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A recombinant version of kallikrein, a vasoactive serine protease and vasoregulator used in China for stroke treatment, appeared safe for patients with acute ischemic stroke in the pilot ReMEDy trial.

The agent, dubbed DM199, did not result in more serious adverse events compared with placebo (43% vs 31% of patients, P=0.29), reported Bruce Campbell, MBBS, PhD, of Australia's Royal Melbourne Hospital.

Serious events leading to discontinuation considered probably or possibly related to the study drug included one case of flushing, one of bradycardia, one of liver function abnormality at day 56, and one of angioedema, he said at a late-breaking session at the American Stroke Association's virtual International Stroke Conference.

Endogenous kallikrein releases bradykinin by cleaving a protein found on vascular epithelial cells and in general circulation.

The exogenous version is thought to promote microvascular circulation acutely by increasing blood flow and reducing inflammation. Continued administration after ischemic stroke may protect brain cells by inhibiting apoptosis and accelerating network reconstitution to improve neural plasticity, according to preclinical data.

The trial was not powered for clinical endpoints and showed no significant impact on 90-day functional outcomes.

However, a post-hoc exploratory analysis showed a much lower likelihood of recurrent severe stroke at 90 days with the active treatment (2.2% vs 15.6% with placebo, P=0.03) in the overall cohort.

The included 92 adults at 12 centers in Australia randomized in a double-blind fashion within 24 hours of ischemic stroke onset to receive an initial IV infusion and then subcutaneous injection of DM199 or placebo on day 1, followed by subcutaneous injections every 3 days over the subsequent 22 days.

Patients could not be on an ACE inhibitor due to concern that an increase in bradykinin would pose a hypotension or angioedema risk.

The trial allowed thrombolysis and thrombectomy (most patients did get one or both), but required a persistent NIH Stroke Scale (NIHSS) score of 6 to 25 more than an hour afterward.

The post-hoc analysis showed a nonsignificantly greater likelihood of excellent functional outcome (NIHSS ≤1) in 36% of patients receiving DM199 compared with 14% on placebo among those not treated with endovascular thrombectomy.

Campbell noted that there was more reperfusion among the placebo group patients, with the difference in proportion who got both a lytic and thrombectomy (6% vs 27% with placebo) approaching statistical significance.

That difference might be important in looking at the results, Campbell told virtual attendees.

"The limitations of the study are primarily that we had thrombolysis and thrombectomy patients, which enhanced generalizability of the study and gave us a good severe stroke population for looking at safety, but it did confound the functional outcomes," he said. "We had this compromise between trying to recruit within 24 hours, but yet allow time to filter out patients who had a rapid recovery after reperfusion -- but [it's] arguable how well that worked with the 1 hour reassess of the NIHSS."

A larger trial is warranted to assess outcomes, he added. And a U.S. phase II/III trial is expected to start this year for DM199 among patients with small vessel occlusion stroke not being treated with thrombectomy or thrombolytic treatment.

Drug developer DiaMedica Therapeutics sees the group of patients not receiving reperfusion therapies as one "in whom it is easier to disentangle a treatment effect," Campbell said. "I think it's a matter of watch and wait to see how those results pan out, but it would be great to have some new treatment modalities beyond reperfusion."

While that group of patients currently has no therapeutic alternative, it's a relatively small population in the U.S., noted session moderator Louise McCullough, MD, PhD, of the University of Texas Health Science Center at Houston.

Overall, though, she said it was encouraging that the results were safe in this small study, particularly with the signal in the group not treated with endovascular clot removal, she told 番茄社区.

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