By Grant Zeng, CFA
DM199 and Acute Ischemic Stroke (AIS)
DiaMedica Therapeutics Inc. (TSX:DMA.V) (OTC:DMCAF) is a clinical stage
biopharmaceutical company focused on the development and commercialization of DM199 for the treatment of acute ischemic stroke (AIS
) and diabetic kidney disease (DKD
The company’s lead drug candidate DM199
is a recombinant human tissue kallikrein (KLK1).
DM199 has undergone clinical testing that demonstrates its exceptional safety as a potential treatment for a variety of disorders. The Company is positing DM199 for the treatment of diabetic kidney disease (DKD)
and post-insult treatment for acute ischemic stroke (AIS).
There are no approved FDA therapeutic treatments for DKD and the only FDA approved drug treatment for AIS is tissue plasminogen activator (tPA)
, which is limited to only 3-4 hours after a stroke.
So far, five clinical trials in over 100 patients have been conducted with DM199. These studies were designed primarily to establish the safety and tolerability of DM199 and characterize the pharmacokinetics after subcutaneous and intravenous dosing. Importantly, the studies also included regular monitoring of blood pressure. Measurable decreases in blood pressure and/or postural hypotension as the dose-limiting tolerability were observed at doses that generated plasma concentrations of DM199 and consistent with the mechanism of action.
DiaMedica is currently conducting a Phase Ib clinical trial
designed to identify a dose of DM199 that is comparable to the human urinary and porcine approved versions in Asia. The results of this study will guide dosing for Phase II and III clinical trials.DM199 for Acute Ischemic Stroke (AIS)
DiaMedica’s lead drug candidate DM199 is a human recombinant tissue kallikrien (rhKLK1) protein.Background of KLK1
Kallikreins (KLK) are a subgroup of serine proteases
having diverse physiological functions. The proteins arise from a family of 15 genes. DiaMedica is developing human tissue kallikrein (KLK1)
to distinguish itself from an unrelated protease called plasma kallikrein
. KLK1 differs from plasma kallikrein in substrate specificity, types of kinins released, localization, and regulatory mechanisms.
KLK1 possesses protease activity with a substrate specificity similar to that of trypsin or chymotrypsin. The most well-characterized activity of KLK1 is its enzymatic cleavage of kininogen
to produce bradykinin (BK) like peptides, collectively known as kinins
, which activate both subtypes of bradykinin receptors (BK-B1, BK-B2). Activation of BK receptors by kinins promote blood flow by inducing an immediate vasodilation followed by longer term angiogenic actions. By this mechanism KLK1-mediated release of kinins has been shown to increase blood flow in a variety of tissues including brain, kidney and heart. This is likely the primary mode
by which kallikrein treatment addresses brain pathologies caused by acute ischemic stroke (AIS
Kinins have a short half-life in vivo
as they are rapidly degraded by ubiquitous enzymes, most notable are the angiotensin converting enzymes (ACE). KLK1 activity also is tightly regulated by inhibitor proteins found throughout the body. Because of these multilayered regulatory systems, it is plausible that levels of bradykinin drop below optimum levels in pathological conditions such as AIS and DKD. Treatments that provide additional supplies of active KLK1 can serve to maintain sufficient bradykinin levels and thereby promote BK-B2 receptor activation.
KLK1 and Stroke
Lower level of the protein tissue KLK1
in the blood and urine has been independently associated with first-ever stroke and lower long term survival and is an independent predictor of recurrence after an initial stroke.
In a 2,478 patient case-controlled clinical study of KLK1 levels in stroke patients, higher KLK1 activity is predictive of fewer stroke recurrences and longer event-free survival time. Event free survival functions were measured using Kaplan-Meier survival curves.
Published preclinical and clinical research with a naturally occurring KLK1 protein has demonstrated reduced blood pressure, cell death, and inflammation and increased angiogenesis (creation of new blood vessels) and neurogenesis. In a preclinical study, DM199 has also demonstrated significant increase in blood flow in the brain after a single dose.
In the People’s Republic of China
, a human urine-extracted version of KLK1 (uKLK1) is currently being used to treat AIS. The product is isolated from human urine and marketed by Techpool Bio-Pharma Inc. under the brand name Kailikang®
. Kailikang® is prescribed to stroke patients up to 48 hours after an AIS and is given by intravenous administration.
More than 40 published clinical studies have shown a beneficial effect of Kailikang® treatment in AIS, including a meta-analysis covering 24 clinical studies involving 2,433 patients.
