South Asian Patients With Diabetic Macular Oedema Treated With Faricimab Assessing the Efficacy, Durability, and Safety (SEAFAR Study)

Diabetic macular oedema (DMO), characterised by accumulation of extracellular fluid in the macula due to breakdown of the blood-retinal barrier, is the most common cause of sight-threatening diabetic retinopathy. It affects approximately one in fifteen people with diabetes, corresponding to more than 20 million individuals worldwide, and is a leading cause of vision impairment. The risk of diabetes is not equally distributed across populations. In the UK, individuals of South Asian heritage (Indian, Pakistani, Bangladeshi, Sri Lankan) have a 2-4 times higher risk of developing type 2 diabetes compared to those of European ancestry, with onset often at a younger age and at lower body mass index (BMI) thresholds. They are also shown to have a higher prevalence of retinopathy and maculopathy compared with White Europeans, with worse systemic risk factors (such as HbA1c, blood pressure, cholesterol). Despite this, there is limited trial-based evidence addressing treatment outcomes for these high-risk groups.

Anti-vascular endothelial growth factor (anti-VEGF) therapy has transformed the management of DMO. Pivotal trials such as RISE/RIDE and VIVID/VISTA established the efficacy of ranibizumab and aflibercept in improving visual outcomes and reducing retinal thickness. More recently, faricimab, a bispecific antibody targeting VEGF-A and Angiopoietin-2, has demonstrated efficacy with the potential for extended durability. In the YOSEMITE and RHINE trials, faricimab provided comparable or superior visual and anatomical outcomes to aflibercept 2mg, with a substantial proportion of patients achieving treatment intervals of up to every 16 weeks.

While YOSEMITE and RHINE enrolled over 1,800 patients, the majority of them were non-Asian (n=1747 versus n=144 for Asians). Subgroup analyses for participants in YOSEMITE and RHINE from Asian countries demonstrated broadly similar outcomes between Asian and non-Asian groups. However, the Asian participants were predominantly from East Asia (China, Japan, Korea, Singapore, Taiwan), which means that these findings cannot be extrapolated to South Asian patients given their potentially distinct genetic, biological, and lifestyle risk profiles. Notably, the ELEVATUM trial, designed to evaluate faricimab in underrepresented groups (African-Caribbean, Hispanic, Pacific Islander), similarly did not include adequate representation of South Asians. Thus, a critical evidence gap remains.

The SEAFAR study is designed to address this unmet need by specifically evaluating faricimab in a UK-based South Asian cohort with DMO. The rationale is threefold:

1. Scientific need: Ethnic differences in disease prevalence, risk factor profiles and possibly treatment response necessitate focused evaluation. Biological differences in angiogenic pathways and systemic disease burden may influence treatment durability and safety. 2. Clinical relevance: In the 2021 Census data by the UK government, 5.5 million people in England and Wales were from Asian ethnic groups - 1.9 million of these identified with the Indian ethnic group, with 1.6 million from the Pakistani ethnic group. 3. Health system impact: If faricimab demonstrates similar or greater durability in South Asians, this could substantially reduce injection frequency and clinic visits. This is particularly relevant in communities with higher disease burden and in a National Health Service (NHS) setting where service capacity is constrained.

A pragmatic, Phase IV, single-arm, open-label design is chosen to mirror routine clinical practice while still enabling comparison with previous trial data. By adopting a treat-and-extend protocol up to 24-week intervals, this study will generate real-world, ethnically relevant evidence on the efficacy, durability and safety of faricimab in South Asian patients with DMO.

HYPOTHESIS AND OBJECTIVES

Faricimab, delivered via a pragmatic treat-and-extend regimen, will produce clinically meaningful visual acuity gains, durable anatomic control of DMO, and an acceptable safety profile at week 88 in South Asian patients, with interim benefits by week 52. All participants will have a forced study visit at Week 52 and Week 88 (exit visit) even if not aligned with their treatment interval.

Primary objective:

1\) To evaluate the change from baseline in best corrected visual acuity at week 88 (+/- 14 days) in the study eye, with best responsive patients completing a 24-week extension of their active dosing phase and initiating their observation phase.

