Abstract
Purpose
Diabetic macular edema (DME) is a leading cause of vision loss in patients with diabetes. In developed countries, intravitreal (IVT) anti-vascular endothelial growth factor (VEGF) injections are the standard-of-care first-line treatment for DME. However, despite the efficacy of anti-VEGF and associated improvements in prognosis, some patients show only a partial response and continue to require monthly injections. The aim of this study was to investigate the effect of switching from aflibercept 2.0 mg to faricimab (which targets both angiopoietin-2 [Ang-2] and VEGF-A) on visual function, retinal anatomy and intraretinal fluid (IRF) dynamics in patients with refractory DME.
Methods
A single-center, observational study of patients with aflibercept-resistant DME who switched to IVT faricimab treatment, comprising a 3-month loading phase, during which faricimab was administered monthly (total of four injections), followed by a treat-and-extend regimen. Visual acuity, anatomical parameters, and fluid dynamics were assessed from baseline to Month 6 in an interim analysis.
Results
Fourteen eyes from 10 patients were included. At Month 6, mean best-corrected visual acuity improved by + 2.7 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (not statistically significant). Mean changes in central macular thickness and outer nuclear layer (ONL) thickness at Month 6 were not significant. However, ONL thickness was significantly reduced in multiples ETDRS macular grid subfields at Month 4. Subretinal fluid volume was negligible through Month 6, with most fluid located in the intraretinal layers (97.8–100%). Total IRF decreased by 22% at Month 4, reaching a nadir of − 37% at Month 2. There was no significant change in mean vascular density from Month 0 to Month 4.
Conclusion
Faricimab treatment led to modest early improvements in visual acuity and retinal anatomy overall in patients with refractory DME. The reduction in total IRF at Month 4 may be attributable to Ang-2 inhibition in these patients, who had previously not responded to anti-VEGF treatment alone. Longer-term studies are needed to evaluate the durability and long-term efficacy of faricimab for the treatment of refractory DME.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12886-026-04651-w.
Keywords: Diabetic macular edema, Faricimab, Refractory, Switch
Key messages
What is known
Despite the success of anti-vascular endothelial growth factor (VEGF) therapies in treating diabetic macular edema (DME), many patients still require monthly injections, and some only show a partial response to them. For those with persistent DME, treatment often involves switching anti-VEGF agents or using corticosteroids; while this can be effective, it is associated with adverse events such as ocular hypertension and cataracts. Faricimab, a novel anti-VEGF and anti-angiopoietin 2 monoclonal antibody, has shown superior drying capacity in the past.
What is new
A detailed analysis of the retinal layers showed a significant reduction in outer nuclear layer (ONL) thickness following faricimab initiation, while inner nuclear layer and outer plexiform layer thickness remained unchanged. The reduction in ONL thickness, indicated a centripetal drying pattern, was achieved by the end of the loading phase.
In our study population, mean vascular density (VD) on optical coherence tomography angiography remained stable at Month 4, and, to our knowledge, these are the first data regarding the effect of faricimab on VD in diabetic patients
Supplementary Information
The online version contains supplementary material available at 10.1186/s12886-026-04651-w.
Introduction
Diabetic macular edema (DME) can complicate any stage of diabetic retinopathy and is the main cause of vision loss in patients with diabetes [1]. In center-involving DME, the first line of treatment in developed countries is intravitreal (IVT) injection of anti-vascular endothelial growth factor (anti-VEGF) agents [2], which have drastically improved the prognosis of this disease. The efficacy of anti-VEGF agents (ranibizumab, bevacizumab [off-label], brolucizumab, and aflibercept) in reducing macular edema and improving visual acuity has been previously demonstrated in multiple studies [3–10]. The choice of anti-VEGF agent has little impact on efficacy in cases of mild visual impairment at baseline, but for patients with low visual acuity (20/50 or worse), aflibercept 2.0 mg was associated with greater improvements in vision at 1 year than ranibizumab or bevacizumab. At 2 years, the advantage over ranibizumab was no longer substantially different, while the efficacy of aflibercept remained superior to that of bevacizumab [8].
