Overcoming Drug Development Obstacles for Some of the Most Challenging Ischemic Conditions

The Kallikrein-Kinin Pathway & Focal Blood Flow

Rick described how their investigational recombinant form of tissue kallikrein is intended to act in ischemic tissue by engaging the kallikrein-kinin system.

In acute ischemic stroke, he said, a clot blocks perfusion to the penumbra, and if that obstruction is not removed with thrombolysis or mechanical thrombectomy, permanent tissue damage can occur. He noted that fewer than 20% of patients currently receive either intervention.

He then described what he sees as a distinguishing feature of the kallikrein-kinin pathway in ischemia. Tissue kallikrein is a naturally occurring protein, and he said that patients at risk for stroke and preeclampsia tend to have lower endogenous levels. In the ischemic penumbra, cells markedly upregulate bradykinin B2 receptors, but the ligand needed to activate them is deficient.

He said that by supplying recombinant KLK1, which generates bradykinin, the therapy is intended to activate these receptors and induce localized vasodilation, drawing blood into areas with compromised perfusion.

“You’ve got cells in the penumbra ischemic area, that have these bradykinin B2 receptors that are upregulated 35-fold, at least in animals. But what’s missing is the ligand bradykinin,” Rick said. “So our treatment… releases bradykinin, and then it attaches to where those receptors are.”

Turning to preeclampsia, Rick characterized the condition as one in which inadequate opening of the uterine spiral arteries limits delivery of oxygen and nutrients to the placenta.

Rick said DiaMedica’s clinical data have shown not only reductions in maternal blood pressure but also changes in Doppler-based measures of uterine artery resistance, specifically the pulsatility index, which reflects downstream blood flow.

“The more resistance, the less blood flow. So, by seeing a significant improvement in this marker, we think we can actually get more blood flow to the placenta.”

Demonstrating Safety in Pregnancy

Rick said the central challenge in developing therapies for preeclampsia is that trials must account for both maternal and fetal safety, noting that any off-target exposure to the fetus could have serious consequences. He explained that this was a key reason DiaMedica focused early on determining whether its recombinant KLK1 could cross the placental barrier.

“You’re dealing with two lives. And if you have some off-target effects that get to the baby, I mean, that could have profound effects,” Rick said. “So the size of our protein is about 26 kilodaltons, whereas the cutoff across the placental barrier is about 500 daltons.”

He described how this question was examined in a clinical study in pregnant women by measuring drug levels in maternal blood and in cord blood at delivery. According to Rick, the data showed detectable levels of the study drug in mothers, with no detection in the fetal circulation. The work was conducted in Cape Town, South Africa, at a clinical unit that had treated and dosed approximately 500 to 600 patients across different trials over the past three years, allowing the team to generate these measurements efficiently.

Rick also said that endogenous levels of tissue kallikrein are lower in women with preeclampsia, and lower still in severe disease, and described the program as a form of protein replacement.

He also referred to prior clinical use of related forms of the protein, isolated from pig pancreas and from human urine, which have been used in large patient populations in Japan and China. He added that DiaMedica has now dosed more than 300 patients across its own studies.