Secondary objectives:

1. Durability: Distribution of maximum dosing interval achieved and the proportion of participants at each interval (Q8W, Q12W, Q16W, Q20W, Q24W). 2. Anatomy: Change in central subfield thickness (CST) on spectral domain optical coherence tomography (SD-OCT) and proportions with absence of DMO (below device-specific inclusion threshold) and absence of intraretinal fluid. 3. Visual acuity categories: Proportions gaining/losing \>=5, \>=10, \>=15 letters. 4. Vision-related quality of life: Change from baseline in VFQ-25/EQ-5D. 5. Diabetic retinopathy severity score (DRSS):

1. Proportion with a 2 step improvement from baseline 2. Proportion with a 3 step improvement from baseline 6. Safety: Ocular/systemic adverse events (AE), serious adverse events (SAE), Suspected Unexpected Serious Adverse Reactions (SUSARs) from baseline through Week 88.

EXPECTED RISKS AND BENEFITS

Risks:

Participants will experience no study-specific risks. Clinical risks as per standard of care include:

* Participants may be exposed to risks related to both the intravitreal injection procedure and the study drug, faricimab. Injection-related risks include endophthalmitis, retinal detachment or tear, vitreous haemorrhage, transient or sustained rise in intraocular pressure, cataract progression, subconjunctival haemorrhage, and ocular discomfort. * Drug-related risks include intraocular inflammation, retinal vasculitis, vascular occlusion, and very rare systemic arterial thromboembolic events such as stroke or myocardial infarction, which are recognised class effects of anti-VEGF therapy. For identified risks for faricimab, please see the Vabysmo 120 mg/mL Summary of Product Characteristics (SmPC). * In addition, participants may experience inconvenience, anxiety, or discomfort associated with repeated clinic visits, ophthalmic imaging, and intravitreal procedures.

Benefits:

Wider benefits to society and healthcare include the generation of population-specific evidence for the efficacy, durability, and safety of faricimab in South Asian patients with DMO, who have historically been underrepresented in pivotal clinical trials. This may support equitable access to evidence-based care and inform NHS service planning by demonstrating whether extended dosing intervals can reduce treatment burden and service demand.

• Distribution of Maximum Dosing Interval Achieved [Срок оценки: Baseline through Week 88 (+/- 14 days), with interim assessment at Week 52 (+/- 14 days)]
• Change From Baseline in Central Subfield Thickness (CST) [Срок оценки: Baseline, Week 52 (+/- 14 days) and Week 88 (+/- 14 days)]
• Proportion of Participants With Absence of Diabetic Macular Oedema [Срок оценки: Week 52 (+/- 14 days) and Week 88 (+/- 14 days)]
• Proportion of Participants With Absence of Intraretinal Fluid [Срок оценки: Week 52 (+/- 14 days) and Week 88 (+/- 14 days)]
• Proportion of Participants Gaining >=5, >=10 and >=15 ETDRS Letters From Baseline [Срок оценки: Baseline, Week 52 (+/- 14 days) and Week 88 (+/- 14 days)]
• Proportion of Participants Losing >=5, >=10 and >=15 ETDRS Letters From Baseline [Срок оценки: Baseline, Week 52 (+/- 14 days) and Week 88 (+/- 14 days)]
• Change From Baseline in Vision-Related Quality of Life (NEI VFQ-25) [Срок оценки: Baseline, Week 52 (+/- 14 days) and Week 88 (+/- 14 days)]
• Change From Baseline in Health-Related Quality of Life (EQ-5D) [Срок оценки: Baseline, Week 52 (+/- 14 days) and Week 88 (+/- 14 days)]
• Proportion of Participants With a 2-Step or 3-Step Improvement in Diabetic Retinopathy Severity Score (DRSS) From Baseline [Срок оценки: Baseline, Week 52 (+/- 14 days) and Week 88 (+/- 14 days)]
• Number of Participants With Ocular Adverse Events [Срок оценки: Baseline through Week 88 (+/- 14 days), with interim assessment at Week 52 (+/- 14 days)]
• Number of Participants With Systemic Adverse Events [Срок оценки: Baseline through Week 88 (+/- 14 days), with interim assessment at Week 52 (+/- 14 days)]
• Number of Participants With Serious Adverse Events (SAEs) [Срок оценки: Baseline through Week 88 (+/- 14 days), with interim assessment at Week 52 (+/- 14 days)]