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NPDR Subset Analysis of ZETA-1 Phase 2 Trial A moderate to severe
NPDR-qualifying subgroup analysis to inform future clinical trials NPDR, non-proliferative diabetic retinopathy.
Primary endpoint: % of subjects with a 2 step improvement in monocular ETDRS
DRSS at Week 24 Study eye: DR graded moderately severe to severe NPDR or mild PDR (monocular DRSS 47, 53, or 61) Fellow eye: No exclusion* Baseline DRSS Scores APX3330 (n=51) Placebo (n=52) DRSS Score - Study Eye 47 Moderately
severe NPDR 22 (43%) 18 (35%) 53 Severe or very severe NPDR 25 (49%) 28 (54%) 61 Mild PDR 4 (8%) 6 (12%) DRSS Score - Fellow Eye 43 or Lower Mild to moderate NPDR or better 15 (29%) 12 (23%) 47 Moderately severe NPDR 15
(29%) 22 (42%) 53 Severe or very severe NPDR 14 (28%) 11 (21%) 61 Mild PDR 1 (2%) 4 (8%) 65 or Higher Moderate to severe PDR 4 (8%) 3 (6%) Note: 15 fellow eyes had CST>320 microns (center-involved DME) *Two APX3330 subjects
did not have available DRSS scores in the fellow eye at screening. BID, twice-daily; CST, central subfield thickness; DME, diabetic macular edema, DRSS, Diabetic Retinopathy Severity Scale; ETDRS, Early Treatment of Diabetic Retinopathy
Study; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. Source: ZETA-1 Table 14.1.2.1. APX3330 600mg/day (BID) Placebo (BID) 1:1 randomization Week 0 Week 4 Week 12 Week 24 Primary
Endpoint ZETA-1 Phase 2 Study Design and Demographics N = 103 3
ZETA-1 Actual Compared to NPDR Subset Difference Between Baseline
Characteristics for ZETA-1 Actual and NPDR Subset ZETA-1 Actual (n) NPDR Subset (n) Population with both eyes evaluable for DRSS1 971 59 Subjects with PDR 22 0 Subjects with DME 15 0 Subjects with PDR or DME2 35 0 Subjects
with one eye better than 43 and no DME 3 0 Source: ZETA-1 Table 16.2.6.1 and Table 16.2.6.2 1 One subject did not have DRSS evaluation in the fellow eye at baseline 2Two subjects had PDR and DME at baseline BCVA, best-corrected visual
acuity; CI-DME, center-involved diabetic macular edema; DME, diabetic macular edema; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. Statistical validation conducted by Summit Analytical, LLC "ZETA-1
Actual" dataset included 97 patients with evaluable DRSS in both eyes at baseline "NPDR Subset" is a moderate to severe NPDR-qualifying subgroup analysis to inform future clinical trials: DRSS Level 43, 47, or 53 in both eyes, with Level 47
or 53 in at least one eye and no CI-DME at baseline Post-hoc analysis of 3 step worsening/improvement on a Binocular DRSS Person-Level Scale, BCVA, and development of PDR 4 38 subjects excluded; NPDR Subset includes subjects at high risk
for progression to PDR
NO DR NPDR PDR ETDRS monocular severity scale1 Binocular person-level
scale1 Very mild Mild Moderate Moderately severe Severe or very severe Mild Patients graded by a central reading center based on fundus photography. DR, diabetic retinopathy; DRSS, Diabetic Retinopathy Severity Scale; ETDRS, Early
Treatment Diabetic Retinopathy Study; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. 1. Chew EY, et al. N Engl J Med. 2010;363:233-44. Binocular DRSS is a Validated and Well-Established Scale to
Evaluate Systemic Therapies for Diabetic Retinopathy 5 10 20 35 43 47 53 60-61 65 71+ Moderate Severe 2,3 4,5 6,7 8,9 10,11 12,13 14,15 16,17+ 1 3 step worsening on the binocular DRSS is considered clinically
NPDR Subset Amplifies 3 Steps or Greater Worsening on the Binocular DRSS
Person-Level Scale ZETA-1 Actual NPDR Subset 3 Step Worsening from Baseline on Binocular DRSS Person-Level Scale DRSS, Diabetic Retinopathy Severity Scale; NPDR, non-proliferative diabetic retinopathy. Source: ZETA-1 Table 14.2.2.7.3
and Table 14.2.2.7.6. 6
NPDR Subset Amplifies 3 Steps or Greater Improvement on the Binocular DRSS
