Breakthrough Clinical Results

ANI Pharmaceuticals announced results from the NEW DAY clinical trial evaluating ILUVIEN (fluocinolone acetonide intravitreal implant) for diabetic macular edema (DME). The primary endpoint, mean total supplemental aflibercept injections, wasn't met in the intent-to-treat population. However, a post-hoc analysis showed a statistically significant reduction in supplemental injections in a subset of patients. Secondary endpoints demonstrated non-inferiority in visual acuity and central subfield thickness compared to aflibercept. ILUVIEN was generally well-tolerated, with a safety profile consistent with previous trials. The results suggest ILUVIEN may reduce treatment burden in DME patients.

Incidence and Prevalence

Latest Estimates of Incidence and Prevalence of Diabetic Macular Edema

Prevalence Rates by Duration of Diabetes

According to a 1985 population-based study in southern Wisconsin, the prevalence of diabetic macular edema (DME) varies significantly based on the duration of diabetes:

• For participants diagnosed with diabetes before age 30 and taking insulin:

• 0% prevalence in those with diabetes less than 5 years

• Increasing to 29% prevalence in those with 20+ years duration

• For participants diagnosed at age 30 or older:

• 3% prevalence in those with diabetes less than 5 years

• Increasing to 28% prevalence in those with 20+ years duration

Recent Studies on DME Prevalence

• A 2021 Japanese study found the prevalence of DME was 1.1% among subjects with ocular complications in Japan, with significant increases observed during the study period.

• In a 2005 study using the Joslin Vision Network, among 2,437 eyes examined:

• 1.4% had early DME

• 0.7% had clinically significant macular edema (CSME)

• A 2007 study following 112 Type I diabetes mellitus patients for 15 years found the incidence of DME after 15 years was 20.5%, with:

• Focal form present in 11.6% of patients

• Diffuse form in 8.9% of patients

• Another 2007 study of 35 type 2 diabetes mellitus patients with poorly regulated blood glucose found that 37.2% had background diabetic retinopathy with macular edema.

Incidence Patterns

The relationship between DME and duration of diabetes showed two peaks of incidence: - First peak in patients with 15-20 years' duration of diabetes mellitus - Second peak in patients with >35 years' duration

Risk Factors

Multiple studies consistently identify these risk factors for DME development:

• Longer duration of diabetes
• Higher glycosylated hemoglobin/poor glycemic control (P=.021 for HbA1c >7.5%)
• Presence of proteinuria/nephropathy (P=.047)
• Higher blood pressure/arterial hypertension (P=.037)
• Insulin use
• High levels of LDL-cholesterol (P=.013)
• Presence of macroangiopathy (P=.022)
• Severity of diabetic retinopathy (P=.029)
• Male gender
• Diuretic use

A 2019 Korean study of long-standing T2DM patients (disease duration ≥15 years) found macular edema was associated with: - Higher glycosylated hemoglobin levels (OR, 1.380; 95% CI, 1.032 to 1.845) - Use of rapid-acting insulin (OR, 5.211; 95% CI, 1.445 to 18.794)

Recent research from a 2024 study identified the GMI/GA ratio (glucose management index to glycated albumin) as a novel risk indicator for microvascular complications in T2DM, including diabetic retinopathy.

Economic Burden

Study Design Parameters

Study Design Parameters and Endpoints in Key Trials for Diabetic Macular Edema

Study Designs

• Randomized controlled trials were predominant, including multicenter, sham-controlled, double-masked studies and Phase I/II prospective trials
• Some studies used retrospective, observational case series examining treatment conversion patterns

Patient Populations

• Inclusion criteria typically specified:

• Type 1 or 2 diabetes with HbA1c < 11% in some trials

• Central retinal thickness (CRT) ≥300 μm

• Best corrected visual acuity (BCVA) ranges (e.g., 73-39 ETDRS letters)

• Center-involved macular edema

• Some trials specifically recruited treatment-naïve patients or those with persistent DME despite previous treatment

Treatment Protocols

• Anti-VEGF agents:

• Ranibizumab (0.3 or 0.5 mg)

• Aflibercept (2.0 mg)

• Bevacizumab (1.25 mg)

• Brolucizumab (6.0 mg in 50 μL versus 3.6 mg in 30 μL)

• Corticosteroids: Dexamethasone (DEX) implant

• Combination approaches:

• Ranibizumab plus targeted retinal photocoagulation

• Anti-VEGF plus optimizing glycemic control

Treatment Frequency

• Varied by protocol:

• Monthly injections (every 4 weeks)

• Three monthly injections followed by PRN treatment

• Every 8 weeks after loading doses

• Every 12 weeks after loading doses

• As-needed based on pre-defined retreatment criteria

Primary Endpoints

• Visual outcomes:

• Change in BCVA from baseline (measured in ETDRS letters)

• Proportion of patients gaining ≥10 letters

• Stable vision (<15-letter loss in BCVA)

• LogMAR visual acuity changes

• Anatomical outcomes:

• Central retinal thickness (CRT) reduction

• Central macular thickness (CMT) changes

• Central subfield mean thickness changes

Secondary Endpoints

• Treatment burden: Number of injections administered
• Safety parameters: Intraocular pressure (IOP), adverse events, intraocular inflammation
• Visual field changes: Goldmann visual field isopter area
• Contrast sensitivity (CS)
• Time to progression from subclinical to clinically significant DME
• HbA1c levels and their impact on treatment response
• Blood pressure changes
• Urine albumin-creatinine ratio (UACR)

Trial Duration and Follow-up

• Durations ranged from 12 weeks to 36 months
• Several pivotal trials had 48-week or 52-week (1-year) endpoints
• Some extended to 104 weeks (2 years) for long-term assessment
• Follow-up visits typically scheduled every 4 weeks

Recent Findings

• HbA1c control (≤7%) significantly improved treatment outcomes with ranibizumab:

• Better BCVA improvement (7.9 ± 6.1 vs 6.1 ± 7.3, P = 0.0478)

• Greater CMT reduction (197.8 ± 125.1 μm vs 164.2 ± 122.8 μm, P = 0.0447)

• Artificial intelligence and telehealth are emerging as tools for improving screening and risk stratification