Moleculin Biotech, Inc. is a clinical stage pharmaceutical company focused on the development of oncology drug candidates, some of which are based on discoveries made at M.D. Anderson Cancer Center. Our clinical stage drugs are Annamycin, an anthracycline designed to avoid multidrug resistance mechanisms with little to no cardiotoxicity being studied for the treatment of relapsed or refractory acute myeloid leukemia, more commonly referred to as AML, and WP1066, an immuno-stimulating STAT3 inhibitor targeting brain tumors, pancreatic cancer and AML. We are also engaged in preclinical development of additional drug candidates, including additional STAT3 inhibitors and compounds targeting the metabolism of tumors.
Our lead product candidate is Annamycin, a Phase II clinical stage anthracycline for the treatment of relapsed or refractory acute myeloid leukemia, more commonly referred to as AML.
Unlike current therapies that risk cardiotoxicity and can have their effectiveness limited due to multidrug resistance, Annamycin appears capable of avoiding both of these problems and has already demonstrated the ability to save lives in clinic. We are now preparing to seek accelerated approval for this game-changing drug.
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.
One of the leading anthracyclines used for induction therapy in acute leukemia patients is doxorubicin, which has reported over $700 million in annual revenues. Despite the importance and success of approved anthracyclines like doxorubicin, they are all unfortunately cardiotoxic, which can result in damage to the heart and limit the dosage amount that may be administered to patients. Additionally, the tumor cells being treated often have or develop resistance to the first line anthracycline, often through what is called “multidrug resistance” making them capable of purging themselves of the current anthracyclines and limiting the effectiveness of the therapy. Consequently, there remains no effective therapy for these patients and most will succumb quickly to their leukemia. This is where we believe Annamycin can be a complete game-changer.
Annamycin is a unique liposome formulated anthracycline (also referred to in literature as “L-Annamycin”) that has been designed to eliminate cardiotoxicity and avoid the multidrug resistance mechanisms that often defeat current anthracyclines. In animal models designed to test for cardiotoxicity, Annamycin as shown to be non-cardiotoxic and in human clinical trials focused on leukemia, it showed fewer dose-limiting toxicities than are normally experienced with doxorubicin (one of the leading first-line anthracyclines used for induction therapy).
Annamycin demonstrated efficacy in 8 of 16 patients in a Phase I study in adult relapsed or refractory AML patients, with 6 of 14 patients completely clearing leukemic blasts. A 30 patient dose-ranging Phase I/II study in acute lymphocytic leukemia demonstrated a similar efficacy profile, with 3 of 8 patients treated with the maximum tolerable dose clearing their leukemic blasts to a level sufficient to qualify for a bone marrow transplant. One of these patients went on to receive a successful curative bone marrow transplant.
We believe Annamycin is better than the currently approved induction therapy drugs in four key ways: (i) it has demonstrated clinical activity in a patient population for whom there are currently no effective therapies, (ii) it appears to be capable of avoiding the “multi-drug resistance” mechanisms that often limit the effectiveness of currently approved anthracyclines; (iii) it has been shown to be non-cardiotoxic in animal models, when compared with doxorubicin; and (iv) in laboratory studies using AML cell lines, it has been shown to be more potent than the leading approved drug.
Based on initial conversations with the FDA, and because of this serious unmet medical need, we believe Annamycin may qualify for for accelerated approval. We also believe Annamycin may qualify for Orphan Drug status, which could entitle us to market exclusivity of up to 7 and 10 years from the date of approval of a New Drug Application (NDA) and Marketing Authorization (MA), in the US and the European Union (EU), respectively.
Cell Signaling And Oncogenic Transcription Factors
Cellular biology depends upon signaling mechanisms to regulate functions such as cell growth, death and adaptation. Signal “transduction” is such a mechanism that converts an upstream stimulus to a cell into a specific cellular response. Signal transduction starts with a signal to a receptor or via a compound capable of passing through the cell membrane and ends with a change in cell function. The end result of this signal is often the activation of “transcription”, whereby genetic information is expressed and, in the case of oncogenic transcription, disease processes are initiated or maintained.
Receptors span the cell membrane, with part of the receptor outside and part inside the cell. See diagram below. When a chemical signal represented by a specific protein binds to the outer portion of the receptor, it conveys another signal inside the cell. Often there is a cascade of signals within the cell, wherein an upstream inducer starts a chain of events that resembles a domino effect. Collectively, this sequence is referred to as a “signaling pathway.” Eventually, the signal creates a change in the cell function by changing the expression of specific genes and production of specific proteins within the cell, and again, in the case of tumor development, such expression results in unwanted inflammatory and proliferative processes.
