MST-188 (purified poloxamer 188)
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MST-188 is an investigational agent, formulated using a purified form of poloxamer 188. Substantial research has demonstrated that poloxamer 188 has cytoprotective and hemorrheologic properties and inhibits inflammatory processes and thrombosis. We believe the pharmacologic effects of poloxamer 188 support the development of MST-188 in multiple clinical indications for diseases and conditions characterized by microcirculatory insufficiency (endothelial dysfunction and/or impaired blood flow). We are enrolling patients in EPIC, a pivotal phase 3 study of MST-188 in sickle cell disease. In addition, our MST-188 pipeline includes development programs in adjunctive thrombolytic therapy (e.g., acute limb ischemia, stroke), heart failure, and resuscitation (i.e., restoration of circulating blood volume and pressure) following major trauma.
The active ingredient in MST-188 is a purified form of poloxamer 188, a nonionic, block copolymer comprised of a central linear chain of hydrophobic polyoxypropylene flanked on both sides by linear hydrophilic polyoxyethylene chains. Although its mechanism of action is not fully understood, the activity of MST-188 is not based on specific receptor/ligand binding interactions, which are the mechanistic bases for most drugs. Rather, its “binding” activity and pharmacologic effects are driven by hydrophobic adhesive interactions.
The cell membrane is comprised predominantly of lipids and proteins. The fundamental structure of the cell membrane is a phospholipid bilayer that forms a fluid, yet stable, selectively-permeable barrier between the aqueous environments of both the cell interior and exterior. The exterior surface of healthy cell membranes normally is hydrophilic, comprised of the polar head groups of lipid molecules that bury their hydrophobic tails in the interior of the bilayer. When a cell membrane is damaged, the interior hydrophobic regions of the lipid bilayer become exposed.
The cell membrane serves many functions, but one of its primary roles is to regulate the passage of ions and large molecules into and out of the cell and, in particular, to maintain critical transmembrane ion concentrations. Damaged cell membranes result in increased diffusion of ions between the intracellular and extracellular environments. The integrity of a cell membrane can be compromised by chemical agents (e.g., air pollutants, free radicals, poisons), physical trauma (e.g., electric shock, frostbite, radiation, thermal burns, hypovolemia) and disease. Cells have evolved endogenous mechanisms for membrane repair, but membrane injury can exceed the cell’s natural repair capacity. If the damage is not repaired, cell ion pumps become overwhelmed and subsequently deplete the cell’s energy stores, leading to cell death.
After intravenous administration, the MST-188 hydrophobic polyoxypropylene core is believed to adhere to hydrophobic domains on cell membranes, which, as described above, become exposed when the membrane is damaged. At sites of adhesion, it physically occupies the available area, minimizing or preventing other hydrophobic adhesive interactions, while displacing water and causing lipid molecules to pack more tightly, effectively “sealing” the damaged area and arresting unchecked transport of ions across the membrane. MST-188 does not bond covalently with the cell membrane and the adhesive interaction is reversible. If the phospholipid density is restored, the physical adhesion may be reversed and MST-188 dislodges from the cell membrane and returns to circulation. While MST-188 adheres specifically to hydrophobic domains, these domains may be widespread in sick or injured patients. As a result, MST-188’s activity broadly targets hydrophobic domains, without regard to the cause of the underlying damage, and, as described below, simultaneously may resolve multiple pathophysiologic processes. At the same time, MST-188 has demonstrated little or no affinity for hydrophilic domains and, thus, does not adhere to healthy cells.
MST-188 is believed to exert multiple pharmacologic effects as a result of its single mechanism of action:
Cytoprotective. Restores cell membrane integrity, providing time for the cell’s natural repair mechanisms to restore the cell to normal function.
Hemorheologic. Inhibits cell aggregation, improving blood flow, particularly in the microcirculation.
Anti-inflammatory. Blocks adhesive interactions between white blood cells and the vessel wall by competing for and physically occupying hydrophobic domains on the vessel walls, which helps prevent an inflammatory process from beginning.
Antithrombotic/pro-fibrinolytic. Helps reduce the pro-thrombotic state that may result from disease or injury and facilitates fibrinolysis.
Potential Applications of MST-188
We believe the pharmacodynamic properties of MST-188 (cytoprotective, hemorheologic, anti-inflammatory, antithrombotic/pro-fibrinolytic) enable it simultaneously to address, or prevent activation of, multiple biochemical pathways that can result in microcirculatory insufficiency, a multifaceted condition principally characterized by endothelial dysfunction and impaired blood flow. The microcirculation is responsible for the delivery of blood through the smallest blood vessels (arterioles and capillaries) embedded within tissues. A healthy endothelium is critical to a functional microcirculation. Without the regular delivery of blood and transfer of oxygen to tissue from the microcirculation, individual cells (in both the endothelium and tissue) are unable to maintain aerobic metabolism and, through a series of complex and interrelated events, eventually die. If microcirculatory insufficiency continues, the patient will suffer tissue necrosis, organ damage and, eventually, death.
MST-188 for Sickle Cell Disease
Sickle cell disease is an inherited genetic disorder that affects millions of people worldwide. It is the most common inherited blood disorder in the U.S., where it is estimated to affect approximately 90,000 to 100,000 people, including approximately 1 in 500 African American births. The estimated annual cost of medical care for patients with sickle cell disease in the U.S. exceeds $1.0 billion.
