Monday, July 29, 2024
10:00 AM ET
DM199 (rhKLK1) is an investigational protein therapy with the potential to treat multiple diseases. Our primary focus is on acute ischemic stroke (AIS) and preeclampsia (PE). 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.
When given within 24 hours of an ischemic stroke’s onset, DM199 (rhKLK1) 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, prostacyclin, and endothelium-derived hyperpolarizing factors 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
KLK1 is the main bradykinin producing enzyme in the human body, and activates the bradykinin 2 receptors (BK2R), which produces nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factors. We believe that these three signaling molecules may work synergistically to lower blood pressure, enhance endothelial health and improve perfusion to maternal organs and the placenta. Production of these signaling molecules are typically depressed or impaired in women suffering from preeclampsia.
Ischemic strokes per year globally
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
Cases of preeclampsia per year globally1
Cases of PE and related hypertensive pregnancy disorders in the U.S. 1,2
Cases of pre-term preeclampsia (<34 weeks gestation) per year in the U.S.3
1. Preeclampsia Foundation. “Preeclampsia and Maternal Mortality: A Global Burden”. Preeclampsia And Maternal Mortality: A Global Burden
2. Centers for Disease Control and Prevention. (n.d.). Births and natality. National Center for Health Statistics.
3. Dimitriadis, E., Rolnik, D.L., Zhou, W. et al. Pre-eclampsia. Nat Rev Dis Primers 9, 8 (2023). https://doi.org/10.1038/s41572-023-00417-6
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.
Treating AISPreeclampsia is a pregnancy disorder impacting multiple physiological systems, distinguished by the abrupt onset of hypertension and organ dysfunction. Following preeclampsia diagnosis, maternal organ function often declines and the only way to stop the disease is to deliver the fetus and placenta; this is the only major pregnancy condition that risks the lives of both the mother and the baby. There has not been an FDA-approved treatment to halt the progression of preeclampsia, and among developed nations, the United States has the highest reported maternal mortality rate, and this rate is increasing. Preeclampsia affects 5% - 8% of all births in the U.S..
The safety and effectiveness of DM199 for the treatment of acute ischemic stroke or preeclmapsia has not been established and is limited to investigational use only.
