The sulfonylurea receptor 1 (SUR1) is a cell membrane protein with more diverse and critically important functions than previously recognized. Long viewed simply as a subunit involved in formation of a subset of ATP-sensitive potassium channels, evidence now shows that SUR1 is newly upregulated in CNS ischemia and injury in association with the transient receptor potential cation channel subfamily M member 4 (TRPM4) pore. This complex is named the NC_Ca-ATP cation channel. Convincing evidence from preclinical and clinical studies demonstrate the potential importance of the blocking these channels, which are key upstream mediators of the development of brain edema and hemorrhage following ischemic and traumatic injury.

Remedy’s lead drug candidate, RP-1127, is a high affinity, well tolerated inhibitor of NC_Ca-ATP channels.

Whereas a neuroprotective effect of RP-1127 on ischemic neurons and astrocytes via blocking upregulated NC_Ca-ATP channels in these cells has been reported by multiple laboratories, it is RP-1127’s prevention of brain swelling and hemorrhage via its effect on NC_Ca-ATP channels in capillary endothelial cells that is the focus of Remedy’s clinical studies. When expressed, these channels lie dormant in the endothelial cell membrane, doing no harm unless they are opened by depletion of intracellular energy. Channel opening leads to sustained influx of sodium, which, if unchecked, leads to cell death. In microvascular endothelial cells, this mechanism results in leaky, dysfunctional capillaries leading to formation of life threatening space-occupying edema and hemorrhage. Closing the channel by administering RP-1127 prevents these often-lethal secondary effects.
 
Thus, while RP-1127 has a general neuroprotective effect, it additionally specifically prevents key pathophysiologies inherent in severe stroke, moderate/severe traumatic brain injury and virtually all spinal cord injuries i.e., swelling and hemorrhage⎯which are significant contributors to improved patient outcomes that have never before been targeted.

Recent evidence also shows that NC_Ca-ATP channels play an important role in organ ischemia outside of the central nervous system, including in the setting of myocardial infarction.

Remedy is the exclusive worldwide licensee of the patent portfolio related to NC_Ca-ATP channels developed by Dr. J. Marc Simard, Professor of Neurosurgery, Pathology and Physiology at the University of Maryland School of Medicine, and has its own wholly owned portfolio of patent applications related to formulation and dosing of RP-1127.

For more information on the science behind RP-1127, please click here.

Indications for Use

Targeted indications for use of RP-1127 include Stroke, Traumatic Brain Injury, Spinal Cord Injury and Organ Ischemia e.g. myocardial infarction.

Stroke

Every 40 seconds of every day someone in the United States has a stroke. Stroke is the third leading cause of death in America, surpassed only by heart disease and cancer, and is the primary cause of serious long-term disability in adults. There are 795,000 strokes in the U.S. each year, resulting in nearly 150,000 deaths. Annual costs to the healthcare system are estimated at $56.8 billion. 

A stroke happens when blood flow to the brain is interrupted because a blood vessel is blocked or bursts open. If blood flow is stopped for longer than a few seconds, the brain is deprived of vital blood and oxygen, brain cells then begin to die and brain damage occurs.

When brain cells die, abilities controlled by that area of the brain can be lost.  The most common areas affected include speech, movement and memory.  While some patients recover completely, more than two-thirds of all stroke victims will have some type of disability.

How a stroke patient is affected depends on where the stroke occurs in the brain and how much of the brain is damaged. There are two major types of stroke: ischemic stroke and hemorrhagic stroke.

Ischemic stroke are the most common type of stroke and occur when a blood vessel that supplies blood to the brain is blocked by a blood clot. These type of strokes most often result from clogged arteries. Ischemic strokes may also be caused by blood clots that form in the heart or other parts of the body and travel through the blood stream to the brain. This is known as a cerebral embolism.

Hemorrhagic strokes arise when a blood vessel in part of the brain becomes weak and bursts open, causing blood to leak into the brain. The flow of blood that occurs after the blood vessel ruptures damages brain cells. While hemorrhagic strokes represent less than 15 percent of all strokes, they account for some 30 percent of all stroke deaths.

There is currently only one FDA-approved drug for the treatment of acute ischemic stroke, tPA (tissue plasminogen activator), a “clot-buster.” Because tPA must be administered within the first few hours from the onset of a stroke (guidelines generally recommend three hours, but in some cases up to 4.5 hours), the drug is used in only a small number of stroke cases, and where used, studies show 1 in 3 patients who receive tPA resolve their symptoms or have major improvement in their stroke symptoms. There is no FDA-approved drug for the treatment of hemorrhagic stroke. Some 95 percent of stroke victims, then, currently receive no drug-based treatment¹.