Although anti-VEGF therapies have revolutionized the treatment of DME, a considerable number of patients require frequent injections, and some achieve only a partial response to treatment [11]. Persistent DME can be defined as eyes showing no clinical response or only a partial response to treatment [11]. The risk of persistent DME varies, and the risk is higher with bevacizumab compared with aflibercept 2.0 mg or ranibizumab [12]. For patients with persistent DME, treatment options typically involve switching between anti-VEGF agents or using IVT corticosteroids. IVT corticosteroids provide an effective alternative to anti-VEGF therapies; however, they are associated with serious adverse events, including ocular hypertension and cataracts [13]. In patients with inadequate response, the subsequent high frequency of injections poses significant economic and organizational challenges, which can reduce treatment adherence and increase the risk of complications [14].
In patients receiving anti-VEGF therapy, occurrences of treatment non-response, treatment resistance, and DME relapse are believed to result from the complex pathophysiology of the disease, which involves multiple signaling pathways [15]. One key pathway in this process involves the peptide ligand angiopoietin-2 (Ang-2) and its receptor, tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (Tie2). This pathway has been shown to play a critical role in retinal diseases [16]. Under pathological conditions, upregulation of Ang-2 activates downstream pathways that destabilize blood vessels and increase their sensitivity to VEGF-A, resulting in vascular leakage, neovascularization, and inflammation [7, 17–20].
Faricimab (Vabysmo®, Roche/Genentech) is the first bispecific monoclonal antibody (mAb) designed for IVT use that uniquely inhibits two signaling pathway components involved in retinal vascular diseases [21, 22]. Faricimab facilitates the independent blockage of VEGF and Ang-2 with anti-inflammatory and anti-angiogenic effects [23]. It is approved for the treatment of neovascular age-related macular degeneration, DME, and retinal vein occlusion [24–26], with its approval for DME based on the two pivotal phase 3 trials, YOSEMITE (NCT03622580) and RHINE (NCT03622593). In these trials, faricimab, administered every 8 weeks (Q8W) or in a treat-and-extend regimen, demonstrated non-inferiority to aflibercept 2.0 mg Q8W in patients with treatment-naïve DME [27].
As faricimab has only been available since 2022 [24, 25], data on its efficacy for patients with DME with inadequate responses to previous anti-VEGF therapies are limited. The study conducted by Rush et al. was the first to examine the outcome of switching patients with aflibercept-resistant DME to faricimab in a real-world setting [28, 29]. This study demonstrated improvements following switching in both visual acuity and central macular thickness (CMT) at 12 months [29]. In contrast, another recent study using a pro re nata (PRN) regimen found no substantial changes in visual acuity or CMT at Month 4 after switching from aflibercept 2.0 mg or ranibizumab to faricimab, although a significant extension in treatment intervals was achieved [30]. These contrasting results may be attributed to differences in treatment regimens, baseline CMT, or the heterogeneous nature of refractory DME. As such, further studies are needed to better understand the potential functional and anatomical benefits of switching from an anti-VEGF agent to faricimab. Additionally, the role of anti-Ang-2 in regulating vascular permeability in refractory DME, particularly through analysis of intraretinal fluid (IRF), remains unexplored.
The aim of this study was to investigate the effect of switching from aflibercept 2.0 mg to faricimab on visual function, retinal anatomy (including vascular density [VD]), and IRF dynamics in patients with refractory DME.
Methods
This was an observational, retrospective and prospective, single-arm, single-center study in patients with aflibercept-resistant DME conducted in the Swiss Visio Montchoisi Ophthalmology Center in Lausanne, Switzerland.
Male and female patients aged ≥ 18 years who had been diagnosed with type 1 or type 2 diabetes and met the following inclusion criteria were enrolled in the study: (1) initiated treatment with IVT faricimab injections for resistant DME (defined as persistent center-involving DME despite ≥ 6 months of anti-VEGF therapy with IVT injections of aflibercept 2.0 mg monthly or every 8 weeks) and (2) had received on-label treatment with faricimab injections in accordance with Prescribing Information, which involved an initial loading phase of four IVT injections administered monthly, followed by a treat-and-extend regimen in which treatment intervals could be extended by 4 weeks at the investigator’s discretion (based on optical coherence tomography [OCT] and best-corrected visual acuity [BCVA] assessments), to a maximum treatment interval of 16 weeks. Both eyes of the same patient could be included if they both met the eligibility criteria. Exclusion criteria are described in the Supplementary Information.