In a double-blinded, placebo-controlled, Phase III
trial of 446 patients treated with uKLK1 or placebo up to 48 hours after a stroke, significant differences were found in the European Stroke Scale and Activities of Daily Living at three weeks of treatment and at three months using the Barthel Index with uKLK1 treated vs placebo
In a 200-patient Phase II study, human urine KLK1 in combination with tPA, the only FDA approved agent for AIS, significantly improves stroke function using Barthel Index (BI) measure.
The conclusion: KLK1 is highly correlated with stroke and treatment of stroke patients with KLK1 products may improve outcome.DM199 Has the Potential to Treat AIS
Like uKLK1, we believe DM199 has the potential to preserve “at risk” brain tissue by establishing better collateral circulation, decreasing inflammation, reducing apoptosis, and helping generate collateral circulation by initiating angiogenesis and neurogenesis.
Studies have shown that DM199 and other KLK1 products increases blood flow in a variety of tissues including kidney, heart and brain. This is believed the primary mode DM199 use to preserve brain tissue after an AIS attack.Five clinical studies
have been completed for DM199, which include single ascending, multiple ascending, PK, 28 day & bridging studies. These studies have demonstrated the safety and efficacy of DM199 for the treatment of AIS.
In a Phase I
study, DM199 demonstrated statistically significant decrease from baseline systolic blood pressure
that was not observed in the placebo group. Since hypertension is the most common modifiable risk factor for stroke, with blood pressure reduction being associated with a reduced rate of stroke recurrence, the effect of DM199 on blood pressure indicates activity in patients.
In all five studies, DM199 has been well tolerated and has demonstrated excellent safety profile with clean safety profile at anticipated dosing levels.
In another comparable study, DM199 demonstrated similar enzymatic activity to two approved KLK1 products in Asia.
(human urine KLK1) has been approved in China for acute ischemic stroke, while porcine KLK1
has been approved in China, Japan and Korean for treatment of diabetic kidney disease, hypertension and retinopathy.Development Plan for DM199 for AIS
DiaMedica is conducting a Phase I bridge clinical study
of DM199 to determine the safety, optimal dose & delivery.
The Phase I
controlled trial was an open-label single ascending study, where healthy volunteers received one of four single doses of DM199 (n=36),
administered as a 30-minute intravenous (IV) or subcutaneous (SQ) infusion. Plasma DM199 concentration, biomarker concentrations, and other safety and pharmacokinetic parameters were measured in the trial.
In December 2016, the company reported positive results from the clinical trial. The study results demonstrated the dose dependent levels of DM199 and identified a dose of DM199 via intravenous (IV)
administration that produced pharmacokinetic and pharmacodynamic activity that were comparable to those produced by the reference drug, human urinary KLK1 (trade name Kailikang®) approved in Asia.
This clinical study also provided clinically relevant safety data via intravenous delivery of DM199 for the first time at dose levels comparable to the currently approved human urinary KLK1 product.
No treatment limiting adverse events were reported in any dose group. A few patients experienced mild orthostatic hypotension which is consistent with the mechanism of action and demonstrated drug activity. The Company plans to publish the full results of the study in a peer reviewed journal.
The company has initiated the second part of the clinical trial to include subcutaneous
(under the skin) delivery of DM199. The objective of this phase is to further refine and identify an optimal dosing of the intravenous and subcutaneous forms of DM199, possibly superior to the human urinary and porcine derived KLK1 products approved in Asia for acute ischemic stroke and diabetic kidney disease.
DiaMedica intends to seek worldwide
approval for DM199 as a novel therapy for acute ischemic stroke (AIS).
The company will also position DM199 in China
as an improved product over the urine-sourced KLK1 protein currently used there. The company also intends to seek worldwide
approval for DM199 as a novel therapy for acute ischemic stroke
. With the potential that effective treatment can be initiated up to 48 hours after the first sign of symptoms, DM199 may fill a large unmet need for stroke patients who cannot receive tPA, benefiting millions of people around the world who currently have limited treatment options.
DiaMedica intends to initiate a Phase II
study of DM199 for AIS in 2017. The Phase II trial will enroll approximately 100 AIS patients and start treatment within 24 hours of stroke over 21 days. The primary end points include:
- Safety and tolerability
- Biomarkers - blood flow and inflammation
- Modified Rankin Scale (mRS)
- National Institute of Health Stroke Scale (NIHSS)
- Activities of Daily Living on Barthel Index (BI)A Huge Market of AIS for DM199
is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. As a result, the affected area of the brain becomes inactive and eventually dies. Strokes can be classified into two major categories: acute ischemic stroke (AIS)
and hemorrhagic stroke
. AIS are those that are caused by interruption of the blood supply by a blood clot (ischemia), while hemorrhagic strokes result from rupture of a blood vessel or an abnormal vascular structure. About 87%
of strokes are acute ischemic strokes, with the remainder classified as hemorrhagic and 1 in 6 people will have a stroke in their lifetime according to the World Stroke Organization.