Remedy Pharmaceuticals is currently conducting a pilot Phase 2 human clinical trial in severe ischemic stroke at two centers in the United States, the University of Maryland Hospital and Massachusetts General Hospital.

Traumatic Brain Injury

Traumatic brain injury (TBI) is the leading cause of death and disability in young people in the United States. TBI happens when a sudden impact causes damage to the brain. This can come from a bump, blow or jolt to the head or even a penetrating head injury.

One of the most common forms of TBI is a concussion, which can also occur from a blow to the body that causes the head to move rapidly back and forth. Concussions are an all-too-familiar sports-related injury.

In young children, falls are the most common cause of TBI, followed by abuse. Firearms and explosion injuries are the leading cause of death and disability in war zones. Overall, firearms, vehicle crashes and falls account for most TBI-related deaths.

The majority of the 1.4 million TBIs that occur each year are concussions or other forms of mild TBI. Approximately 275,000 TBI victims will experience severe enough trauma that they will be hospitalized.

TBI can cause a wide range of functional changes affecting thinking, sensation, language, and/or emotions. It can also cause epilepsy and increase the risk for conditions such as Alzheimer’s disease, Parkinson’s disease, and other brain disorders that become more prevalent with age. Some 50,000 die each year from their injuries. 

The Centers for Disease Control estimates that at least 5.3 million Americans, approximately 2% of the U.S. population, currently have a long-term or lifelong need for help to perform activities of daily living as a result of a TBI. The direct cost of care for these patients, excluding inpatient care, is estimated at $56 billion annually.

There are currently no approved pharmaceutical therapies for traumatic brain injury, with the only treatment being intracranial pressure management techniques such as craniectomy.

Remedy Pharmaceuticals is currently the IND sponsor of a Phase 2 human clinical trial in moderate and severe TBI at two centers in the United States, the University of California at San Diego and University of Maryland Hospital. This study is being conducted by the INTRuST Consortium, and is funded by the Department of Defense.

Spinal Cord Injury

Every year some 12,000 Americans experience a spinal cord injury (SCI). These can be devastating, causing permanent physical and emotional distress. There are presently some 250,000 people in the U.S. living with a spinal cord injury.

The majority of SCIs are caused by motor vehicle accidents or falls, and 80 percent of victims are male. Most spinal cord injuries from violence⎯which accounts for some 15 percent of SPI incidents⎯are due to gunshot wounds. Sports and recreation-related incidents make up 18 percent of SCIs.

An injury to one of the spinal cords eight cervical segments causes quadriplegia (tetraplegia)—loss of all or most function in all four limbs. Injury to the spinal cord’s thoracic, lumbar, or sacral regions causes paraplegia—loss of function of the legs. Complete paralysis means that the person as no voluntary use of the affected limbs. 52% of spinal cord injured individuals are considered paraplegic and 47% quadriplegic.

Secondary conditions such as pressure sores, respiratory complications, urinary tract infections, spasticity, and scoliosis are a major health issue for people living with SCI and all told, SCIs cost the nation an estimated $9.7 billion each year.

The only approved drug for treating SCI is methylprednisolone, a steroid medication, although its use is decreasing due to concerns over its efficacy and risk/benefit.

Animal studies funded by the Christopher Reeves Foundation, using Remedy Pharmaceuticals RP-1127 have shown significant clinical potential.

Organ Ischemia

Remedy Pharmaceutical’s has strong intellectual property claims and impressive scientific data from animal studies to indicate that RP-1127 has clinical value in the treatment of ischemia in various organs, including Myocardial Infarction (heart attack).

Heart attack is the leading cause of death in the United States. More than 1.5 million Americans suffer a heart attack every year. One third will die. The cost of medical care for heart disease is some $275 billion annually.

A heart attack occurs when one or more of the coronary arteries that supply blood to the heart are completely blocked and blood to the heart muscle is cut off.

Remedy Pharmaceuticals is exploring clinical trials of RP-1127 for this indication.

CNS Surgery

There are 22,020 new diagnoses of brain tumors each year in America and 13,210 resulting deaths. Surgery to remove brain rumors causes edema post operatively that is treated with high dose steroids which are mostly effective in reducing edema, but have unwanted side effects including induction of hypertension and diabetes.

RP-1127 has the potential to prevent edema formation, reduce steroid use, and improve neurological outcomes following neurosurgery to remove cancerous brain tumors.

¹ Mechanical thrombectomy as an intervention option for acute ischemic stroke is growing but is constrained to a small minority of patients.