Here, we present the interim analysis of the study, assessing functional (BCVA) and anatomical outcomes at Month 6 after switching from aflibercept 2.0 mg to faricimab in patients with refractory DME. BCVA was measured on a Snellen decimal scale and then converted to an approximate Early Treatment Diabetic Retinopathy Study (ETDRS) letter score. Anatomical parameters including CMT, outer nuclear layer (ONL) thickness, inner nuclear layer/outer plexiform layer (INL/OPL) thickness, IRF and subretinal fluid (SRF) were measured on spectral domain OCT (Heidelberg Engineering Ltd, Heidelberg, Germany). ONL thickness, INL/OPL thickness, and retinal fluid volumes were evaluated using an artificial intelligence-based automated fluid quantification system (RetinAI Discovery® 3.8.0 [Ikerian AG, Bern, Switzerland]). VD, defined as the percentage of the sample area occupied by vessel lumens following binary image reconstruction, was measured on OCT angiography (AngioVue Imaging System [Optovue Inc., Fremont, CA, USA]).
The primary outcome was the mean change from baseline in BCVA assessed monthly to Month 4 (receipt of final loading dose) and at Month 6. Secondary outcomes, evaluated as changes from baseline at Month 4 and Month 6, included the proportions of participants with a ≥ 15-letter loss, a 10–14-letter loss, a − 9 to + 9-letter change, a 10–14-letter gain, or a ≥ 15-letter gain in ETDRS letter score. Additional secondary outcomes included mean changes in CMT, ONL and INL/OPL thickness, IRF and SRF volumes, and VD (assessed at baseline and at Month 4 only); as well as the proportion of patients with any IRF and/or subretinal fluid (SRF). Safety was assessed by the incidence of ocular and non-ocular adverse events related to or suspected to be related to the treatment.
The results of this interim 6-month analysis had no impact on the continuation of the study. Continuous variables are presented uniformly as mean ± standard deviation (SD) for clarity and readability; normality tests were performed and statistical comparisons were chosen accordingly (t-tests for normally distributed variables and Wilcoxon–Mann–Whitney tests for non-normal variables). Categorial variables are presented as proportions (percentages). The study also included multiple secondary OCT and OCTA parameters to explore imaging patterns across layers and regions; given the small sample size and exploratory nature of these analyses, no formal adjustment for multiple comparisons was applied, and results were interpreted cautiously, focusing on effect sizes, consistency, and descriptive trends rather than isolated p-values. We acknowledge the potential correlation between eyes from the same participant; however, due to the limited sample size, analyses were restricted to descriptive statistics and simple bivariate comparisons, as correlation-adjusted or mixed-effects models were not appropriate. Statistical analyses were performed using Microsoft Excel 2019 (version 16.78) and Stata (version 12.0), with statistical significance therefore defined as a p value < 0.05.
Results
From June to December 2023, data for 20 eyes from 16 patients who were switched to faricimab due to aflibercept-resistant, center-involving DME were available. Six eyes were excluded from the analysis because they did not meet inclusion criteria; therefore, 14 eyes from 10 patients were assessed. Baseline characteristics of the study population are summarized in Table 1.
Table 1.
