DiaMedica Therapeutics, Inc.

Stroke Disease

New Approach to Treating Acute Ischemic Stroke

According to the World Stroke Organization, acute ischemic stroke is a global public health threat, affecting more than 7.5 million people worldwide. The U.S. Centers for Disease Control estimate that approximately 700,000 ischemic strokes occur in the United States each year.  While the number of people suffering strokes continues to climb, the last drug introduced for the treatment of acute ischemic stroke, Alteplase® (tPA), was approved over 25 years ago.  With the limited approved treatment window for Alteplase (<4.5 hours), less than 10% of stroke sufferers are generally able to receive Alteplase.

Recent scientific research combined with promising early studies of DM199, as described below, have led to a new understanding of the role KLK1 plays in promoting healthy blood vessels and improving patient physical recoveries from stroke and reducing in the risk of stroke recurrence.

Low KLK1 Levels Associated with Stroke

Studies have shown that stroke patients have lower KLK1 levels and that low KLK1 levels after a stroke may be a predictor of recurrent stroke:

Annals of Neurology (2011) 70:265-73;

Abstract:

Objective:
Tissue kallikrein (TK) cleaves kininogen to produce the potent bioactive compounds kinin and bradykinin, which lower blood pressure and protect the heart, kidneys, and blood vessels. Reduction in TK levels is associated with cardiovascular disease and diabetes in animal models. In this study, we investigated the association of TK levels with event-free survival over 5 years in Chinese first-ever stroke patients.

Methods:
We conducted a case–control study with 1,268 stroke patients (941 cerebral infarction, 327 cerebral hemorrhage) and 1,210 controls. Plasma TK levels were measured with an enzyme-linked immunosorbent assay. We used logistic regression and Cox proportional hazards models to assess the relationship between TK levels and risk of first-time or recurrent stroke.

Results:
Plasma TK levels were significantly lower in stroke patients (0.163 ± 0.064mg/l vs 0.252 ± 0.093mg/l, p < 0.001), especially those with ischemic stroke. After adjustment for traditional risk factors, plasma TK levels were negatively associated with the risk of first-ever stroke (odds ratio [OR], 0.344; 95% confidence interval [CI], 0.30–0.389; p < 0.001) and stroke recurrence and positively associated with event-free survival during 5 years of follow-up (relative risk, 0.82; 95% CI, 0.74–0.90; p < 0.001). Compared with the first quartile of plasma TK levels, the ORs for first-ever stroke patients were as follows: second quartile, 0.77 (95% CI, 0.56–1.07); third quartile, 0.23 (95% CI, 0.17–0.32); fourth quartile, 0.04 (95% CI, 0.03–0.06).

Interpretation:
Lower plasma TK levels are independently associated with first-ever stroke and are an independent predictor of recurrence after an initial stroke. ANN NEUROL 2011;

Disease Markers Volume 2015, Article ID 159750, 8 pages

Abstract:

Aim. Tissue kallikrein (TK) protein content in plasma has been shown to be negatively associated with both incident and recurrent strokes. The aims of this study were to develop a novel method for detecting TK activity and to investigate its association with event-free survival over 5 years in Chinese first-ever stroke patients. Methods. We designed a case-control study with 321 stroke patients (174: ischemic stroke, 147: hemorrhagic stroke) and 323 healthy local controls. TK activity was measured by a novel assay utilizing the immunological characteristics of TK and the catalysis of benzoyl arginine ethyl ester hydrochloride (BAEE). Results. TK protein levels above 0.200 mg/L in plasma were not associated with urinary TK activity or the risk of stroke recurrence. TK activity was significantly lower in stroke patients compared with controls (1.583 ± 0.673 Eu/mL versus 1.934 ± 0.284 Eu/mL, ). After adjusting for traditional risk factors, TK activity was negatively associated, in a dose-response manner, with the risk of overall stroke recurrence and positively associated with event-free survival during a 5-year follow-up (relative risk (RR), 0.69; 95% CI, 0.57–0.84; ). Conclusions. Our findings suggest that urinary TK activity may be a stronger predictor of stroke recurrence than plasma TK levels.

DM199 May Restore the Body’s Natural Ability to Produce NO, PGI2, & EDHF

With DM199 (rhKLK1) therapy, we believe that KLK1 levels and the natural function of the Kallikrein-Kinin system may be restored to enable the body’s natural ability to produce the required nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factors (EDHF) and deliver them to where they are needed to promote blood flow (vasodilation), fight harmful inflammation and repair injured blood vessels and to help patients recover from acute ischemic stroke and to reduce the risk of stroke recurrence. This is because the KLK1 protein sits on the top of the molecular pathway that drives the natural production of nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factors.

Phase 2 Clinical Trial Results – ReMEDy1

DiaMedica’s ReMEDy1 Phase 2 trial in acute ischemic stroke was completed in May of 2020.  This study met its primary safety and tolerability endpoints.  In addition, in subjects which did not receive mechanical thrombectomy, the group more closely aligned with DiaMedica’s ongoing ReMEDy2 trial, the following results were observed:

Subjects Treated With:
DM199 (n=25) Placebo (n=21)
Full/Near Full Physical Recovery 36% 14%
Deaths 12% 24%
Stroke-in-Evolution/Recurrent Ischemic Events 0% 19%

Patients were allowed to enroll in the ReMEDy Phase 2 trial if they received Alteplase (tPA) but were not responding positively to the treatment.

The safety and effectiveness of DM199 for the treatment of acute ischemic stroke or preeclampsia has not been established and is limited to investigational use only.