Tissue Kallikrein for Ischemic Stroke

(ReMEDy2 Trial)

Recruiting at 46 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called DM199 (recombinant human tissue kallikrein) for individuals who have experienced a moderate ischemic stroke, which occurs when a blood clot obstructs blood flow to the brain. The study aims to determine if DM199 is safe and effective for those with limited treatment options who have not received treatments like mechanical thrombectomy. Participants should exhibit noticeable stroke symptoms that began within the last 24 hours and are not improving with standard clot-busting drugs. Individuals with moderate stroke symptoms who have not undergone certain treatments may be suitable for this trial. As a Phase 2, Phase 3 trial, this study measures DM199's effectiveness in an initial group and represents the final step before FDA approval, offering a chance to advance stroke treatment.

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.

Is there any evidence suggesting that DM199 is likely to be safe for humans?

Research has shown that DM199, a lab-made version of a natural protein, has undergone safety testing in people. Studies have found DM199 to be generally safe and well-tolerated. For instance, earlier trials reported no major side effects among participants. While some mild side effects can occur, they were neither serious nor life-threatening.

This treatment is being developed for conditions like acute ischemic stroke, suggesting confidence in its safety. However, as this trial progresses to a later phase, more participants are being tested to confirm these safety findings. This process helps ensure a thorough understanding of any potential risks. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for stroke?

Most treatments for ischemic stroke, like thrombolytics and antiplatelets, work by dissolving clots or preventing new ones from forming. But DM199 works differently, using recombinant human tissue kallikrein to enhance blood flow and protect brain cells by promoting natural processes in the body. Researchers are excited about DM199 because it may offer neuroprotective benefits and improve recovery outcomes by harnessing a unique biological pathway not targeted by current therapies. This innovative approach has the potential to provide a new, complementary option for stroke patients, particularly those who are not candidates for standard clot-busting treatments.

What evidence suggests that recombinant human tissue kallikrein might be an effective treatment for ischemic stroke?

Studies have shown that DM199, a type of medicine, improves blood flow by widening blood vessels. This is crucial for treating acute ischemic stroke (AIS), which occurs when the blood supply to the brain is blocked. Research suggests that DM199, which participants in this trial may receive, might enhance stroke recovery by improving circulation and reducing damage. Some early findings indicate it could aid physical recovery after a stroke. Initial trials suggest it might also lower the risk of future strokes. Overall, promising evidence indicates that DM199 is effective in treating moderate strokes. ^{1 3 4 5 6}

Who Is on the Research Team?

Scott Kasner, MD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

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.

Participant and/or legally authorized representative is able to provide informed consent.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. ahajournals.org ahajournals.org/doi/10.1161/STROKEAHA.124.048858

Recombinant Human Tissue Kallikrein-1 for Treating ... With an extended course of therapy for weeks after acute ischemic stroke, these multifaceted effects may also reduce the risk of stroke ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12130357/

A Phase 1C, Open Label, Single Ascending Dose Study ... KLK1 has a known role in vasodilation and blood flow regulation, with potential implications for treatment of acute ischemic stroke (AIS) by focally enhancing ...

3. diamedica.com diamedica.com/remedy2

ReMEDy2 Trial DM199 (rhKLK1) is an investigational stroke therapy and is intended to improve patients' potential for full or nearly full physical recovery and ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05065216

Treatment of Acute Ischemic Stroke (ReMEDy2 Trial) This is a Phase 2/3 study evaluating the safety and efficacy of DM199 (rinvecalinase alfa) in treating participants with moderate stroke severity, ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6348491/

Human tissue kallikrein in the treatment of acute ischemic stroke Treatment with human, kallikrein or recombinant KLK1 is hypothesized to have both immediate and long-lasting actions that may improve outcomes following AIS.

6. ijclinicaltrials.com ijclinicaltrials.com/index.php/ijct/article/view/238

Safety, tolerability and pharmacokinetic profile of ... DM199 is a recombinant form of human tissue kallikrein (KLK1) that is being developed for ischemia-related diseases such as acute ischemic stroke.