Baseline population characteristics
| Baseline population characteristics (n = 14 eyes) | |
|---|---|
| Mean ± SD agea, years | 68.1 ± 7.2 |
| Sex, n (%) | |
| Male | 12 (85.7) |
| Female | 2 (14.3) |
| Race or ethnicity, n (%) | |
| Caucasian | 8 (57.1) |
| Black | 2 (14.3) |
| Unknown | 4 (28.6) |
| Systemic comorbidities, n (%) | |
| Hypertension | 11 (78.6) |
| Cancer (past or present) | 2 (14.3) |
| Smoking status | |
| Current | 2 (14.3) |
| Former | 5 (35.7) |
| Never | 4 (28.6) |
| Unknown | 3 (21.4) |
| Diabetes | |
| Type, n (%) | |
| Type 1 | 3 (21.4) |
| Type 2 | 11 (78.6) |
| Mean (± SD) time since diagnosis, years | 12.1 ± 7.6 |
| Diabetic retinopathy, n (%) | |
| Moderate, non-proliferative | 2 (14.3) |
| Severe, non-proliferative | 12 (85.7) |
| Proliferative | 0 (0.0) |
| Phakic lens status, n (%) | 7 (50.0) |
| Aflibercept 2.0 mg | |
| Mean (± SD) number of IVT injections before switch | 13.1 ± 7.9 |
| Intervals, n (%) | |
| 4 weeks | 10 (71.4) |
| 6 weeks | 1 (7.1) |
| 8 weeks | 3 (21.4) |
| Mean intervals before switch, weeks | 5.0 (1.7) |
| Reason for switch, n (%) | |
| Persistence of retinal fluid | 12 (85.7) |
| Recurrence of retinal fluid with extension | 2 (14.3) |
| Mean (± SD) BCVA, ETDRS letter score | 75.0 ± 10.3 |
| Mean (± SD) CMT, µm | 321.6 ± 56.1 |
| Retinal fluid, n (%) | |
| Intraretinal | 14 (100.0) |
| Subretinal | 0 (0.0) |
aAge at randomization
BCVA best-corrected visual acuity, CMT central macular thickness, ETDRS Early Treatment Diabetic Retinopathy Study, IVT intravitreal, SD standard deviation
Mean ± SD ETDRS letter score did not statistically differ from baseline (75.0 ± 10.3) at Month 4 (73.9 ± 12.0, p = 0.41) or Month 6 (77.7 ± 8.5, p = 0.06), with the majority of eyes recording a change in score of less than 10 letters (Table 2), although there was a small increase in median BCVA at Month 6 versus baseline and Month 4 (Fig. 1). However, one eye at Month 4 and two eyes at Month 6 gained ≥ 10 letters from baseline, while one eye from a different patient lost ≥ 15 letters at Month 4 (due to worsening of a cataract) (Table 2). At Month 6, no eyes had a significant loss in ETDRS letter score (Table 2). The proportion of eyes with a score of ≥ 70 at baseline (≥ 0.5 on the Snellen scale) was 78.6% (11/14), 78.6% (11/14) of eyes at Month 4 and 92.3% (12/13) of eyes at Month 6; a score of ≥ 80 was observed in 42.9% (6/14) of eyes at baseline, 28.6% (4/14) of eyes at Month 4, and 53.8% (7/13) of eyes at Month 6.
Table 2.
Proportion of eyes that gained or lost ≥ 10 and ≥ 15 ETDRS letters at month 4 and month 6
| ETDRS letter score change from baseline, n (%) | |||||
|---|---|---|---|---|---|
| Months | Loss ≥ 15 letters | Loss 10–14 letters | Change − 9 to + 9 letters | Gain 10–14 letters | Gain of ≥ 15 letters |
| Month 4 | 1 | 0 | 12 | 1 | 0 |
| (7.1) | (0.0) | (85.7) | (7.1) | (0.0) | |
| Month 6 | 0 | 0 | 11 | 2 | 0 |
| (0.0) | (0.0) | (84.6) | (15.4) | (0.0) | |
ETDRS Early Treatment Diabetic Retinopathy Study
Fig. 1.
BCVA (ETDRS letter score) at baseline, Month 4, and Month 6
BCVA best-corrected visual acuity, ETDRS Early Treatment Diabetic Retinopathy Study
The mean change in CMT from baseline through to Month 6 was not statistically significant, and there was no significant difference from baseline in mean ONL thickness at Month 1 or Month 6 (Table 3). There was a statistically significant reduction in ONL thickness observed from baseline to Month 4 in the central subfield (− 6.8 μm, p = 0.0444), inner superior (− 7.1 μm, p = 0.0217), inner temporal (− 5.2 μm, p = 0.0236), inner inferior (− 3.5 μm, p = 0.0410), outer superior (− 3.6 μm, p = 0.0054), and outer inferior (− 1.9 μm, p = 0.0088) subfields, and in the whole macula (− 3.1 μm, p = 0.0089) (Table 3). Mean INL/OPL thickness remained mostly unchanged from baseline through to Month 6. The inferior 6 mm subfield was the only subfield in which a statistically significant decrease in mean INL/OPL thickness of − 1.5 μm (p = 0.0152) was observed at Month 4 (Table 3).
