyl groups shown in this chemical diagram are cleaved off by natural enzyme esterases, leaving pure morphine to accumulate in the brain.
MBI’s scientific founder, Dr. Waldemar Priebe, invented the diacetyl ester of a glucose decoy known as “2-DG”, which became WP1122. We believe based on pre-clinical testing that, just like heroin, WP1122 crosses the blood brain barrier where its acetyl groups are cleaved off, allowing the resulting 2-DG to accumulate in the brain at a much higher rate than free 2-DG can do by itself.
Adding to the difficulty in getting free 2-DG across the blood brain barrier in therapeutic quantities, is the relatively short half-life of 2-DG. The free form of 2-DG is rapidly metabolized and rendered ineffective within minutes of entering the body. In contrast, WP1122 has a half-life of approximately 6 hours, making it much more feasible to deliver quantities adequate for a therapeutic effect.
[1] Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels and it is one of four fundamental elements in the progression of inflammatory and proliferative disorders, along with cell survival (where the normal process of cell death is switched off), abnormal or hyper-proliferation (where cells replicate too quickly) and immune system misdirection (where the immune system is either shut down or activated in the wrong way).
[2] SRC (pronounced “sarc”, as it is short for sarcoma) represents a family of tyrosine kinases (a type of enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates) often studied in connection with cancer research where normally healthy cellular signaling has gone awry. JAK represents another family of tyrosine kinases that transduce signals via the JAK-STAT pathway. They were initially named “just another kinase”, but were ultimately published as “Janus kinase” for the two-faced Roman god of doorways. The Abelson oncogene or ABL is yet another tyrosine kinase linked to cancer and other inflammatory disease activation. Because there are variations of each of these kinases within their respective families they are further differentiated by number, such as JAK1, JAK2, JAK3 and so on.