Tissue Kallikrein for Ischemic Stroke

(ReMEDy2 Trial)

Recruiting at 37 trial locations

Overseen By Kayla Slupek

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: DiaMedica Therapeutics Inc

Must not be taking: ACE inhibitors, HAE treatments

Disqualifiers: Hemorrhagic stroke, Large vessel occlusion, MT, HAE, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 3 weeks

728 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 2/3 study evaluating the safety and efficacy of DM199 (rinvecalinase alfa) in treating participants with moderate stroke severity, who present within 24 hours of Acute Ischemic Stroke (AIS) onset due to small and medium vessel occlusions. This study focuses on participants with limited treatment options. Participants who have or will receive mechanical thrombectomy (MT) are not eligible for participation. Additionally, participants who have received fibrinolytics are excluded unless they experience a persistent neurological deficit of moderate severity six or more hours after fibrinolytic treatment. Participants considered for this trial should not be denied the use of standard of care (SoC) AIS therapies, such as fibrinolytics or MT, when appropriate. The double-blinded study will be randomized and placebo-controlled at up to approximately 100 sites.

Will I have to stop taking my current medications?

The trial requires participants who are currently taking an ACE inhibitor (a type of blood pressure medication) to switch to another blood pressure medication for the duration of the study. If you are on an ACE inhibitor, you must not have taken it within 24 hours before starting the study drug.

What data supports the effectiveness of the drug Recombinant human tissue kallikrein (DM199) for ischemic stroke?

Research suggests that tissue kallikrein can help improve blood flow and reduce brain damage after a stroke by promoting the production of kinins, which are substances that widen blood vessels. Studies in animals have shown that kallikrein can reduce stroke-related brain injury and inflammation, suggesting it may be beneficial for treating ischemic stroke in humans. ^{1 2 3 4 5}

How is the drug DM199 different from other treatments for ischemic stroke?

DM199, a form of recombinant human tissue kallikrein, is unique because it enhances blood flow by generating kinins, which are natural vasodilators (substances that widen blood vessels). Unlike standard treatments that focus on removing blood clots, DM199 promotes long-term vascular health and has anti-inflammatory and anti-oxidative properties, offering neuroprotection even when administered after a stroke. ^{1 3 6 7 8}

Research Team

Scott Kasner, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

Adults over 18, weighing between 50-160 kg, who've had an Acute Ischemic Stroke within the last 24 hours but can't have clot-dissolving drugs or mechanical clot removal. They should have a moderate stroke severity score and be in good health before the stroke. Pregnant women and those on certain blood pressure meds are excluded.

Inclusion Criteria

I am not eligible for molecular targeted therapy.

Participant is willing and able to comply with the study protocol, in the Investigator's judgment.

I am 18 years old or older.

Exclusion Criteria

You are expected to live for less than a year before the study starts.

I have not been part of a drug study or taken experimental drugs in the last 30 days.

I have alpha 1-antitrypsin deficiency.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive DM199 or placebo with an initial IV dose followed by SC doses twice a week up to Day 21

3 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments at Day 90

90 days

1 visit (in-person) at Day 90

Treatment Details

Interventions

• Recombinant human tissue kallikrein

Trial Overview The ReMEDy2 Trial is testing DM199 (recombinant human tissue kallikrein) for safety and effectiveness in treating strokes when standard treatments aren't suitable. Participants will either receive DM199 or a placebo at random, without knowing which one they're getting.

Participant Groups

Group I: DM199 Experimental Treatment 1 Intervention

DM199 administered by a single intravenous (IV) dose followed by subcutaneous (SC) doses at 2 hours (+10 hours) of the IV dose completion and then 2 times per week up to Day 21.

Group II: Placebo for DM199 Solution for Injection Placebo Group 1 Intervention

Placebo administered by a single intravenous (IV) dose followed by subcutaneous (SC) doses at 2 hours (+10 hours) of the IV dose completion and then 2 times per week up to Day 21.

Recombinant human tissue kallikrein is already approved in China for the following indications:

Approved in China as KLK1 for:

• Ischemic stroke

Who Is Running the Clinical Trial?

DiaMedica Therapeutics Inc

Lead Sponsor

Trials

7

Recruited

1,200+

Findings from Research

Tissue kallikrein (KLK1) is a natural enzyme that helps regulate blood flow and could be a promising pharmacological treatment for acute ischemic stroke (AIS) by promoting vasodilation and vascularization.

KLK1 has been clinically used in China for treating subacute AIS, and this review discusses its biochemical mechanisms and supporting human clinical data, suggesting it may enhance current treatment strategies for large vessel occlusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human tissue kallikrein in the treatment of acute ischemic stroke. Alexander-Curtis, M., Pauls, R., Chao, J., et al.[2020]

Human tissue kallikrein is a key enzyme involved in inflammation and is a potential target for treating conditions like asthma and rheumatoid arthritis, making it important for therapeutic development.