Table 3.
Mean changes from baseline in CMT, and ONL and INL/OPL thickness
| Layer | Subfield | Thickness [µm], n = 14 eyes | p value | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Month 0 | Month 1 | Month 2 | Month 3 | Month 4 | Month 6 | Month 0–1 |
Month 0–2 |
Month 0–3 |
Month 0–4 |
Month 0–6 |
||
| CMT | C1 | 321.6 (56.1) | 320.0 (64.5) | 314.0 (59.8) | 310.8 (65.0) | 312.8 (59.8) | 318.1 (63.8) | 0.7239 | 0.0800 | 0.0960 | 0.1486 | 0.5505 |
| ONL | C1 | 113.4 (24.1) | 112.7 (22.7) | 109.5 (21.4) | 111.1 (25.1) | 106.6 (18.1) | 110.6 (16.7) | 0.4788 | 0.0720 | 0.3295 | 0.0444* | 0.4699 |
| S3 | 97.5 (26.6) | 95.3 (30.0) | 93.6 (28.4) | 94.0 (25.9) | 90.4 (24.6) | 94.2 (22.3) | 0.2648 | 0.1642 | 0.1647 | 0.0217* | 0.2995 | |
| T3 | 100.1 (20.4) | 99.5 (20.0) | 98.1 (19.6) | 96.6 (16.2) | 94.9 (15.3) | 97.9 (15.1) | 0.5285 | 0.2577 | 0.064 | 0.0236* | 0.8260 | |
| I3 | 95.6 (18.5) | 95.3 (23.9) | 94.7 (21.7) | 91.9 (20.1) | 92.2 (14.1) | 92.1 (12.9) | 0.9999 | 0.3267 | 0.0920 | 0.0417* | 0.3490 | |
| N3 | 98.2 (11.5) | 97.5 (13.0) | 96.4 (12.9) | 95.9 (11.7) | 95.5 (9.0) | 95.6 (8.2) | 0.2066 | 0.1662 | 0.1067 | 0.0720 | 0.4885 | |
| Mean3 | 97.9 (18.2) | 96.9 (20.8) | 95.7 (19.7) | 94.6 (17.5) | 93.2 (14.3) | 95.0 (12.8) | 0.6660 | 0.1670 | 0.0480* | 0.0238* | 0.3794 | |
| S6 | 81.6 (13.5) | 79.8 (13.7) | 79.6 (11.9) | 79.4 (11.2) | 78.0 (11.6) | 79.9 (11.5) | 0.3044 | 0.0392* | 0.0178* | 0.0054* | 0.1466 | |
| T6 | 84.1 (17.2) | 83.7 (17.7) | 84.5 (16.9) | 82.6 (14.9) | 81.0 (12.8) | 83.7 (16.3) | 0.7523 | 0.8258 | 0.2846 | 0.0910 | 0.7289 | |
| I6 | 74.8 (8.7) | 74.4 (11.2) | 74.4 (9.6) | 73.1 (8.3) | 72.9 (7.3) | 75.1 (10.5) | 0.6894 | 0.6094 | 0.0087* | 0.0088* | 0.4823 | |
| N6 | 78.9 (11.4) | 76.2 (9.2) | 76.9 (9.1) | 77.1 (9.1) | 75.7 (5.6) | 76.7 (7.4) | 0.091 | 0.0654 | 0.3107 | 0.1060 | 0.4666 | |
| Mean6 | 79.9 (11.9) | 78.5 (12.4) | 78.9 (11.4) | 78.0 (10.4) | 76.9 (8.7) | 78.9 (10.8) | 0.5822 | 0.1659 | 0.0216* | 0.0083* | 0.5718 | |
| Mac | 78.2 (11.2) | 77.5 (11.8) | 77.1 (11.5) | 76.6 (10.5) | 75.1 (9.0) | 76.9 (7.7) | 0.1370 | 0.1200 | 0.0208* | 0.0089* | 0.4501 | |
| INL/OPL | C1 | 50.7 (15.8) | 49.6 (17.4) | 50.6 (17.4) | 49.0 (14.7) | 49.1 (13.2) | 51.2 (13.2) | 0.9367 | 0.9496 | 0.0622 | 0.6810 | 0.6823 |
| S3 | 68.6 (10.4) | 68.5 (10.2) | 68.9 (10.6) | 66.9 (9.7) | 69.9 (10.3) | 70.1 (10.2) | 0.2868 | 0.8256 | 0.1300 | 0.6821 | 0.8255 | |
| T3 | 66.6 (11.1) | 67.4 (11.1) | 66.7 (9.4) | 65.9 (10.4) | 66.4 (8.0) | 67.1 (9.2) | 0.1102 | 0.5913 | 0.1005 | 0.8746 | 0.998 | |
