A recombinant formulation of human tissue kallikrein (KLK1) is safe and tolerable in patients with acute ischemic stroke, phase 2 results suggest.
KLK1 is an endogenous vasoactive serine protease and vasoregulator.
The formulation studied in this trial was DM199, which is being developed by DiaMedica Therapeutics.
Compared with placebo in the ReMEDy trial, treatment with DM199 did not entail an increased risk for serious adverse events. Although the trial was not designed to assess the efficacy of DM199, a post hoc analysis suggested a potential benefit.
“Further evaluation of DM199 in a larger trial is probably warranted,” said Bruce C. Campbell, MBBS, a professorial fellow in medicine at Royal Melbourne Hospital in Australia, during his presentation.
“There’s currently a phase 2/3 study being initiated with DM199 in the United States, focused on patients who are not receiving reperfusion therapies.” No therapeutic option is available for this population.
The findings were presented at the International Stroke Conference (ISC) 2021.
The kidneys, muscle tissue, and salivary glands produce KLK1, which also can be derived from urine. Preclinical data suggest that KLK1 has a two-phase mechanism of action in stroke. First, the drug improves microcirculation and reduces inflammation. Then, it reduces neuronal apoptosis and inflammation and accelerates network reconstitution.
KLK1 is approved in China for use in ischemic stroke up to 48 hours after onset. A meta-analysis of 16 trials indicated that the treatment may be beneficial following ischemic stroke.
DM199 is the first recombinant human KLK1 formulation. Campbell and colleagues conducted the phase 2 ReMEDy study at 12 centers in Australia to assess the safety of DM199 in patients with ischemic stroke.
Eligible participants were age 18 years or older, presented within 24 hours of ischemic stroke onset, and had a National Institutes of Health Stroke Scale (NIHSS) score of 6 to 25. For patients receiving thrombolysis or thrombectomy, the qualifying NIHSS was assessed at more than 1 hour after treatment.
Patients with severe premorbid disability, defined as a modified Rankin Scale (mRS) score of 4 or higher, were excluded. Patients who were unable to cease ACE inhibitors, which are thought to pose a risk or hypertension if taken concomitantly with KLK1, also were excluded.
Patients were assigned randomly to DM199 or placebo. They received an initial intravenous infusion and subsequent subcutaneous injection of the assigned treatment on Day 1 and further subcutaneous injections every 3 days during the following 22 days.
The primary outcome was safety, as measured by the incidence of serious adverse events. Secondary outcomes included neurological recovery (NIHSS score), functional recovery (defined as the Day 90 mRS score), and biomarkers.
The investigators enrolled 92 patients. Of this group, 47 (51%) received DM199 and 45 (49%) received placebo. The population’s mean age was 71.0 years, and median NIHSS score was 10.
The most common adverse events were constipation, nausea, and headache. Serious adverse events were reported in 20 (43%) patients who received DM199 and 14 (31%) patients who received placebo (P = .29).
Four participants in the active group and three in the control group discontinued treatment because of at least one treatment-emergent adverse event. The investigators judged that no serious adverse events in the DM199 arm were related to treatment.
Clinical or functional outcomes at Day 90 did not differ significantly between groups. In a post hoc analysis of 91 evaluable patients, the rate of severe recurrent stroke was 2% in the DM199 group and 16% in the placebo group (P = .028). Four of the seven placebo patients died after stroke recurrence.
Among 46 patients who did not undergo mechanical thrombectomy, the rate of full or near-full recovery at 90 days (defined as an NIHSS score of 0 to 1) was 36% in the DM199 group and 14% in the placebo group (P = .15). The rate of mortality was 12% in the DM199 arm and 24% in the placebo arm.
“The limitations of the study are primarily the fact that we had all these thrombolysis and thrombectomy patients, which enhanced the generalizability of the study and gave us a good severe stroke population for looking at safety, but it did confound the functional outcomes,” Campbell said.
“We had this compromise between trying to recruit within 24 hours and yet allow time to filter out patients who had a rapid recovery after reperfusion.”
Blood Flow Regulation
Several lines of evidence suggest that the KLK1 system is involved in blood flow regulation, Philip B. Gorelick, MD, MPH, adjunct professor of neurology at Northwestern University Feinberg School of Medicine in Chicago, Illinois, told Medscape Medical News.
Animal models that lack KLK1 have impaired vascular response to change in blood flow, he noted. In addition, people with a mutational defect that causes loss of function of the KLK1 protein may also have loss of brachial artery response to changes in blood flow.
The safety data from this study “provide a foundational springboard for the development of a larger scale and more definitive safety and efficacy study of this novel therapeutic agent,” Gorelick said.
The criteria for the acute treatment of ischemic stroke traditionally focused on time windows, but these criteria “now encompass physiologic parameters based on, for example, neuroimaging-derived tissue and blood flow metrics,” Gorelick said.
“In light of the new complexities for treatment of acute ischemic stroke, the study of DM199 going forward may need to address questions in relation to the role of this novel agent with or without administration of intravenous thrombolytic therapy or mechanical thrombectomy, and the presence of potentially salvageable brain tissue based on neuroimaging-derived physiologic parameters,” he said.
Further, Gorelick added, “it will be interesting to determine the influence of DM199 on metrics such as blood pressure variability and blood pressure lowering, parameters that may influence acute ischemic stroke outcomes.”
International Stroke Conference (ISC) 2021. Late-breaking abstract 7. Presented March 18, 2021.
DiaMedica Therapeutics funded the study. Campbell and Gorelick disclosed no relevant financial relationships.