The study found that three variants of human tissue kallikrein, despite having different amino acid substitutions, do not show significant differences in their biochemical properties or interactions with inhibitors, suggesting they may function similarly in the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression and characterization of human tissue kallikrein variants. Chan, H., Springman, EB., Clark, JM.[2006]

Systemic delivery of the kallikrein gene significantly reduced stroke-related mortality, high blood pressure, and aortic hypertrophy in hypertensive rats, indicating its potential as a protective treatment against stroke.

Kallikrein gene delivery also reduced neurological deficits and brain damage in a rat model of ischemic stroke, promoting healing processes like angiogenesis and neurogenesis, and its protective effects were linked to the kinin B2 receptor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experimental therapy with tissue kallikrein against cerebral ischemia. Chao, J., Chao, L.[2019]

In a study of 321 stroke patients and 323 healthy controls, tissue kallikrein (TK) activity was found to be significantly lower in stroke patients, indicating a potential link between reduced TK activity and stroke occurrence.

Higher urinary TK activity was associated with a lower risk of stroke recurrence and better event-free survival over a 5-year period, suggesting that urinary TK activity could be a more reliable predictor of stroke outcomes than plasma TK levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tissue Kallikrein Activity, Detected by a Novel Method, May Be a Predictor of Recurrent Stroke: A Case-Control Study. Ran, X., Zhang, Q., Wang, DW.[2022]

Recombinant human tissue kallikrein was successfully produced in E. coli, demonstrating proper folding and full enzymatic activity, which is crucial for its potential therapeutic applications.

The study confirmed that the recombinant kallikrein is pure and structurally similar to natural kallikrein, with specific disulfide bonds intact, ensuring its functionality in hydrolyzing peptide substrates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isolation and characterization of human tissue kallikrein produced in Escherichia coli: biochemical comparison to the enzymatically inactive prokallikrein and methionyl kallikrein. Lu, HS., Hsu, YR., Lu, LI., et al.[2013]

Recombinant human tissue kallikrein (rhK1) was successfully expressed in the egg whites of laying hens, achieving a maximum enzymatic activity of 59 U/mL that lasted over 7 days, indicating a feasible method for producing this enzyme.

The rhK1 produced showed similar biochemical properties to natural enzymes, including thermostability and hypotensive effects, suggesting its potential for therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression and preliminary characterization of recombinant human tissue kallikrein in egg white of laying hens. Gao, B., Sun, HC., Fang, HX., et al.[2020]

A monoclonal antibody was developed to create immunoassays that can specifically measure different forms of tissue kallikrein in body fluids, which is important for understanding its biological functions.

These assays can differentiate between total immunoreactive tissue kallikrein, its complex with alpha 1-proteinase inhibitor, and the enzymatically active form, enhancing research on tissue kallikrein-kinin systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunoassays for the determination of human tissue kallikrein (TK) in different body fluids based on monoclonal antibodies. Witzgall, K., Godec, G., Shimamoto, K., et al.[2019]

The study successfully demonstrated that recombinant human tissue kallikrein (rhK1) can be expressed in the egg white of laying hens using a viral vector, achieving high levels of secretion (up to 107 U/mL) that lasted for over 6 weeks after a single injection.

This method of using recombinant adeno-associated virus (rAAAV) for gene expression in oviduct cells shows promise for producing other recombinant proteins, indicating a potentially effective system for biopharmaceutical production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant avian adeno-associated virus-mediated oviduct-specific expression of recombinant human tissue kallikrein. Wang, AP., Sun, HC., Wang, JY., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Human tissue kallikrein in the treatment of acute ischemic stroke. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Expression and characterization of human tissue kallikrein variants. [2006]

3. United States pubmed.ncbi.nlm.nih.gov

Experimental therapy with tissue kallikrein against cerebral ischemia. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Tissue Kallikrein Activity, Detected by a Novel Method, May Be a Predictor of Recurrent Stroke: A Case-Control Study. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Isolation and characterization of human tissue kallikrein produced in Escherichia coli: biochemical comparison to the enzymatically inactive prokallikrein and methionyl kallikrein. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Expression and preliminary characterization of recombinant human tissue kallikrein in egg white of laying hens. [2020]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Immunoassays for the determination of human tissue kallikrein (TK) in different body fluids based on monoclonal antibodies. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Recombinant avian adeno-associated virus-mediated oviduct-specific expression of recombinant human tissue kallikrein. [2020]