Matthew Henderson, BA
Rutgers Robert Wood Johnson Medical School
Dr. Robert Bhisitkul MD, PhD from UCSF presented the phase 1 trial results of RZ402, an orally administered plasma kallikrein inhibitor (PKI) targeting diabetic macular edema (DME). The plasma kallikrein-kinin system (KKS) promotes vascular inflammation and permeability in response to microvascular injury and has been implicated in the pathophysiology of DME. RZ402 was developed to block a key mediator in the KKS pathway and reduce vascular leakage.
Two randomized, placebo-controlled phase 1 trials were conducted to assess the safety, tolerability, and pharmacokinetics of RZ402 oral solution in healthy volunteers. The first was a single-ascending-dose study with cohorts receiving a single 25, 100, or 250 mg dose. The second was a multiple-ascending-dose with cohorts receiving doses of 25, 100, 250, or 400 mg once daily for 14 days.
Safety was assessed with systemic and ophthalmic evaluations. Pharmacokinetic profile was measured using serial plasma RZ402 concentrations. In the multiple-ascending-dose study, plasma kallikrein activity was measured as a biomarker of RZ402 activity.
In the both trials, RZ402 was found to be safe and well tolerated across all doses with no dose-limiting toxicities observed. While more subjects in the single dose arm who received RZ402 experienced adverse events compared to placebo (54% vs. 33%), most were procedure-related with only 3 (diarrhea, nausea, headache) deemed possibly related to the study drug.
A favorable pharmacokinetic profile was also demonstrated. Peak plasma concentrations and 24-hour trough were found to exceed target levels and RZ402 inhibited plasma kallikrein in a dose-dependent manner.
Dr. Bhisitkul concluded that the phase 1 RZ402 trials met primary safety and pharmacokinetic endpoints and support the potential for a once daily oral therapy for patients with DME. A phase 2 trial in patients with DME is expected to be initiated later this year.