| I3 | 69.1 (10.5) | 69.1 (11.4) | 67.0 (10.7) | 68.0 (10.4) | 66.4 (8.6) | 68.2 (8.6) | 0.1672 | 0.0572 | 0.2696 | 0.0510 | 0.4881 | |
| N3 | 70.5 (13.0) | 70.2 (14.4) | 69.5 (13.7) | 69.2 (11.9) | 69.2 (11.6) | 70.9 (13.2) | 0.6620 | 0.3436 | 0.1655 | 0.2434 | 0.7531 | |
| Mean3 | 68.7 (10.7) | 68.8 (11.2) | 68.0 (10.3) | 67.5 (9.8) | 68.0 (8.5) | 69.1 (9.3) | 0.3073 | 0.1863 | 0.1159 | 0.6374 | 0.8505 | |
| S6 | 51.3 (6.5) | 51.0 (6.9) | 51.1 (5.9) | 50.6 (5.7) | 51.0 (5.6) | 50.7 (6.0) | 0.3416 | 0.5867 | 0.2954 | 0.3404 | 0.2966 | |
| T6 | 54.6 (8.8) | 54.3 (8.9) | 54.1 (8.0) | 54.7 (8.9) | 53.9 (7.3) | 55.6 (10.2) | 0.3760 | 0.4305 | 0.9491 | 0.5019 | 0.9248 | |
| I6 | 50.5 (8.8) | 49.5 (6.6) | 49.6 (5.5) | 49.6 (4.7) | 49.0 (4.1) | 49.7 (5.6) | 0.2821 | 0.0562 | 0.1651 | 0.0152* | 0.1623 | |
| N6 | 55.0 (7.5) | 53.9 (7.9) | 53.6 (7.7) | 54.1 (6.9) | 53.5 (6.2) | 54.0 (6.3) | 0.1064 | 0.0890 | 0.3258 | 0.1715 | 0.5478 | |
| Mean6 | 52.9 (6.6) | 52.2 (7.1) | 52.1 (6.3) | 52.3 (6.1) | 51.8 (5.3) | 52.5 (6.5) | 0.1552 | 0.0780 | 0.2571 | 0.1565 | 0.5297 | |
| Mac | 50.7 (6.9) | 50.8 (7.4) | 50.1 (6.7) | 50.1 (6.3) | 49.6 (5.7) | 50.4 (5.3) | 0.0909 | 0.1315 | 0.1315 | 0.1456 | 0.7765 | |
*p < 0.05. Data are expressed in mean (SD)
Macular subfields (ETDRS grid): C1 refers to the central 1 mm subfield; I3, N3, S3, and T3 correspond to the inner 3 mm inferior, nasal, superior, and temporal subfields, respectively; I6, N6, S6, and T6 refer to the outer 6 mm inferior, nasal, superior, and temporal subfields; Mean3 represents the mean of all inner 3 mm subfields; Mean6 represents the mean of all outer 6 mm subfields; Mac denotes the macula, with thickness measured over the entire macular area; and CMT indicates the central macular thickness. INL refers to the inner nuclear layer; ONL to the outer nuclear layer; and OPL to the outer plexiform layer. SD denotes the standard deviation
The presence of SRF was almost negligible from baseline through to Month 6, measuring between 0 and 3 nL (Supplementary Table 1). Therefore, most of the retinal fluids in the study eyes were in the intraretinal subfield, representing total fluid measurements of between 97.8% and 100%. Although not statistically significant, a decrease in total IRF across the macula was observed, reduced by 22% from baseline to Month 4, reaching a nadir of − 37% at Month 2. However, at Month 6, the fluid had increased above baseline levels (Supplementary Table 1).
