Study Subjects

• Major Inclusion Criteria:
  • At least 18 years of age
  • Diagnosis of Type 1 or Type 2 DM and center involving DME (defined as CST > 325 um)
  • BCVA between 25 and 73 ETDRS letters
• Major Exclusion Criteria:
  • High risk Proliferative Diabetic Retinopathy (PDR) in the study eye
  • A1c > 10%
  • Untreated diabetes or initial treatment < 3 months of day 1
  • Uncontrolled blood pressure
  • Tractional retinal detachment, fibrosis, or epiretinal membrane involving the fovea

Randomization Scheme and Interventions

• Patients were randomized 1:1:1 according to the following treatment arms:
  • Faricimab 6 mg every 4 weeks for 6 months followed by 8-week dosing
  • Faricimab 6 mg every 4 weeks for 4 months followed by PTI protocol driven T&E approach up to every 16 week intervals
  • Aflibercept 2mg every 4 weeks for 5 months followed by every 8 weeks
• Randomization stratified based on BCVA letter score (64 ETDRS letters or better vs. 63 letters or worse), prior intravitreal anti-VEGF therapy and region (US and Canada, Asia, rest of the world)
• To ensure masking, patients presented every 4 weeks and were administered sham injection when they were not treated with the drug
• PTI regimen: automated, protocol-driven dosing regimen based on treat and extend. PTI group received q4week injections until CST < 325 microns at or after week 12.

Endpoints

• Primary endpoints: To evaluate the efficacy of intravitreal faricimab on Best Corrected Visual Acuity outcomes, as measured by change from baseline to 2 years, as defined as the average of weeks 92, 96, and 100.
• Secondary Endpoint:
  • The proportion of patients receiving treatment at different intervals in the PTI arm at week 96 and over time.
  • Change in CST from baseline at 2 years and over time
  • Absence of DME, intraretinal fluid (IRF), subretinal fluid (SRF), or both IRF and SRF over time.
  • Proportion of patients who had at least 2-step ETDRS DRSS improvement from baseline at week 96

Results

• Study Population: 951 patients across 174 centers
  • 317 patients randomized to faricimab 8 week intervals
  • 319 patients randomized to faricimab T&E
  • 315 patients randomized to aflibercept 8 week intervals
  Study completion through week 100 was 87%.
• Primary outcome: BCVA change from baseline as measured in ETDRS letters in RHINE
  • +10.9 ETDRS letter (CI +9.5 to +12.3) in faricimab q8w
  • +10.1 ETDRS letters (CI +8.7 to +11.5 ETDRS letters) in faricimab PTI
  • +9.4 ETDRS letters (CI +7.9 - 10.8 ETDRS letters) in aflibercept q8w
• Secondary outcome:
  • Mean number of injections at year 1:
    • 8.7 ± 2.50 for Faricimab PTI arm
    • 9.3 ± 1.52 injections in faricimab q8w
    • 9.3 ± 1.36 injections in aflibercept q8w
  • In year 2, the faricimab T&E arm received 3.6 ± 1.98 injections versus 4.7 ± 0.82 injections for q8w faricimab and 4.5 ± 0.99 injections in aflibercept q8w.
  • Durability: At week 96, 224 patients (78%) in faricimab T&E arm achieved every 12-week dosing intervals or longer.
  • Anatomic: Adjusted mean 2 year CST reductions at year 2 were greater in faricimab q8w (-202.6 um) vs aflibercept q8w (-185.6 um) p<0.05. The adjusted mean 2 year CST reductions were not statistically significant between the PTI faricimab arm and aflibercept q8w groups.
  • Higher proportion of patients in the faricimab groups achieved absence of protocol defined DME (88-93% faricimab q8w, 85-88% faricimab PTI, 80-84% aflibercept q8w) at year 2.
  • Proportion of patients with at least a 2-step ETDRS DRS improvement from baseline to week 96 was comparable between all groups. In RHINE, faricimab q8 week group had a higher proportion of patients with a 2 step improvement compared to aflibercept q8 weeks (53.5% vs 43.8%, P< 0.0475), but similar rates between faricimab PTI and aflibercept q8weeks (44.3% for faricimab PTI, p>0.05).
• Safety:
  • Incidence of serious ocular adverse events was low and comparable between study arms (4% vs. 6% vs. 4%)
  • The incidence of intraocular inflammation (IOI) was low and similar between three treatment arms (1% faricimab q8w vs 1% faricimab PTI vs 2% aflibercept q8w)
  • No IOI events were associated with retinal occlusive events and no events of retinal vasculitis or occlusive vasculitis were reported.

Conclusions

• The 2-year results demonstrated the durability, efficacy, and safety of faricimab in patients with DME. Clinically significant visual acuity gains with faricimab treatments arms (every-8-weeks and T&E) remained comparable with aflibercept treatment arm (every 8 weeks).
• This data reinforced the potential for dual inhibition of angiopoietin-2 and VEGF-A with faricimab as a novel, multitargeted strategy towards DME treatment.