Joel A. Pearlman, MD, PhD: Phase 2a Data on Oral RZ402 for DME

RZ402, a novel orally administered plasma kallikrein inhibitor, achieved modest reductions in central subfield thickness (CST), with a tolerable clinical profile, in patients with diabetic macular edema (DME), according to Phase 2a data presented at the 128th Annual American Academy of Ophthalmology (AAO) Meeting.

In an interview with HCPLive, presenter Joel A. Pearlman, MD, PhD, Retina Consultants Medical Group, described how this innovative oral approach may provide an alternative pathway to existing treatments for DME, particularly anti-vascular endothelial growth factor (VEGF) therapies.

“This was a Phase 2 trial, so a limited cohort of patients with a singal towards reducing CST to a modest extent,” Pearlman told HCPLive. “It may have applicability as a primary treatment for DME, for patients who have mild edema and maybe adjunctive treatment for patients who have a suboptimal response to the current anti-VEGF treatments.”

Plasma kallikrein is a serine protease that activates bradykinin, influencing vascular permeability and vasodilation. Its role for DME has garnered attention, as it operates independently from the VEGF pathway and could offer complementary benefits alongside existing treatments.

This Phase 2a study included 100 participants, randomized into three ascending dose groups (50 mg, 200 mg, and 400 mg) and a control group of 25 participants. These patients could have received up to three prior anti-VEGF injections, provided the last was administered at least eight weeks before randomization. Patients presented with a central subfield thickness (CST) of ≥320 microns for males and ≥305 microns for females, and visual acuity of 20/32 or worse.

The trial took place over three months, with an additional follow-up month—primary endpoints focused on safety, including adverse events (AEs) and serious adverse events (SAEs). Upon analysis, these preliminary results indicated that RZ402 was generally well tolerated, with mild AEs and no significant ocular complications. Notably, hypertension and gastrointestinal effects were minimal, and liver function remained stable.

The treatment did yield modest reductions in CST across all dosing regimens, with decreases ranging from 25 to 47 microns. In patients with CST over 400 microns, RZ402 demonstrated an ability to lower CST compared with placebo, where CST increased. However, best-corrected visual acuity (BCVA) improvements were not observed, according to Pearlman.

Despite the study's short duration, these results suggest RZ402 could play a significant role in DME management. Its safety profile and potential for further efficacy warrant the initiation of a Phase 2b/3 study, promising continued exploration into its therapeutic capabilities.

“Next steps would be phase 2b/3 trial using a larger cohort of patients to nail down the signal and the efficacy on CST, and as a secondary endpoint, look at effects on BCVA outcomes,” Pearlman told HCPLive.

Disclosures: Relevant disclosures for Pearlman include 4DMT, Apellis, Genentech, Rezolute, and others.

References

_{Pearlman JA. Results from a Phase 2a Study of a Novel Orally Administered RZ402 a Plasma Kallikrein Inhibitor in Patients With Diabetic Macular Edema. Presented at the American Academy of Ophthalmology (AAO) 2024 Meeting. Chicago, Illinois. October 18-21, 2024.}