According to the company, it is planning to hold an end-of-phase 2 meeting with the FDA to discuss the results.
Ocuphire Pharma Inc. today announced topline efficacy and safety results from its ZETA-1 Phase 2 trial (NCT04692688) evaluating oral APX3330 for the treatment of diabetic retinopathy (DR).
The company noted in its news release that the phase 2 trial for its oral diabetic retinopathy candidate missed the primary endpoint, which was a precedented endpoint for local administration of anti-VEGF intravitreal injections, but it statistically significant reduction of disease progression at 24 weeks.
Mina Sooch, MBA, founder and CEO of Ocuphire Pharma, said in a news release that the company’s goals in the retina phase 2 were to explore multiple endpoints to evaluate the potential for APX3330 as the first oral drug to safely benefit diabetic patients with eye disease.
“Although we did not meet the primary endpoint (a precedented endpoint for local administration of anti-VEGF intravitreal injections), we are pleased that the ZETA-1 results on key pre-specified endpoints demonstrated positive outcomes with a favorable systemic and ocular safety profile that support our plans to move forward to an End-of-Phase 2 meeting with the FDA,” Sooch said in the release.
Sooch noted that given the systemic delivery of APX3330, it is important to evaluate its effect on both eyes. APX3330 achieved statistical significance on a key pre-specified secondary endpoint – binocular 3-step or more worsening of DRSS (diabetic retinopathy severity score) – a clinically meaningful outcome that demonstrates the ability to slow the worsening of this progressive disease and is a potential Phase 3 registration endpoint.
“With the financial strength provided by our recent global Nyxol license agreement, we have considerable flexibility to design and initiate the pivotal stage of the APX3330 program,” Sooch explained in the news release. “We thank the study participants, clinical investigators and their site staffs for participating in the trial.”
Peter K. Kaiser, MD, professor of Ophthalmology at the Cole Eye Institute of the Cleveland Clinic Foundation, pointed out in the news release that diabetes epidemic, and the associated increase in the number DR patients, has become a major burden on the healthcare system.
“Diabetic patients with non-proliferative retinopathy currently have limited treatment options to prevent progression of retinopathy and loss of vision,” he said in the news release. “The current treatment paradigm is for physicians to wait and monitor early-stage DR patients, with anti-VEGF or steroid injectable therapy or laser treatment reserved for patients who advance to proliferative DR or DME.”
Kaiser said he was encouraged by the data from ZETA-1 showing that APX3330 can potentially slow disease progression.
“In diabetic patients, APX3330 has demonstrated a favorable safety profile and has the advantage of being an oral agent treating both eyes at once. If these results are confirmed in Phase 3 and APX3330 is subsequently approved, healthcare providers would have an important new primary preventative therapeutic option that could be used in a large number of patients who are earlier in the course of disease,” Kaiser added in the release. “This would potentially reduce the number of patients who experience devastating vision loss.”
According to the release, ZETA-1 was a randomly assigned, double-masked, placebo-controlled Phase 2 trial designed to evaluate the efficacy and safety of APX3330 in diabetic retinopathy patients. ZETA-1 was conducted at 25 U.S. sites and enrolled 103 patients with at least one eye meeting criteria for moderately severe to severe non-proliferative DR (NPDR) or mild proliferative diabetic retinopathy (mild PDR).
The ETDRS diabetic retinopathy severity scale (DRSS) is a categorical tool for clinical trials that contains 10 discreet steps, from no retinopathy to severe proliferative retinopathy, derived from the grading of fundus photographs for each eye at a central reading center. Each patient’s study eye had a baseline DRSS step of 5, 6 or 7. The patients were randomly assigned to receive 600 mg APX3330 or placebo daily (BID) over 24 weeks. Primary and secondary endpoints evaluated +/- 1, 2, 3, and 4 step improvement and worsening in DRSS at week 12 and week 24, change in best-corrected visual acuity (BCVA), change in central subfield thickness (CST) and safety and tolerability. Patient demographics and baseline characteristics were well-balanced across both treatment groups.
In the ZETA-1 Phase 2 trial, APX3330 did not meet the primary endpoint (% of patients with a ≥ 2-step improvement in DRSS at week 24 in the study eye). Given the oral systemic delivery of APX3330, however, it is important to evaluate the effect on both eyes. A potential Phase 3 registration primary endpoint is a ≥ 3-step worsening of DRSS as a composite of both eyes (binocular).
According to the news release, this secondary endpoint was pre-specified and evaluated in the ZETA-1 trial. APX3330 demonstrated statistically significant reduction of disease progression at 24 weeks: No (0%) APX3330-treated patients had a binocular ≥ 3-step worsening of DRSS from baseline compared with 16% for placebo-treated patients (p=0.04). This endpoint is the planned Phase 3 primary endpoint for future registration trials that will be confirmed at the EOP2 meeting with the FDA.
The company noted that additional efficacy endpoints were directionally favorable to support the effect of APX3330 in slowing the progression of DR and preserving vision. Visual acuity was stable with APX3330 and a trend was seen with fewer APX3330 treated patients losing 5 or more letters of distance vision compared to placebo patients (6% vs 19%, p=0.07). APX3330 showed a favorable safety and tolerability profile. Treatment-related adverse events were uncommon, and most were mild in severity. There were no treatment-related serious adverse events. No changes were observed in liver, kidney, or heart function as well as complete blood count and comprehensive metabolic panel.
The company also noted that further analysis of the trial data is ongoing and detailed results will be presented at multiple medical meetings, including Angiogenesis, Exudation and Degeneration, February 10-11, and The Macula Society Annual Meeting, February 15–18.