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FDA Places Clinical Hold on Phase 2/3 ReMEDy2 Trial of DM199 in Acute Ischemic Stroke

After 3 instances of clinically significant, transient hypotension—which resolved after treatment halt—recruitment for the trial of the investigational recombinant KLK1 tissue protein has been paused.

DiaMedica Therapeutics announced this week that the FDA has placed a clinical hold on the company’s ongoing phase 2/3 ReMEDy2 trial (NCT05065216) of its investigational treatment for acute ischemic stroke, known as DM199.1

The hold, according to DiaMedica, was initiated after 3 serious adverse events (AEs) were reported to the agency—at which time recruitment was also paused by DiaMedica—related to clinically significant, transient hypotension. These AEs occurred following initiation of the intravenous (IV) dose of DM199, and blood pressure levels of all 3 individuals recovered to their baseline levels within minutes after the infusion was halted.

“Patient safety is very important as we plan and conduct our clinical studies. Patient blood pressure is easily and routinely monitored in stroke patients which is why our study sites were able to quickly identify the issue and immediately stop the dosing of DM199, after which the patients then recovered within minutes and suffered no injuries. We are committed to working diligently with the FDA to resolve this issue and resume the trial as soon as reasonably practicable,” Kirsten Gruis, MD, chief medical officer, DiaMedica, said in a statement.1

DM199 is a recombinant form of human tissue kallikrein-1 (KLK1), a protein that has been utilized in various forms to treat patients in Asia for some time, though DiaMedica is the first to have developed a pharmaceutically active recombinant form. The treatment is also being studied for the treatment of chronic kidney disease, in addition to acute ischemic stroke. In September 2021, the FDA granted fast track designation to DM199 for the treatment of acute ischemic stroke.2

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ReMEDy2 is a phase 2/3 adaptive designed, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of DM199. It is a follow-up to the phase 2 ReMEDy1 trial (NCT03290560), which featured 91 individuals randomly assigned to placebo (n = 45) or DM199 (n = 46). Over the course of the 90-day follow-up period, recurrent ischemic stroke occurred in 6 patients (13.3%) in the placebo arm—4 of which were fatal—compared with none in the DM199 arm (P = .012). As well, when excluding those who were pretreated with mechanical thrombectomy, recurrent stroke occurred in 4 individuals (19%) in the placebo arm (n = 21), all fatal, compared with none in the DM199 arm (n = 25), which was significantly different (P = .037).3

“While having to pause enrollment in the ReMEDy2 trial was not desirable, we remain confident about the future potential of DM199 and are committed to refining the dosing procedures and methods that will further enhance patient safety,” Rick Pauls, president and chief executive officer, DiaMedica, said in a statement.1 “We also take comfort in that the transient hypotension observed is yet another clinical indicator that DM199 may be biologically active in stroke patients and may provide a meaningful improvement in stroke outcomes.”

In November 2021, the FDA had granted a “may proceed” notice to the company for an amended protocol to the ReMEDy2 trial, allowing for a second independent primary end point of stroke recurrence by day 90, in addition to the original end point of functional outcome recovery post stroke by day 90.2

The trial’s patient population includes those for whom thrombolysis or mechanical thrombectomy are not medically appropriate or available due to constraints of clot location, comorbidity risks, or time from estimated onset of stroke—an amount DiaMedica noted represents approximately 80% of all patients with acute ischemic stroke. The target enrollment number is roughly 350 participants at 75 sites across the US. Those enrolled in the trial will be treated for 3 weeks with either DM199 or placebo, initiated within 24 hours of symptom onset, and final follow-up at 90 days.

REFERENCES
1. DiaMedica Therapeutics Announces Clinical Hold of its Phase 2/3 ReMEDy2 Clinical Trial for DM199. News release. DiaMedica. July 6, 2022. Accessed July 8, 2022. https://www.diamedica.com/investors/press-releases/detail/1646/diamedica-therapeutics-announces-clinical-hold-of-its-phase
2. DiaMedica Therapeutics Announces Fast Track Designation Granted to DM199 for the Treatment of Acute Ischemic Stroke. News release. DiaMedica. September 30, 2021. Accessed July 8, 2022. https://www.diamedica.com/investors/press-releases/detail/1630/diamedica-therapeutics-announces-fast-track-designation
3. DiaMedica Therapeutics Announces Addition of Stroke Recurrence as a Second Independent Primary Endpoint in ReMEDy2 Phase 2/3 AIS Trial. News release. DiaMedica. November 8, 2021. Accessed July 8, 2022. https://www.diamedica.com/investors/press-releases/detail/1633/diamedica-therapeutics-announces-addition-of-stroke