Anti-VEGF intravitreal therapy is the first choice of treatment for nAMD (21, 22). Efficacy is variable and, in some cases, there is little or no response (4). In addition for those who do respond repeated frequent injections are usually required to maintain the desired effect (23). Some cases may develop tachyphylaxis and fibrosis can also occur (4, 23, 24).
Faricimab is the first bi-specific antibody approved for intraocular use and inhibits both VEGF and angiopoietin 2 (Ang2), both of which are considered to be essential in the maintenance of vascular homeostasis (25). We aimed to assess the effectiveness of the novel faricimab (Vabysmo™) in a real-world study in 11 consecutive eyes assessing BCVA as a functional outcome and OCT variables as anatomical ones (SRF, IRF, dPED, CRT, and FT).
This new compound is labelled for up to 16-week dosing intervals depending on response and following a loading dose of 4 monthly injections. However, in this group of patients, a treat-and-extend treatment regimen was used, and not all received the loading doses.
The AVENUE and STAIRWAY clinical trials demonstrated that faricimab was not inferior to ranibizumab (12, 26). In these studies, treatment intervals were extended to 12 to 16 weeks for the treatment of nAMD (12, 26). Previous studies using aflibercept have shown that extending treatment intervals beyond the manufacturer’s recommended dosing regimen has been demonstrated to be effective (17, 27).
It is thought that the design of faricimab, by targeting and inhibiting two regions during the physiological process of neovascularisation, a more sustained and effective response to treatment is enabled. As a consequence, some patients may need fewer than 3 injections per year. We demonstrated this in our small patient group: Case 5, a patient who had been previously undergoing 5–6 weekly intravitreal injections (IVI) of aflibercept for 3 years, had full resolution of the SRF after receiving only one initial faricimab injection and no signs of neovascular activity were observed for > 24 weeks on OCT. Similarly, Case 4 with a history of 5–6 weekly IVI of aflibercept, achieved neovascular inactivity for > 13 weeks after the first dose Although these numbers are small, it raises the question of the necessity of the initial loading dose of four monthly intravitreal injections of faricimab in patients already undergoing anti-VEGF therapy in some individuals
However, we realized that persistent SRF can be found even after three doses of faricimab, as seen for example in Case 7 in which the SRF resolution and improvement of BCVA was observed only after the 4th injection of faricimab. It may be that using loading dose is important in patients who have not had previous anti-VEGF therapy. However it is probably more likely that the need for loading doses and an increased frequency of treatment doses is dependent on the type of nAMD. nAMD is clearly a number of different phenotypes with presumed underlying different potentially complex genotypes. A way forward would be to identify the response to therapy identifying specific OCT ‘biomarkers’. It is hoped that the potential of artificial intelligence (AI) to determine these biomarkers might be harnessed to identify these. Using these biomarkers will enable us to distinguish which treatment regimen is the most appropriate for each patient. This personalised medicine approach would be more cost-effective and reduce the number of appointments and IVI needed per year.
Recently, Ozdemir et al. (2022)(40) highlighted patient preferences for anti-VEGF treatments. Though the most important attribute was vision quality, medical costs and fewer overall clinic visits were also important factors. For this reason, we believe that new retinal therapies allowing for fewer injections and appointments as observed with faricimab are beneficial for both doctors and patients.
The mean BCVA in our patients increased up to 38.19% and five eyes (45.45%) gained at least one line of vision after the first IVI. These are very encouraging results since most of the here reported eyes (72.72%) were not treatment–naïve and had already undergone multiple anti-VEGF IVI prior to starting treatment with faricimab.
Our real-world results with faricimab in terms of improvement of BCVA and resolution of subretinal fluid or subretinal pigment epithelium haemorrhage are similar or even better when compared to other licensed anti-VEGF treatments at one month after the first injection (28). Furthermore, the these results are similar or better compared to those reported in CTs such as TENAYA and LUCERNE, which demonstrated non-inferiority in mean change BCVA compared to aflibercept in nAMD patients (15). Matsumoto et al. also showed significant BCVA improvement one month after the first injection of brolucizumab in nAMD patients (29), however, this IVT has been associated with ocular inflammation (30, 31, 32).
In addition, excluding the large fibrovascular PEDs and haemorrhages, we observed a significant reduction in CRT (more than 10 µm) and FT (more than 16 µm) in both naïve and resistant anti-VEGF nAMD eyes after the first faricimab injection. However, we should be cautious to interpret these findings, as a reduction in anatomical thickness may not necessarily be relevant to the long-term functional outcome (33).
We also observed a complete resolution of SRF and IRF at one month in 6 of the 8 eyes and 2 of the 3 eyes, respectively. It is known that IRF is associated with worse visual results in nAMD patients and with higher rate of atrophy and fibrosis (33). Thus, despite our hopeful results, they must be valued in long term.
Drusenoid PED pathogenesis and its implication in nAMD is still unknown but it is though that they are associated with an increased risk of advanced AMD with atrophy or fibrosis development (34). Thus, achieving a flattening or reduction in a PED early in disease might be of benefit. Javaheri et al. demonstrated that one-third of 586 eyes had a flattened PED after an initial ranibizumab injection (35). Our results are similar, and we observed that 28.57% eyes which had a dPED at baseline achieved a complete flattened dPED at month one after a single injection of faricimab without recurrence of the dPED for a minimum of four months in three patients. In addition, all eyes with the presence of dPED had at least a partial resolution. We also observed changes in the morphology of dPED, as Rispoli et al (2021) described with Brolucizumab (36).
An important response with anatomical and functional improvements was noticed in three patients (Cases 1, 10 and 11) who presented with subretinal and/or subRPE haemorrhages at one month after faricimab treatment. Thus, this novel compound may be a useful agent in treating extensive retinal haemorrhages, subRPE haemorrhages and fibrovascular PED. Further studies investigating this specifically would be helpful to see if this observation is confirmed.
In addition, we had the opportunity to compare the different responses to aflibercept and faricimab in different eyes of the same patient (89 y.o. female) (Case 4), who was treated every month for three months. The faricimab-treated eye had a better response to treatment rather than the fellow eye with aflibercept in terms of BCVA, IRF and CRT. The advantage of intravitreal faricimab injection compared to other could be the greater affinity for VEGF-A in combination with the possibility of neutralizing Ang2, both of which have been implicated in angiogenesis (11, 25, 37–39).
As described in the TRUCKEE study, we also observed promising outcomes for visual acuity, safety, and central macular thickness in both naïve and previously treated patients after faricimab injections. In addition, faricimab was well tolerated in all eyes (11 eyes). Only mild eye irritation or ocular discomfort were reported and were presumed due to the pre-procedural use of iodine to sterilise the conjunctiva. No intraocular inflammation, retinal vasculitis or occlusive retinitis were observed.
There are several limitations to the study due to its retrospective nature, very small sample size and short follow-up. Moreover, we only had three treatment naïve eyes, while most eyes were previously treated with other anti-VEGF injections such as aflibercept or ranibizumab.
Further studies with larger patient numbers, and longer follow-up periods are needed to assess the efficacy of faricimab in nAMD and to help determine the need for loading doses in this patient group.
Although our results cannot be directly extrapolated to treatment naïve patients, our initial results are comparable and at times better than observed in clinical trials (CTs).
Given previous safety concerns with already approved drugs for the intravitreal treatment of nAMD following the successful and within acceptable safety-margins completion of clinical trials, we believe it is important for clinicians to start sharing as soon as possible independent real-world outcomes.
To the best of our knowledge, this is the first report of independent real-world outcomes looking at efficacy and safety using faricimab in nAMD.