New data from a post-hoc analysis of Ocuphire Pharma’s ZETA-1 study evaluated efficacy and safety results on oral APX3330, its investigative candidate intended for diabetic retinopathy (DR) treatment.
The results were presented at the 2024 Association for Research in Vision and Ophthalmology (ARVO) annual meeting.
Let’s start with a refresher on APX3330.
As Ocuphire’s lead late-stage asset for a retinal indication, APX3330 is a twice-daily, small-molecule oral tablet drug candidate.
Its target: The apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/Ref-1) protein
- Also known as: Ref-1
Why this is important: Blocking Ref-1 leads to a decrease in vascular endothelial growth factor (VEGF) and in proangiogenic and proinflammatory transcription factors found in retinal and choroidal vascular diseases.
Now this study.
The randomized, double-masked, placebo-controlled phase 2 trial (NCT04692688) enrolled 103 patients with at least one eye that met the criteria for moderately severe to severe non-proliferative DR (NPDR) or mild proliferative DR (MPDR).
Note: Each patient’s study eye had a baseline Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) step of 5, 6, or 7.
And the set up?
Patients were randomized into two groups to receive either of the following for 24 weeks:
- APX3330 (120 mg)
- Five times a day: three tablets in the morning; 2 tablets in the evening
- Daily placebo
- Five times a day: three tablets in the morning; 2 tablets in the evening
So what was measured?
Measured at Week 24, the primary outcome measure was a ≥ 2-step improvement in DRSS scores in the study eye.
Secondary outcome measures included:
- Change in DRSS scores
- Assessed +/- 1, 2, 3, and 4-step improvement and worsening at weeks 12 and 24;
- Mean change (at Week 24) in:
- DRSS scores
- Best-corrected visual acuity (BCVA)
- Central subfield thickness (CST)
- Participants with no DR/diabetic macular edema (DME) progression (at Week 24)
Before we get to these results, didn’t the company already report on this study?
It did! Ocuphire released topline data back in January 2023.
Those results:
APX3330 failed to meet its primary endpoint (% of patients with a ≥ 2-step improvement in DRSS at week 24 in the study eye).
However, for the prespecified secondary endpoint, APX3330 achieved a statistically significant reduction in disease progression at 24 weeks.
None of the APX3330-treated patients exhibited a binocular ≥ 3-step worsening of DRSS from baseline compared with 16% for placebo-treated patients (P= 0.04).
See here for more data.
Let’s move on to this new post-hoc analysis.
The subset analysis was conducted using a 17-step binocular person-level scale of 68 participants from the ZETA-1 study.
- Their baseline DRSS score: 47 or 53 in at least one eye; 43, 47, or 53 in the other eye
Now the findings.
First: The data was presented by Daniel Su, MD, a retina specialist at Retina-Vitreous Associates Medical Group (LA Retina) in Los Angeles, California
- The presentation: Oral APX3330, a Ref-1 Inhibitor, Slows Progression of Diabetic Retinopathy on a Binocular DRSS Person-Level Scale
Next: The analysis found that no participants of the APX3330 group “had a ≥ 4-step worsening at Week 24 compared to 15.2% in the placebo group, representing a 100% reduction between groups (p=0.07).
What else?
Along with this, only 5.7% of APX3330 participants demonstrated “≥ 3-step worsening at week 24 compared to 15.2% of placebo subjects, representing a 62.5% reduction between groups (p=0.26).”
How many participants developed PDR?
By Week 24, only 11% of APX3330 participants developed PDR vs 26% in the placebo group (p=0.13).
And overall?
Similar to the original topline data, the post-hoc results found APX3330 demonstrated favorable safety and tolerability, with similar ocular adverse events (AEs) between both treatment groups.
Nice! So what next?
Ocuphire’s CEO George Magrath, MD, MBA, MS, stated that the company is working with the FDA on its Special Protocol Assessment (SPA) to finalize an upcoming phase 2/3 study.
Note: The ZETA-1 trial’s secondary endpoint is expected to be the primary endpoint in the phase 3 trial.
And the overall significance?
Per Dr. Magrath: APX3330 has the potential to become an oral binocular therapeutic option for delaying or preventing DR in patients currentlying lacking options prior to developing vision-threatening complications.
The 2024 annual ARVO meeting is being held May 5-8, 2024, in Seattle, Washington