There was no statistically significant change from baseline in mean VD at Month 4 (Supplementary Table 2). VD at the superficial capillary plexus (SCP) and deep capillary plexus (DCP) remained comparable in all subfields at all timepoints.
At the end of the loading phase, treatment intervals were extended in 6 out of 14 patients (43%). Compared with the intervals prior to the switch, 5 patients (36%) experienced an extension of their interval, 2 patients (14%) had a reduced interval, and 7 patients maintained the same interval.
No adverse events, including intraocular inflammation, elevation of intraocular pressure, or endophthalmitis were reported during the study.
Discussion
This observational study assessed the real-world efficacy of switching from aflibercept 2.0 mg to faricimab in patients with refractory DME and demonstrated its potential to improve retinal anatomy and decrease fluid volume at the end of the loading phase (Month 4).
Despite an upward trend, no significant change in mean visual acuity was observed at Month 4 or Month 6 in our study population. This may be due to relatively high baseline visual acuity in our cohort, which limits the potential for improvement. Additionally, the treatment switch had no effect on mean CMT, which remained stable during both the loading phase and at Month 6, likely due to our cohort’s already low baseline (321.6 μm). These findings are consistent with a recent study in which patients switched to faricimab from ranibizumab or aflibercept 2.0 mg [30]. However, that study used a PRN treatment regimen immediately after the switch, without a loading phase; this may have limited the frequency of injections and, consequently, the effectiveness of faricimab in improving visual acuity and reducing retinal fluid in these patients with persistent DME [30]. In contrast, another study of aflibercept-resistant patients reported an overall improvement in BCVA, with 21.6% of patients (11/51) achieving a gain of ≥ 3 lines on Snellen visual acuity (equivalent to ≥ 15 letters) at 12 months, and a significant reduction from baseline CMT at 4 and 12 months after switching to faricimab [29]. In preliminary results reported for the study, 41.7% of patients had already achieved a gain of ≥ 2 lines (≥ 10 letters) at 4 months [28]. These contrasting results suggest that a loading phase may help stabilize functional and anatomical outcomes in some patients with treatment-refractory DME; however, its benefit may not be universal, and the need for prolonged monthly injections should be evaluated on a case-by-case basis rather than assumed for all patients.
DME-induced retinal thickening primarily affects the inner retina, particularly the INL [31]. However, while increased INL thickness is associated with DME, an increased OPL thickness correlates with reduced visual acuity [32]. In our study, a specific analysis of the retinal layers showed a significant reduction in ONL thickness after faricimab initiation, while INL/OPL thickness remained largely unaffected. This difference may reflect the multiple causes of thickening in the inner retinal layers. Fluid in the ONL is largely driven by microaneurysms in the DCP, while fluid in the INL is typically secondary to vessel leakage in the SCP and DCP, resulting from blood–retinal barrier disruption mediated by inflammation [33]. The observed reduction in ONL thickness in this study may result indirectly from localized fluid reduction due to the anti-Ang-2 action on microaneurysms. While microaneurysms are generally resistant to anti-VEGF, faricimab has been shown to reduce the size of pre-existing microaneurysms and to decrease the number of newly formed microaneurysms in patients with DME [34]. In our study, ONL thickness reduction was first observed across the whole macula and outer subfields at Month 3, before extending to the inner subfields by Month 4, suggesting a centripetal drying pattern at the end of the loading phase. To the best of our knowledge, this observation has not been previously reported. A possible explanation for this pattern is provided by biophysical modeling of retinal fluid dynamics in macular edema by Ruffini and colleagues, which suggests that fluid exudation predominantly occurs in parafoveal regions, whereas maximal tissue deformation and fluid accumulation occur centrally due to higher foveal mechanical compliance and lower Müller cell density [35]. In this context, parafoveal regions - characterized by greater structural support from Müller cells and higher permeability - may respond earlier to anti-VEGF therapy, with fluid clearance initiating peripherally and progressing centripetally toward the fovea. Moreover, spatial heterogeneity in hydraulic conductivity across the retinal thickness, with lower water permeability in the central retina, may play a protective role that also results in slower central fluid resolution compared with peripheral areas. However, by Month 6, ONL thickness was no longer significantly reduced compared with baseline, likely reflecting the initiation of the treat-and-extend regimen at Month 4, which may have allowed partial recurrence of exudation as injection intervals were extended per protocol in some patients.