According to the World Heart Federation (WHF), each year approximately 15 million
suffer a stroke of which 6 million will die and 5 million will be permanently disabled. Worldwide, stroke is the leading cause of adult disability and the second leading cause of death in developed countries.
Each year in the US
, approximately 800,000 people experience a new or recurrent stroke (ischemic or hemorrhagic). Approximately 610,000 of these are first events and 185,000 are recurrent stroke events.
Stroke represents an area of tremendous unmet medical need.
Currently, the only FDA approved therapeutic-based treatment is tissue plasminogen activator (tPA
, also known as Activase® and Altapase), a protein involved in the breakdown of blood clots (thrombolysis) to re-establish normal blood flow (recanalization). However, tPA is only effective if administered within 3-4.5 hours (preferably closer to within the 3 hour timepoint) of an acute ischemic stroke, as outside this therapeutic window tPA is not only ineffective but its use leads to a greater risk of hemorrhage (bleeding in the brain). As such, only 5-7% of AIS patients
are treated with tPA.
Therefore, a clear unmet therapeutic need exists for the vast majority of stroke patients who do not receive tPA. New therapeutic options in development include tissue protection focused therapies (hours to days after the stroke) that preserve and protect brain cells beyond the tPA therapeutic window, and are especially targeted toward preserving viable cells in the penumbra hours after a stroke. This represents a potential $10+ billion
market opportunity for a drug that is able to successfully obtain approval of a therapy outside of the tPA 4.5-hour therapeutic window
.DM199 May Be Administered up to 48 hours post-AIS
From the characteristics and unique mechanism of action for AIS, we believe DM199, as a recombinant KLK1 protein, has the potential to preserve brain tissue after AIS attack. In addition, clinical trials with a human urinary KLK1 suggest DM199 may be administered up to 48 hours post-AIS.
As demonstrated by the beneficial effect of timely tPA treatment, restoring blood flow to the ischemic brain region is among the most critical factors for successful recovery from AIS. DM199
does this by generating additional bradykinin to activate BK-B2 receptors. Activation of this pair of receptors triggers several important physiological responses that could be beneficial following AIS.
First, activation of the BK2 receptor activates the endothelial nitric oxide synthetase enzyme (eNOS)
to produce nitric oxide (NO), which relaxes blood vessels and improves blood flow. NO has been known to play a complex role in cerebral ischemia. Ischemia can activate neuronal
NO synthase (NOS), resulting in production of NO that is toxic to surrounding neurons. Inducible NOS, which is not normally present in healthy tissues, is induced shortly after ischemia and contributes to secondary damage. However, NO generated from endothelial
eNOS is critical in maintaining cerebral blood flow and reducing infarct volume. Its up-regulation is neuroprotective against cerebral ischemia. Overall these results suggest that the tissue KLK1, through activation of eNOS and subsequent NO production, might modulate endothelial function and promote cell survival and could have protective effects on the brain in the setting of ischemic stroke.
Second, activation of both the BK-B1 and BK-B2 receptors can increase angiogenesis
(creation of new blood vessels). Activation of the BK-B1 receptor leads to an increase in basic fibroblast growth factor, which is known to improve both angiogenesis and neurogenesis in animal models of stroke. Activation of the BK-B2 receptor leads to transactivation of the VEGF receptor and release of VEGF
itself. VEGF is a potent growth factor that triggers angiogenesis and could improve collateral perfusion in stroke.
DM199 is Developed as a Biobetter in Asia
Currently, two KLK1 products are approved in Asia. uKLK1 (Kailikang®)
is derived from human urine (human urine KLK1) and is approved in China
for the treatment of acute ischemic stroke. Another KLK1 product is derived from pig (porcine KLK1, trade name Kallidinogenase
) and is approved in Japan, China and Korea for diabetic kidney disease and hypertension.
Both approved KLK1 products faces the issues of endotoxin risk, impurity and antibody formation, which limit the utilization. For Kailikang®, there is also an issue of limited supply since manufacturing requires very large quantities of human urine at what the Company believes has a high cost of goods sold.
DM199 is recombinant KLK1, which eliminates the side effects of both human urine and porcine KLK1. DiaMedica has mastered the complicated manufacturing process for DM199 with high expression and stability. The company can produce commercial scale of DM199 (up to 200 Liter) under cGMP with very low costs.
DiaMedica is developing DM199 as a new product worldwide
use and in Asia as a biobetter product
to replace approved uKLK1 and porcine KLK1 in China & Japan.
If approved, we estimate the worldwide peak sales of DM199 for AIS could surpass $1 billion
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