Sickle cell disease is characterized by the “sickling” of red blood cells, which normally are disc-shaped, deformable and move easily through the microvasculature carrying oxygen from the lungs to the rest of the body. Sickled, or crescent-shaped, red blood cells, on the other hand, are rigid and sticky and tend to adhere to each other and the walls of blood vessels. The hallmark of the disease is recurring episodes of severe pain commonly known as crisis or vaso-occlusive crisis. Vaso-occlusive crisis occurs when the proportion of sickled cells rises, leading to obstruction of small blood vessels and reduced blood flow to organs and bone marrow. This obstruction results in intense pain and tissue damage, including tissue death. Over a lifetime, the accumulated burden of damaged tissue frequently results in the loss of vital organ function and a greatly reduced lifespan. In fact, organ failure is the leading cause of death in adults with sickle cell disease1 and the average life expectancy is around 45 years.2
We estimate that, in the U.S., sickle cell disease results in approximately 100,000 hospitalizations and, in addition, approximately 69,000 emergency department treat-and-release encounters each year. Further, although the number is difficult to measure, we estimate that the number of untreated vaso-occlusive crisis events is substantial and in the hundreds of thousands in the U.S. each year.
1. Powars, D .R. et al. November 2005. Outcome of Sickle Cell Anemia: A 4-Decade Observational Study of 1056 Patients. Medicine. Vol 84 No. 6: pp 363-376.
2. Platt et al., June 1994. Mortality in Sickle Cell Disease: Life Expectancy and Risk Factors for Early Death. NEJM. Vol 330; No. 2: 1639-1644.
EPIC (Evaluation of Purified 188 In Crisis)
We are enrolling patients in EPIC, a randomized, double-blind, two-arm, placebo-controlled phase 3 study of MST-188 in sickle cell disease. The primary objective is to demonstrate that MST-188 reduces the duration of vaso-occlusive crisis in patients with sickle cell disease. We plan to enroll 388 subjects from approximately 40 sites in the U.S. and 30 sites outside of the U.S. Please see our Clinical Trials page for more information regarding this phase 3 study.
In July 2013, we announced that our thorough QT/QTc clinical study of MST-188 met its primary endpoint and demonstrated that, based on analysis of electrocardiograms, MST-188 did not have an adverse effect on cardiac repolarization, as measured by prolongation of the QT interval. Sixty four subjects received MST-188 and it was generally well-tolerated at both therapeutic and supratherapeutic doses.
MST-188 for Complications of Arterial Disease
Data from experimental models demonstrate the potential for MST-188, when used alone or in combination with thrombolytics, to improve outcomes in patients experiencing complications of arterial disease resulting from atherosclerotic and thromboembolic processes. We believe that, based on the similar pathophysiology of atherosclerotic arterial disease, an agent that is effective in one form of occlusive arterial disease also may be effective in its other manifestations. We plan to first demonstrate the potential of MST-188 in patients with acute limb ischemia, a complication of peripheral arterial disease.
Arterial disease resulting from atherosclerotic and thromboembolic processes is associated with significant morbidity and mortality. It is a common circulatory problem in which plaque-obstructed arteries reduce the flow of blood to tissues. Atherosclerosis occurs with advanced age, smoking, hypertension, diabetes and dyslipidemia. Peripheral arterial disease, or PAD, refers to disease affecting arteries outside the brain and heart and often refers to blockage of arteries in the lower extremities. Progression of PAD is associated with ongoing obstruction, or occlusion, of the peripheral arteries, which can occur slowly over time or may lead to a sudden, acute occlusion. Acute limb ischemia, or ALI, is a sudden decrease in perfusion of a limb, typically in the legs, that often threatens viability of the limb. The condition is considered acute if clinical presentation occurs within approximately two weeks after symptom onset. ALI rapidly threatens limb viability because there is insufficient time for new blood-vessel growth to compensate for loss of perfusion.
There are an estimated 8 to 12 million people with PAD in the United States. This prevalence is expected to increase, not only in the U.S., but throughout the world, as the population ages, cigarette smoking persists, and the prevalence of diabetes mellitus and obesity grows. Acute limb ischemia is an orphan disease within PAD with significant unmet needs. Despite urgent revascularization with thrombotic agents or surgery, for patients presenting with ALI, the 30-day amputation rate is 10% to 30% and the mortality rate is 15% to 20%.
Timely restoration of blood flow is central to the treatment of acute events associated with arterial disease. Current treatments for ALI focus on dissolution of the blood clots and improving blood flow in large arteries and include revascularization with thrombolytics, endovascular treatment, open surgery, or various combinations of these approaches. The principal goal is to restore blood flow and tissue perfusion as rapidly as possible – rapid restoration of tissue perfusion is critical to regaining clinical function.
A pharmacologic agent that simultaneously can address the limitations of current treatment options is needed to improve clinical outcomes. We believe the mechanistic activities of MST-188 to shorten time to thrombolysis, reduce re-thrombosis and, independent of these, improve blood flow, as well as protect tissues from reperfusion injury, will have utility in treating acute complications of thrombotic arterial disease.
We are planning to conduct a phase 2, clinical proof-of-concept study to evaluate the safety and efficacy of MST-188 as an adjunctive therapy in acute limb ischemia. We expect to initiate the study in early 2014. We anticipate that the study will enroll approximately 60 patients and compare one or more doses of MST-188 in combination with a thrombolytic against the thrombolytic alone.