Due to increased vascular permeability, which typically occurs in diabetic retinopathy, retinal capillary plexuses seem to play a significant role in the pathogenesis of DME [36]. Yet, in our study population, the VD of SCP and DCP remained stable at Month 4, and to our knowledge, there are currently no other data on the effect of faricimab on VD in diabetic patients. In a previous study of comparing eyes with DME and non-DME eyes, VD in the DCP was reduced and the prevalence of microaneurysms in both retinal layers was increased in eyes with DME [37]. Increased microvascular damage and a higher occurrence of microaneurysms in the DCP were observed in poor responders than those with a good response to anti-VEGF therapy [37]. However, the direct effects of anti-VEGF therapies on VD in DME are less clear. Among the prospective studies addressing this, one observed a decrease in VD in the central subfield at as early as the first injection of aflibercept, which persisted during the loading phase [38]. Another also observed a reduction in VD at 6 months, extending to the inner ring [39]. In contrast, Korobelnik et al. did not observe any changes in VD in patients treated with aflibercept 2.0 mg over a 48-week follow-up [40], and in cases of resistant DME, IVT dexamethasone implants do not appear to alter VD either [41].
This study is limited by its observational, single-arm, single-center design, and its small sample size. Owing to the limited number of participants, statistically significant findings should be interpreted with caution and are better viewed as indicative of trends rather than definitive conclusions. Furthermore, this preliminary analysis presented the effects of faricimab on DME only up to Month 6 after the treatment switch, and therefore does not allow for assessment of long-term follow-up or whether treatment intervals could be extended. On the other hand, the strength of this study is the precise delineation of retinal layers and quantification of retinal fluid via an artificial intelligence tool, which allowed us to characterize the spatial and temporal evolution of refractory DME after the introduction of faricimab.
Conclusion
In conclusion, 6 months of treatment with faricimab appears to have a modest effect on BCVA in real-world patients with resistant DME. However, switching to faricimab may improve retinal anatomy, primarily by decreasing fluid accumulation in the ONL, via a potential centripetal effect observed by the end of the loading phase. A bounce-back in ONL thickness after Month 4 to pre-treatment levels suggests that patients with resistant DME may require monthly treatment beyond 4 months. The reduction in total IRF at Month 4 may indicate a role for Ang-2 inhibition in the efficacy of faricimab these patients, who had previously not responded to anti-VEGF treatment. Further research with extended follow-up is needed to evaluate the long-term efficacy and durability of faricimab for the treatment of resistant DME.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
Medical writing support was provided by Natasha Hornby, PhD, of OPEN Health Group, and was funded by Roche Pharma (Schweiz) AG, in accordance with Good Publication Practice (GPP) guidelines (www.ismpp.org/gpp- 2022).
Author contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Nicolas Owlya, Mickael Barbosa, Nicolò Bartolomeo, and Aude Ambresin. The first draft of the manuscript was written by Nicolas Owlya, Nicolò Bartolomeo, and Aude Ambresin, and all authors commented on draft versions of the manuscript. All authors read and approved the final manuscript.
Funding
No funding was received for conducting this study.
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study design was approved by the local ethics committee (Commission cantonale d’éthique de la recherche sur l’être humain CER-VD -part of Swissethics) for data collection and analysis (BASEC 2023 − 00814; authorized on 28th Jun 2023) and was conducted in accordance with the Declaration of Helsinki. Informed consent to participate was obtained from all the participants in the study. Clinical trial number: not applicable.
Consent for publication
Not applicable.
Competing interests
Grant for medical writing - 2024.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
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Supplementary Materials
Data Availability Statement
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.