Vepoloxamer (MST-188)

This page contains Forward Looking Statements.*

Vepoloxamer (MST-188), an investigational agent, is purified poloxamer 188, a nonionic, block copolymer comprised of a central linear chain of hydrophobic polyoxypropylene flanked on both sides by linear hydrophilic polyoxyethylene chains. 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 vepoloxamer 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 vepoloxamer in sickle cell disease. In addition, our vepoloxamer pipeline includes development programs in adjunctive thrombolytic therapy (e.g., acute limb ischemia, stroke), heart failure, and resuscitation following major trauma (i.e., restoration of circulating blood volume and pressure).

What is Vepoloxamer and How Does it Work?

Vepoloxamer is purified 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, studies have shown that vepoloxamer’s mechanism of action is biophysical and driven by its ability to modulate surface tension of cell membranes.

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 vepoloxamer 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.  Vepoloxamer 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 vepoloxamer dislodges from the cell membrane and returns to circulation. While vepoloxamer adheres specifically to hydrophobic domains, these domains may be widespread in sick or injured patients. As a result, vepoloxamer’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, vepoloxamer has demonstrated little or no affinity for hydrophilic domains and, thus, does not adhere to healthy cells.

Vepoloxamer 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 Vepoloxamer

We believe the pharmacodynamic properties of vepoloxamer (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.

Microcirculatory Insufficiency

Sickle Cell Disease (SCD)

Vepoloxamer 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 premature death in adults with sickle cell disease1 and the average life expectancy is around 45 years.2

We estimate that, in the U.S., there are approximately 80,000 to 100,000 hospitalizations related to vaso-occlusive crisis of sickle cell disease 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 vepoloxamer in sickle cell disease. The primary objective is to demonstrate that vepoloxamer reduces the duration of vaso-occlusive crisis in patients with sickle cell disease. We plan to enroll 388 subjects from approximately 70 medical centers within and 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 vepoloxamer met its primary endpoint and demonstrated that, based on analysis of electrocardiograms, vepoloxamer did not have an adverse effect on cardiac repolarization, as measured by prolongation of the QT interval. Sixty four subjects received vepoloxamer and it was generally well-tolerated at both therapeutic and supratherapeutic doses.

Complications of Arterial Disease

Vepoloxamer for Complications of Arterial Disease

Data from experimental models demonstrate the potential for vepoloxamer, 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 vepoloxamer 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 vepoloxamer 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.

Development Status

We are enrolling a Phase 2, randomized, double-blind, placebo-controlled, clinical proof-of-concept study of vepoloxamer in combination with rt-PA against rt-PA alone in patients with acute limb ischemia. The primary objectives are to evaluate the safety and efficacy of vepoloxamer in combination with rt-PA and whether vepoloxamer results in more rapid thrombolysis and tissue perfusion. The secondary objectives will be to assess the clinically-meaningful benefit of vepoloxamer in combination with rt-PA by measures such as duration of thrombolytic therapy, amputation-free survival, target limb re-interventions, and the need for endovascular or open surgical re-interventions. The study will enroll approximately 60 patients with acute lower limb ischemia receiving catheter-directed rt-PA from study sites within and outside the U.S.

A Brief History of Vepoloxamer


Poloxamer 188 – Refers to unpurified, excipient-grade poloxamer 188 material, which was the active ingredient in drug product tested in early clinical studies conducted by CytRx and Burroughs Wellcome. Associated with elevated serum creatinine.

Vepoloxamer (also known as MST-188) – Refers to purified poloxamer 188, which is the active ingredient in drug product previously tested in CytRx’s Phase 3 study in sickle cell disease and currently being developed by Mast Therapeutics. Certain low molecular weight substances present in poloxamer 188 that are associated with elevated serum creatinine are not present in vepoloxamer. No clinically significant elevations in creatinine have been observed in completed clinical studies conducted with vepoloxamer (>300 administrations).

The CytRx Corporation/Burroughs Wellcome Alliance

Poloxamer 188 is an extensively studied compound. It was originally used as an emulsifying agent in topical wound cleansers and parenteral nutrition products. The potential therapeutic use of poloxamer 188 was largely conceived by Dr. Robert Hunter, MD, PhD (Distinguished Professor and Chairman, Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston). While at Emory University, Dr. Hunter identified the compound’s rheologic, cytoprotective, and antithrombotic activities through an extensive series of laboratory studies. His work led to the formation of CytRx Corporation, a start-up company led by Jack Luchese which licensed Dr. Hunter’s inventions from Emory. CytRx conducted a wide range of pre-clinical and clinical studies with poloxamer 188 (the drug product was then known as RheothRx). These studies led to a major alliance with Burroughs Wellcome. Burroughs Wellcome also performed an extensive series of nonclinical studies and eight clinical trials, primarily focused on acute myocardial infarction (AMI). Early studies investigating poloxamer 188 were promising. The largest AMI trial planned to enroll approximately 20,000 patients. However, during the 3,000-patient lead-in phase of that study, elevations in serum creatinine were observed, particularly in those patients aged 65 years and older and in subjects with elevated creatinine at baseline. This phenomenon was referred to as “acute renal dysfunction” and eventually resulted in the discontinuation of the program by Glaxo Wellcome, which had recently been formed by the merger of Glaxo and Burroughs Wellcome.