Importantly, while normal healthy cell function relies on signaling mechanisms, diseases are capable of co-opting these mechanisms with negative consequences. Proliferative and inflammatory diseases depend upon signaling pathways that are responsible for coordinating functions such as cell growth, survival and cell differentiation. A particular class of proteins referred to as Signal Transducers and Activators of Transcription (such proteins are “STATs”) plays an important role in regulating the process of disease cell survival and proliferation, angiogenesis and immune system function and is persistently activated in a large number of human inflammatory processes and in hyper-proliferating diseases. Because certain of these proteins are known to be co-opted by tumor cells, we refer to them as “oncogenic transcription factors,” of which certain STATs are a subset.
Some STATs, such as STAT3, can be activated by any one of many different upstream inducers, making them very difficult to target by blocking just one or more of these upstream inducers. We believe that blocking a targeted STAT directly rather than via its multiple upstream inducers should result in greater efficacy with lower toxicity.
In the diagram shown here, any one of many different pathways (some of which are shown here as Growth Factor Receptors, Cytokine Receptors and Non-Receptor Tyrosine Kinases) triggers the activation of STAT3 proteins in a process called “phosphorylation”. In this process, phosphates attach to corresponding receptors on STAT3 and the two phosphorylated STAT3 (“p-STAT3”) proteins bind together in a pair referred to as a “dimer”. Once the dimer is formed, it enters the cell nucleus and triggers gene transcription. Conversely, if we prevent the dimer from forming (i.e., by blocking phosphorylation), we can prevent the triggering of unwanted gene transcription and effectively inhibit the disease process.
The upstream effectors shown in this diagram (SRC, JAK and ABL) are just some of those capable of activating STAT3 once they themselves are activated by a variety of signal compounds. The complexity and diversity of pathways capable of activating STAT3 makes it very difficult to develop safe and effective drugs that attempt to target the upstream effectors.
Published research has identified STAT3 as a master regulator of a wide range of tumors and clearly links STAT3 activation with the progression of these tumors. For this reason, it is believed that inhibiting the activation of STAT3 should be an effective way to reduce or eliminate the progression of these diseases.
Many research efforts have been directed toward development of specific methods to control activation of STAT3, but most have focused on targeting the upstream effectors of these pathways like growth factors, cytokines, and specific kinases including Janus kinases (JAKs). However, we believe that the multifactorial nature of the activation of STAT3 limits the effectiveness of such upstream approaches. Since the activity of p-STAT3 is a final and determinative step in triggering unwanted transcription, we believe it is preferable to inhibit p-STAT3 more directly and independently from upstream effectors.
We believe the WP1066 Portfolio represents a novel class of agents capable of hitting multiple targets, including p-STAT3, regardless of their upstream method of activation. By inhibiting the presence of p-STAT3, WP1066 directly attacks tumor cells, as has been demonstrated in numerous preclinical tests involving a wide range of tumor cells. We believe the effectiveness of WP1066 is not only the result of attacking tumors directly, but also indirectly by stimulating the immune system, increasing the patient’s natural ability to fight off tumor development. STAT1 is believed to stimulate T-cell activity and thereby the immune system responsible for fighting tumors. WP1066 has been shown to increase the activity of STAT1 at the same time it inhibits the activity of p-STAT3. We believe this dual activity makes WP1066 a uniquely promising anticancer drug candidate.
We believe the combination of the direct and indirect effects of WP1066 are to be credited with significant tumor suppression and increased survival in a number of in vivo cancer models. Below is one example showing a dramatic increase in survival by treating mice with metastatic melanoma with WP1066.
In Vivo Activity
In experimental biology, in vitro (Latin for “in glass”) studies are those that are conducted using components of an organism that have been isolated from their usual biological surroundings in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments are commonly called “test tube experiments”. In contrast, studies that are conducted with living organisms in their normal intact state are referred to as in vivo (Latin for “within the living”). We have shown in vivo that WP1066 inhibits tumor growth and blocks angiogenesis. As well, we have shown in numerous mouse tumor models that WP1066 dramatically increases survival.
In vivo activity has been confirmed in a wide range of tumors, including metastatic melanoma, glioblastoma, head and neck tumors, bladder cancer, renal cancer and pancreatic cancer.
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.
 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).
 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.