DM199 is an investigational protein therapy with the potential to treat multiple diseases. Our initial focus is on acute ischemic stroke (AIS) and cardio-renal disease. DM199 is intended to restore normal levels of the naturally occurring protein KLK1, which acts on interrelated mechanisms in the blood vessels and kidneys to improve circulation and overall function.
How DM199 Stands Out
We believe DM199 may provide new treatment options with significant benefits over the current standards of care, which are only available to approximately 20%1 of AIS patients. In the treatment of AIS, DM199 is being investigated with a treatment window of up to 24 hours from the onset of a stroke, potentially providing a therapeutic treatment option in the United States for the approximately 80%1 of AIS patients with no therapeutic treatment option and who generally only receive supportive care. In the treatment of cardio-renal disease, we believe that DM199 has the potential to reduce blood pressure and maintain, or possibly improve kidney function, by both improving blood flow (as measured by eGFR) and reducing albuminuria (as measured by the urinary albumin to creatinine ratio). We are not aware of any approved therapies in the United States or the European Union to address low KLK1 levels. DiaMedica’s clinical trials have been and/or are being conducted in the United States, Europe and Australia. In the trials completed to-date, DM199 has been generally safe and well tolerated. 1. Market research conducted by SyneosOne in 2020 and Journal of Stroke and Cerebrovascular Diseases, Volume 29, Issue 2, February 2020.
DM199 may also have distinct advantages over existing KLK1 replacement therapies approved in Asia. KLK1, derived from human urine, is widely used in China (marketed under the brand name Kailikang® by Shanghai Pharma) for the treatment of AIS, and we believe that over 600,000 patients were treated in 2022. We believe that DM199, a synthetic form of KLK1, administered subcutaneously could result in improved efficacy given the more stable pharmacokinetics (drug exposure levels) observed in the subcutaneous dosing administered in our prior trials. Additionally, we believe that a synthetic form of KLK1 may avoid the potential manufacturing risks of Kailikang. Specifically the risk of endotoxins, impurities and antibody formation associated with a drug that is extracted from human urine. DM199, as a synthetically produced form of KLK1, may also address potential supply constraints that make Kailikang difficult and expensive to produce given the logistical challenges in sourcing of human urine. These factors may contribute to DM199 being a product candidate that is better positioned to achieve the manufacturing regulatory compliance required for commercial approval worldwide as compared to a urine-derived protein.
Restoring Normal Physiologic Function
Mechanism of Action of DM199 for Stroke
When given within 24 hours of an ischemic stroke’s onset, DM199 is intended to increase production of bradykinin which in turn may activate a greater number of the increased bradykinin 2 receptors present in arteries affected by AIS, referred to as the ischemic penumbra, and thereby improve collateral circulation in the ischemic penumbra. By delivering vital oxygen and nutrients to brain tissues in need, there is the potential to preserve/restore neuronal function and reduce the size of the ischemic penumbra minimizing tissue death (infarction) and brain damage.
Our blood vessels have the natural ability to constrict and dilate. This elasticity helps blood flow throughout the body so we can maintain an uninterrupted supply of oxygen and nutrients to vital organs like our brain. When a part of the brain has a sudden interruption in the supply of blood a stroke will occur, potentially leading to permanent disability. The most common form of stroke is an ischemic stroke, which is caused by restricted blood flow due to the narrowing or blockage of an artery in the brain.
In response to an ischemic stroke, the expression of BK2 receptors is selectively and significantly increased in the artery(ies) affected by the stroke1, signaling the need for BK and its vasodilatory effects to restore blood flow to this specific area of the brain, without causing systemic, or body-wide, vasodilation.
This critical cascade to increase blood flow begins with the human tissue kallikrein-1 protein, also known as KLK1, which circulates in the blood and acts upon low molecular weight kininogen to release BK. Inside the blood vessels, BK binds to and activates the BK2 receptors expressed on the surface of endothelial cells which line the interior of the blood vessel. Once the BK2 receptor becomes activated, it triggers the production of nitric oxide and prostaglandin, which migrate deeper into the blood vessel wall causing smooth muscle cells to relax and the blood vessel dilates, thus allowing more vital blood to flow.
For individuals with diminished or low levels of KLK1, commonly seen in stroke patients, the body is unable to supply enough KLK1 to produce the necessary BK to activate the additional BK2 receptors and restore blood flow to the affected brain area, known as the ischemic penumbra.
Within minutes after the onset of ischemic stroke, the neurons in the ischemic penumbra may cease to function properly resulting in sudden disability for the patient. If left untreated, these neurons may eventually die resulting in brain damage and permanent disability.
But that doesn’t have to happen. DiaMedica’s investigational drug product candidate, DM199, is a synthetic form of the KLK1 protein that is being clinically tested as a therapy intended to augment KLK1 levels and potentially improve collateral circulation in the ischemic penumbra.
DM199 can be administered intravenously or subcutaneously. It travels into the bloodstream and is rapidly delivered to the blood vessels of the ischemic penumbra without needing to pass through the blood-brain barrier.
DM199 is intended to increase production of BK which in turn activates a greater number of the increased BK2 receptors in the ischemic penumbra, thus improving collateral circulation in the ischemic penumbra. By delivering vital oxygen and nutrients to brain tissues in need, there is the potential to preserve/restore neuronal function, reducing the size of the ischemic penumbra, and tissue death (infarction) minimizing brain damage. 1. PLOS ONE, June 18, 2018; https://doi.org/10.1371/journal.pone.0198553
Mechanism of Action of DM199 for Cardio-Renal Disease
KLK1 is believed to promote the dilatation of the efferent arterioles in the kidney, improving micro vascularization and blood flow while reducing hypertension and improving kidney function. In addition, KLK1 is thought to improve the kidney's ability to filter blood (glomerular function) by reducing inflammation, oxidative stress and fibrosis. It is further hypothesized that KLK1 plays a role in regulating the epithelial sodium channel (ENaC), which regulates the body’s retention or elimination of sodium.
Acute Ischemic Stroke (AIS)
Ischemic strokes per year globally (700K in the U.S.)
Ischemic strokes per year in the U.S.
Of AIS patients have no direct treatment options
World Stroke Organization Global Fact Sheet 2022 & CDC Stroke Facts October 2022
Stroke is characterized by the rapidly developing loss of brain function due to a blockage of blood flow in the brain. As a result, the affected area of the brain becomes inactive and eventually dies. According to the U.S. Center for Disease Control and Prevention (CDC) in October 2022, about 87% of strokes in the U.S. are ischemic in nature. According to the World Stroke Organization in 2022, worldwide, stroke remains the second leading cause of death and the third leading cause of death and disability combined..
Cardio-renal disease involves the increase in blood pressure and progressive loss of kidney function. One of the most serious consequences of untreated chronic kidney disease (CKD) is end stage renal disease (ESRD), where the kidneys have ceased to function and the individual requires continuous, on-going dialysis or kidney transplantation. Kidney disease is reaching epidemic proportions in the United States. Tens of millions of Americans are afflicted with cardiovascular and renal disease, a potentially devastating condition.
The safety and effectiveness of DM199 for the treatment of acute ischemic stroke or cardio-renal disease has not been established and is limited to investigational use only.