Person-Level Scale 3 Step Improvement from Baseline on Binocular DRSS Person-Level Scale DRSS, Diabetic Retinopathy Severity Scale; NPDR, non-proliferative diabetic retinopathy. Source: ZETA-1 Table 14.2.2.7.3 and Table
14.2.2.7.6. ZETA-1 Actual NPDR Subset APX3330 (n=29) Placebo (n=30) APX3330 (n=47) Placebo (n=50) 7
NPDR Subset Shows Enhanced Treatment Benefit on the Binocular DRSS Person-Level
Scale 3 step improvement < 3 step change 3 step worsening Placebo 3 step improvement < 3 step change 3 step worsening APX3330 DRSS Change from Baseline DRSS, Diabetic Retinopathy Severity Scale; NPDR,
non-proliferative diabetic retinopathy. Source: ZETA-1 Table 14.2.2.7.3 and Table 14.2.2.7.6. APX3330 (n=29) Placebo (n=30) APX3330 (n=47) Placebo (n=50) ZETA-1 Actual NPDR Subset 8
ZETA-1 Actual: Fewer APX3330 Subjects Worsened and More Improved Compared
to Placebo Subjects DRSS, Diabetic Retinopathy Severity Scale Source: ZETA-1 Table 14.2.3.7.1. 9 Worsening Improvement
NPDR Subset Exhibits Increased Treatment Benefit in Subjects with 3 Steps or
Greater Worsening DRSS, Diabetic Retinopathy Severity Scale. Source: ZETA-1 Table 14.2.3.7.3. 10 Worsening Improvement
NPDR Subset Demonstrates Enhanced Treatment Effect with Fewer APX3330 Subjects
Developing PDR Compared to Placebo Development of PDR in Either Eye (DRSS 61 after Baseline) NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. *One placebo subject did not have evaluable
post-baseline data due to discontinuation of study drug. Source: ZETA-1 Table 14.2.6.7.3 and Table 14.2.6.7.5. ZETA-1 Actual NPDR Subset APX3330 (n=29) Placebo (n=30) APX3330 (n=47) Placebo (n=49*) 11
BCVA Comparable Between Treatment Groups at Week 12 and Week 24 7+ letters
worsening <7 letters change 7+ letters improvement Placebo 7+ letters worsening <7 letters change 7+ letters improvement APX3330 BCVA Change from Baseline BCVA, best-corrected visual acuity, study eye; NPDR, non-proliferative
diabetic retinopathy. One APX3330 subject had study eye data only. Source: ZETA-1 Table 14.3.6.6 and Table 14.3.6.8. ZETA-1 Actual NPDR Subset APX3330 (n=29) Placebo (n=30) APX3330 (n=48) Placebo (n=50) 12
Ocular AEs similar between APX3330 and placebo Pruritis and rash were typically
mild and self-limited Participants with DR continued routine medications to manage comorbid conditions AE, adverse event; DME, diabetic macular edema, DR, diabetic retinopathy. Source: ZETA-1 Tables 14.3.1.1, 14.3.1.7, 14.3.1.10,
16.2.7. Placebo (n=52) APX3330 (n=51) Total AEs 120 91 Total treatment-related AEs 14 14 Participants with treatment-related AEs 10 (20%) 10 (19%) Withdrawals due to treatment-related AEs 1 (2%) 1 (2%) AEs in >5% of
Participants All AEs Treatment-related AEs Placebo (n=52) APX3330 (n=51) Placebo (n=52) APX3330 (N=51) Ocular AEs DME 5 (10%) 2 (4%) 1 (2%) 0 DR 6 (12%) 1 (2%) 1 (2%) 0 Vitreous detachment 3 (6%) 0 0 0 Cataract 1
(2%) 3 (6%) 0 0 Non-ocular AEs Pruritus (itching) 1 (2%) 6 (12%) 1 (2%) 3 (6%) Rash 1 (2%) 3 (6%) 1 (2%) 2 (4%) COVID-19 5 (10%) 1 (2%) 0 0 SARS CoV-2 test positive 3 (6%) 0 0 0 APX3330 was Well-Tolerated in
NPDR Subset Demonstrates Potential Benefit of APX3330 in Patients with High Risk
NPDR NPDR subset suggests treatment effect on 3 steps or greater worsening on the binocular DRSS person-level scale 3% of APX3330 subjects compared to 20% of placebo subjects had 3 steps or greater worsening at Week 24 NPDR subset
suggests enhanced treatment effect on development of PDR 7% of APX3330 subjects compared to 27% of placebo subjects developed PDR (DRSS 61 after baseline in either eye) at Week 24 APX3330 was well-tolerated NPDR subset informs planned
clinical trial investigating APX3330 in slowing PDR conversion in high risk NPDR patients DRSS, Diabetic Retinopathy Severity Scale; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. 14