Addressing Renal Toxicity and Pursuing Sickle Cell Disease

Glaxo returned the poloxamer 188 program to CytRx, which then investigated the source of the renal dysfunction and determined the elevation in serum creatinine was attributable to preferential absorption of certain low molecular weight substances by the proximal tubule epithelial cells in the kidney, causing an osmotic nephrosis. Nonclinical studies demonstrated the osmotic nephrosis was reversible and deemed to be an exaggeration of the normal vacuolar reabsorption pathway. CytRx developed a proprietary manufacturing method based on supercritical fluid chromatography that reduced the level of low molecular weight substances present in poloxamer 188, creating a purified poloxamer 188 compound, which has been assigned the unique generic name “vepoloxamer” by the United States Adopted Names (USAN) Council.

Nonclinical testing of vepoloxamer demonstrated less accumulation in kidney tissue, less pronounced vacuolization of proximal tubular epithelium, more rapid recovery from vacuolar lesions, and less effect on serum creatinine. A full report of the differential effects of vepoloxamer and poloxamer 188 on renal function has been published by Mast Therapeutics.1

Satisfied that it had identified the source of renal dysfunction, CytRx sought to re-introduce vepoloxamer into clinical development. The company lacked the resources to conduct a large heart attack study and, instead, focused the development of vepoloxamer in sickle cell disease, a genetic condition with a significant unmet need and which is a rare (orphan) disease in the United States. Under Burroughs Wellcome, poloxamer 188 had demonstrated positive results in a pilot Phase 2 study. In that study (n=50), vepoloxamer markedly and significantly reduced the duration of vaso-occlusive crisis, pain intensity, and total analgesic use and showed trends to shorter days of hospitalization in the subgroup of patients who received the full dose of study drug (n=31). These data were reported more fully by Adams-Graves et al.2 Notably, CytRx conducted safety studies in both adult and pediatric sickle cell patients and even at significantly higher levels of exposure than the anticipated therapeutic doses, there were no clinically significant changes in serum creatinine observed and no acute kidney failure reported. Based on these promising Phase 1 and 2 results, CytRx launched a randomized, double-blind, placebo-controlled Phase 3 study of vepoloxamer in 350 patients with sickle cell disease. The primary endpoint of this initial Phase 3 study was a reduction in the duration of a crisis. However, CytRx concluded the study at 255 patients, in part due to capital constraints. Despite its early conclusion and certain design flaws, the study demonstrated treatment benefits in favor of vepoloxamer. However, it did not achieve statistical significance in the primary study endpoint (p=0.07). Mast believes that enrolling fewer than the originally-planned number of patients and certain features of the study’s endpoint and observation period adversely affected the outcome of the study. In particular, the study assumed that most patients would resolve their crisis within one week (168 hours). However, a substantial number of patients did not achieve crisis resolution within 168 hours and were assigned a “default” value of 168 hours, which had a potentially significant effect on the primary endpoint. Notably, in a post hoc “responder’s analysis” of the intent-to-treat population (n=249), which analyzed the proportion of patients who achieved crisis resolution within 168 hours (e.g. excluding those who had been assigned the default of 168 hours), over 50% of subjects receiving vepoloxamer achieved crisis resolution within 168 hours, compared to 37% in the control group (p=0.02). Data from the Phase 3 study are reported more fully by Orringer et al.3 Following conclusion of the Phase 3 study, CytRx merged with a private company and modified its business strategy by discontinuing development of all of its existing programs (including vepoloxamer) to focus on assets held by the private company with which it merged.


After the corporate reorganization at CytRx, a group of individuals, including Dr. Hunter, formed a private entity, which they named SynthRx, Inc., to acquire rights to the data, know-how, and extensive clinical, pre-clinical, and manufacturing information necessary to continue development of vepoloxamer. SynthRx developed new intellectual property and conducted additional analyses of the existing data. However, they were unable to raise capital to fund additional clinical development of vepoloxamer, particularly during a period of economic recession in the U.S.

Mast Therapeutics

In 2010, Mast met with Dr. Hunter and his colleagues to negotiate the acquisition of SynthRx and thereby continue the development of vepoloxamer. The merger was finalized in April 2011.

Beginning in April 2011, Mast re-established the unique manufacturing process through a partnership with Pierre Fabre (FRA) and met with the FDA multiple times to discuss a pivotal study protocol for vepoloxamer in sickle cell disease. In early 2013, Mast initiated the “EPIC” study, a 388-patient pivotal Phase 3 trial of vepoloxamer in sickle cell disease that is being conducted in approximately 70 sites around the world. In 2014, building upon promising nonclinical data of vepoloxamer in combination with thrombolytics, Mast initiated its second clinical program featuring vepoloxamer, a Phase 2, proof-of-concept study of vepoloxamer in combination with recombinant tPA in patients with acute limb ischemia. In early 2015, based on recent nonclinical animal studies showing improvements in cardiac ejection fraction and key biomarkers and prior studies showing vepoloxamer improved cardiac function without increasing cardiac energy requirements, Mast announced its intent to initiate a Phase 2 clinical study of vepoloxamer in chronic heart failure.

1. Emanuele, M. and Balasubramaniam, B. Differential Effects of Commercial-Grade and Purified Poloxamer 188 on Renal Function. Drugs in R&D April 2014. Available at
2. Adams-Graves P, Kedar A, Koshy M, et al. RheothRx (Poloxamer 188) Injection for the Acute Painful Episode of Sickle Cell Disease: A Pilot Study. Blood 1997;90:2041-6
3. Orringer EP, Casella JF, Ataga KI, et al. Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: A randomized controlled trial. JAMA 2001;286(17):2099-106

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