Ocuphire Announces Publication Featuring its Oral Ref-1 Inhibitor APX3330 in Phase 2 Trial for the Treatment of Retinal Disease

Source: Ocuphire Pharma

Ocuphire Pharma announced the publication of a commentary article in the Journal of Cellular Signaling featuring its Ref-1 Inhibitor, APX3330, for the treatment of retinal disease. The article is titled “APE1/Ref-1 as a Novel Target for Retinal Disease.”

The Journal of Cellular Signaling is an open-access peer reviewed journal which features articles on latest research findings and perspectives on cellular and molecular signaling—an essential process that orchestrates and integrates various biological functions through multiple signaling cascades and effector molecules. The article can be accessed online at the following link: Welcome to Scientific Archives | APE1/Ref-1 as a Novel Target for Retinal Diseases.

“We have now published over 21 peer-reviewed articles on APX3330 and over 70 articles on the APE1/Ref-1 target in various journals, with 5 publications specifically related to retinal disease,” Mark R. Kelley, PhD, Professor in the Department of Pediatrics and Glick Eye Center at Indiana University School of Medicine and member of Ocuphire’s Medical Advisory Board, said in a company news release. “This published commentary article discusses the comprehensive data on both Ref-1 as a novel retina target as well as our oral inhibitor, APX3330, predicted to reach human retinal concentrations several-fold greater than the dose required to show efficacy in mice. APX3330 simultaneously blocks key pathways involved in angiogenesis and inflammation processes, thereby conferring protection to the retina. APX3330 represents the Ref-1 program’s lead compound, with pipeline candidates APX2009 and APX2014 that could be formulated for intravitreal sustained release delivery.”

Highlights from the APE1/Ref-1 Review Article:

  • Ref-1 protein regulates multiple transcription factors regulating inflammation and angiogenesis.
  • As a Ref-1 inhibitor, APX3330 decreases both abnormal angiogenesis and inflammation by blocking activation of HIF-1a, which then leads to reduced VEGF signaling and lower production of pro-inflammatory cytokines such as NF-kB, TNF-alpha, and STAT3.
  • At the 300 mg oral twice per day dose being used in the ongoing phase 2 clinical trial in patients with diabetic retinopathy (DR), APX3330 is expected to reach several-fold higher retinal Cmax, and many-fold concentrations above 15.4 ug/ml retinal AUC, than the efficacious dose of oral gavage 25 mg/kg twice per day given to mice in the L-CNV model of retinal disease.
  • In five phase 2 studies involving over 300 patients, APX3330 given oral (systemically) was well tolerated with no significant safety issues identified. No AE was observed in ≥ 5% of patients treated with APX3330. Mild rash and mild diarrhea were observed in 1% of APX3330 treated patients and were thought to be possibly drug-related.
  • Ocuphire is presently recruiting for ZETA-1 phase 2 clinical trial, which will enroll subjects across 20 U.S. sites with the primary endpoint of the percentage of subjects with >2-step improvement on the Diabetic Retinopathy Severity Scale score.

The primary endpoint for the ZETA-1 trial is the Early Treatment Diabetic Retinopathy Score (ETDRS) diabetic retinopathy severity score (DRSS). This score is based on vascular abnormalities in retinal photographs, and a 2-step or more improvement in this score is the accepted regulatory endpoint for the treatment of DR. In the PANORAMA study which examined the effect of the anti-VEGF drug Eylea on DRSS, this primary endpoint was met with significantly more patients responding to treatment compared to placebo after 24 weeks of 2mg dosing intravitreal every 16 weeks. In the mouse L-CNV model, the efficacy of oral APX3330 was similar to Eylea intravitreal injections. Taken together with the other safety, PK, and preclinical data, this provides a strong rationale for pursuing diabetic retinopathy in the ZETA-1 trial. Visual function and central retinal thickness will also be measured given the expected efficacy in treatment of diabetic macular edema (DME).

“With its dual mechanism of action targeting pathogenic inflammation downstream to Ref-1, we believe APX3330 could represent an important new therapeutic approach in addressing a number of ocular conditions, including as a single agent for diabetic retinopathy and as an adjunctive therapy to anti-VEGF in diabetic macular edema, wet age-related macular degeneration, and other retinal diseases,” said Mina Sooch, MBA, President and CEO of Ocuphire Pharma. “We are fortunate to build on the past 11 phase 1 and 2 clinical trials studying inflammation in liver diseases by Eisai and angiogenesis in oncology by Apexian. As our clinical program surrounding Ref-1 inhibition continues to mature, we expect APX3330 to generate more attention ahead of our Phase 2 data readout in diabetic retinopathy anticipated next year.”

The progressive pathogenesis of retinal and choroidal disease often involves vascular leakage, retinal ischemia, and the release of vasoproliferative growth factors and inflammatory mediators. Earlier treatment options to prevent or delay irreversible vision loss for patients with diabetic eye disease are critical. Although biologic therapies such as Eylea (which are injections directly into the eye) have been approved in the field, the invasive nature of treatment leads to a reluctance by physicians to adopt bi-monthly chronic injection regimens during the early stages of disease progression. Today, diabetic retinopathy remains closely monitored by retinal specialists but largely untreated. An alternative (oral) treatment modality presents immense potential to be used as monotherapy for non-proliferative or early proliferative stages of diabetic retinopathy.

“As an oral tablet with a favorable safety profile demonstrated in the early clinical trials, APX3330 could offer a convenient solution for a large and growing global population of diabetes-related retinal diseases,” said Peter Kaiser, MD, Professor of Ophthalmology at the Cole Eye Institute, Cleveland Clinic. “More importantly, APX3330 has the potential to reduce the burden of intravitreal injections on the patients.”

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