Rezolute presented Phase IIa trial results for RZ-402, an orally administered plasma kallikrein inhibitor (PKI), at the American Academy of Ophthalmology (AAO) 2024 meeting in Chicago, indicating potential as a novel treatment for diabetic macular edema (DME). The study (NCT05712720) evaluated RZ-402's efficacy and safety in patients with mild to moderate non-proliferative diabetic retinopathy (NPDR) with center-involved DME (ci-DME). DME, characterized by anti-vascular endothelial growth factor (VEGF) and inflammatory mechanisms, often sees incomplete responses to anti-VEGF therapies in approximately 50% of patients, highlighting the need for therapies targeting alternative mechanisms.
RZ-402: Targeting the Kallikrein-Kinin System
RZ-402 targets the kallikrein-kinin system (KKS), which contributes to DME through a VEGF-independent pathway. Overactivation of plasma kallikrein leads to inflammation and macular edema. By inhibiting plasma kallikrein, RZ-402 aims to address the vascular aspects of DME, either as a standalone therapy, in combination with anti-VEGF treatments, or as a proactive measure to prevent DME onset. The oral administration of RZ-402 allows for continuous drug exposure and systemic absorption, treating both eyes simultaneously.
Phase IIa Trial Design and Results
The Phase IIa trial assessed RZ-402's efficacy and safety over three months in patients who had previously received a maximum of three anti-VEGF injections. Inclusion criteria included a best-corrected visual acuity (BCVA) of 78 letters or more on the Early Treatment Diabetic Retinopathy Study (ETDRS), a central subfield thickness (CST) of at least 320 microns (males) or 305 microns (females), and stable glycemic control. Patients were randomized to receive RZ-402 at doses of 50mg (n=25), 200mg (n=25), or 400mg (n=25), or placebo (n=25).
Dr. Joel Pearlman from Retina Consultants Medical Group reported that RZ-402 demonstrated clinically significant improvements in CST, the study's primary endpoint. The 200mg dose achieved the most substantial reduction in CST of -47μm (p=0.02). In study eyes with a baseline CST of at least 400 microns, the mean CST change was significant only for the 200mg dose. Pooled results across all RZ-402 doses showed a statistically significant overall decrease in mean CST (p=0.05). A case study highlighted an anti-VEGF-naïve patient with cysts and significant intraretinal fluid who achieved cyst resolution and a CST improvement of over 100 microns with the 200mg dose.
Safety and Tolerability
The overall incidence of adverse events (AEs) was mild and similar to the placebo group. No AEs associated with PKI treatments were reported, and few severe adverse events (SAEs) occurred, all deemed unrelated to RZ-402 by the investigator. No abnormalities were observed in liver enzymes, significant gastrointestinal (GI) events, or changes in vitals, safety labs, and electrocardiogram (ECG) results.
Expert Opinion
Key opinion leaders (KOLs) interviewed by GlobalData emphasized the growing interest in kallikrein inhibitors, noting their potential role in reversing macular edema. However, KOLs are interested in further understanding the effectiveness and durability of kallikrein inhibitors compared to VEGF inhibitors.
Implications for DME Treatment
The RZ-402 results indicate its potential in treating or preventing DME, potentially influencing clinical practice and reducing patient burden, particularly for working-age individuals. It may benefit patients who do not respond adequately to existing DME pharmacotherapies or those seeking to mitigate DME onset. The oral administration of RZ-402 as a PKI is a first in the DME space. Rezolute plans to advance RZ-402 through a Phase IIb/III trial to further evaluate its efficacy and safety, potentially reshaping the future of DME treatment and other ophthalmology areas.
GlobalData’s Pharma Intelligence Center reports that there are 15 Phase III, 32 Phase II, and 8 Phase I candidates being investigated for DME globally.
