A Study to Learn More About How Well 8 Milligram Aflibercept Works and How Safe it is in Chinese Participants With Diabetic Macular Edema

EYLEA (aflibercept 40 mg/mL solution for injection) at a dosage level of 2 mg administered intravitreally (IVT) is approved in over 100 countries for the treatment of DME. Despite the proven efficacy and safety of EYLEA in patients with DME, there remains an unmet need for alternative therapies that can decrease the burden of DME treatment via a reduction in the required frequency of IVT injections, while improving visual and anatomic outcomes. The overall one and two year results of PHOTON, a global phase 2/3 trial evaluating high dose (HD or 8 mg) aflibercept in participants with center-involved diabetic macular edema (DME), demonstrate the benefit of HD aflibercept for reducing the frequency of injections required for the treatment of DME while providing visual and anatomic outcomes non-inferior to and a safety profile indistinguishable from EYLEA, 2 mg aflibercept, the established standard of care for the treatment of DME. The observed reduction in the number of HD aflibercept injections required for the treatment of DME over 2 years in PHOTON is expected to translate into the benefit of reducing the burden of treatment and, thereby improving the quality of life for DME patients, their caregivers and health care providers. This study aims to investigate the efficacy and safety of HD aflibercept in Chinese participants with DME over 60 weeks with the primary objective of achieving non-inferior best corrected visual acuity (BCVA) with an extended dosing interval (every 16 weeks after 3 initial monthly injections) vs. 2 mg aflibercept (every 8 weeks after 5 initial monthly injections) similar to the results obtained in PHOTON. This study is designed to support the registration of HD aflibercept for the treatment of DME in China.

Primary Objective: The primary objective of the study is to determine if treatment with HD aflibercept at intervals of 16 weeks provides non-inferior best-corrected visual acuity (BCVA) compared to 2 mg aflibercept dosed every 8 weeks in Chinese participants

Secondary Objectives:

• To determine the effect of HD aflibercept vs. 2 mg aflibercept on anatomic and other visual measures of response;

• To evaluate the safety, immunogenicity and pharmacokinetics (PK) of HD aflibercept in Chinese participants.

Primary endpoint:

• Change from baseline in BCVA by ETDRS letter score at Week 48

Secondary endpoints:

• Change from baseline in BCVA by ETDRS letter score at Week 60

• Participants gaining ≥15 letters at Week 48 and Week 60

• Participants achieving an ETDRS letter score of at least 69 (approximate 20/40 Snellen equivalent) at Week 48

• Participants with no IRF and/or no SRF in the center subfield at Week 48

• Change from baseline in central subfield thickness (CST) at Week 48

• Change from baseline in leakage on fluorescein angiography (FA) at Week 48

• Change from baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ) total score at Week 48

• Occurrence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) through Weeks 48 and 60

• Participants developing a treatment-emergent ADA response or Nabs to aflibercept through EOS at Week 60

• Systemic exposure to aflibercept as assessed by plasma concentrations of free, adjusted bound, and total aflibercept from baseline through Week 48 This study is a phase 3, multi-center, randomized, double-masked, active-controlled study in Chinese participants with DME involving the center of the macula to investigate the efficacy and safety of HD aflibercept versus 2 mg aflibercept.

The primary objective of the study is to determine if treatment with HD aflibercept at 16 week intervals provides non-inferior BCVA compared to 2 mg aflibercept dosed every 8 weeks in Chinese participants.

322 eligible participants randomized in a 1:1 ratio to the following 2 treatment groups:

1. 2q8: 2 mg aflibercept every 8 weeks following 5 initial monthly doses (n=161) and

2. HDq16: HD aflibercept every 16 weeks following 3 initial monthly doses (n=161). The study consists of a screening period, a treatment period, and an end of study (EOS) visit at Week 60. The study duration for a participant is approximately 63 weeks. The EOS is defined as the last visit of the last participant. No study treatment will be administered at the EOS visit at Week 60.

HD aflibercept is the sponsor's study intervention under investigation. The following intervention groups are included in the study:

• 2 mg aflibercept every 8 weeks (2q8)

• 8 mg aflibercept every 16 weeks (HDq16)