On October 18, at the 128th Annual Meeting of the American Academy of Ophthalmology (AAO) 2024 in Chicago, IL, US, clinical trial results were presented for the Phase IIa trial of Rezolute’s RZ-402 (NCT05712720), evaluating its application in the treatment of diabetic macular edema (DME). DME is a disease driven by anti-vascular endothelial growth factor (VEGF) and inflammatory mechanisms. Historically, 50% of DME patients do not respond completely to anti-VEGF therapies due to other causes of the disease. Therefore, it is of paramount interest that therapies are developed to target other mechanisms of action within the DME space. According to GlobalData, the Phase IIa trial’s results may have significant implications for drug development in the DME space, broadening the range of therapeutic approaches available for this indication.
RZ-402 is an innovative, orally administered plasma kallikrein inhibitor (PKI) that is currently under investigation as a potential alternative treatment for DME. The kallikrein-kinin system (KKS) is considered to contribute to DME in a VEGF-independent pathway, where the overactivation of plasma kallikrein ensues in inflammation and subsequent macular edema. This emphasises the need for alternative treatment options in this area, such as plasma kallikrein inhibitors, to effectively target the vascular aspects of DME, either as a standalone therapy, in combination with anti-VEGF treatments, or as a proactive measure to prevent the onset of the condition. Additional advantages of RZ-402 include its potential for continuous drug exposure due to its oral dosing and systemic absorption, along with its ability to treat both eyes simultaneously.
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The objective of this Phase IIa study was to evaluate RZ-402’s efficacy and safety over a three-month period in patients with mild to moderate non-proliferative diabetic retinopathy (NPDR) with centre-involved DME (ci-DME) who had previously received a maximum of three anti-VEGF injections no less than eight weeks prior to randomisation. The criteria for inclusion also comprised a best corrected visual acuity (BCVA) of 78 letters or more on Early Treatment Diabetic Retinopathy Study (EDTRS), a central subfield thickness (CST) of at least 320 microns and 305 microns in males and females, respectively, and stable glycemic control. Patients were administered RZ-402 at doses of 50mg (n=25), 200mg (n=25), and 400mg (n=25), along with a placebo control group (n=25), over three months, with a follow-up one month later.
In results reported on October 18 by Dr Joel Pearlman, MD, PhD, Retina Consultants Medical Group, with regards to efficacy, RZ-402 proved its ability to demonstrate improvements of clinical significance in central subthreshold thickness (CST), which was a primary endpoint of the study. Notably, the 200mg dose achieved the most substantial reduction in CST of -47µm (p=0.02). Among study eyes that had a CST of at least 400 microns at baseline, the mean CST change was only significant for the 200mg dose, although pooled results across all RZ402 doses showed a statistically significant overall decrease in mean CST (p=0.05). Additionally, a case study in the presentation highlighted an anti-VEGF-naïve patient who presented with cysts and significant intraretinal fluid and cysts at baseline, and who attained cyst resolution and an improvement in CST of over 100 microns upon treatment with the 200mg dose.
With regards to safety, the overall adverse events (AEs) were mild and akin to that of the placebo group. AEs associated with PKI treatments were not reported in the trial, and there were few severe adverse events (SAEs), all of which were deemed unrelated to RZ-402 by the investigator. Additionally, there were no abnormalities observed with liver enzymes, no gastrointestinal (GI) events of significance, and indifferent vitals, safety labs, and electrocardiogram (ECG) results.
Key opinion leaders (KOLs) interviewed by GlobalData have emphasised the growing attention on kallikrein inhibitors, with one KOL stating that “kallikrein inhibitors are a hotspot right now. There are…companies looking at oral kallikrein inhibitors…kallikrein inhibitors seem to play a role in reversing macular oedema.” KOLs are keen to further learn how effective kallikrein inhibitors are in comparison to VEGF, and what their durability is like.
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By GlobalDataThe results presented on RZ-402 showcased its great potential in treating or preventing DME, with the potential to influence both clinical practice and patient burden experienced by DME patients, as many are of working age. It will be especially beneficial to patients who do not respond adequately to existing pharmacotherapies for DME or to help those looking to mitigate the onset of DME. The convenience of this therapy will include its ability to improve CST as an oral PKI, a first within the DME space. If Rezolute further promotes the efficacy and safety of RZ-402 through its anticipated Phase IIb/III trial, this drug may be set on a trajectory to reshape the future of the DME space, and potentially other ophthalmology spaces as well.
According to GlobalData’s Pharma Intelligence Center, there are currently 15 Phase III candidates, 32 Phase II candidates, and eight Phase I candidates being investigated for DME globally.
