According to the Vision Academy Steering Committee, an ideal treatment with anti-VEGF drugs should comply with the following characteristic: maximize and maintain visual acuity benefits for all patients; allow to decide when to treat next, rather than whether to treat now; allow to titrate the treatment intervals to match patient’s needs; allow treatment at each monitoring visit [20].
Advantages in VA results and treatment burden derived from the treat and extend (T&E) protocol in comparison with pro re nata (PRN) [21]. However, physicians and clinical services face every day a high volume of patients, thus their unmet need is the optimization of functional and anatomic results with a lower number of visits and injections, looking for a more efficacious molecule and regimen of treatment.
As of today, the scientific community agrees that the resolution of retinal fluid and anatomic response is the key point for functional recovery. A growing number of clinical experiences and reports show that eyes that reach a dry retina early perform better in a medium-long follow-up period and need a lower number of intravitreal injections [14, 16–17, 22].
Therefore, the fluid-free interval between two drug injections becomes crucial for choosing a treatment as a definition of stability assessment [23].
Brolucizumab is the newest anti-VEGF drug commercially available. Its use was approved in Europe at the beginning of 2020, and it has become available in Italy in December 2020.
Its strength in fluid resolution and its optimal performance in stability assessment that were shown in the registrative trials [15, 23–24] are now under evaluation in a real-world setting.
The present study evaluated the early resolution of clinical activity in naïve wet AMD, assessed by the changes of OCT parameters, after the induction protocol of three consecutive monthly IVT-B and evaluation at w16.
In 28 enrolled naïve eyes, at w16, CTR and CRV reduced significantly, and SRF, IRF, PED, and HRSM almost disappeared in most cases. A statistically significant reduction of CTR and CRV was present at W4, W8, and W12, and, interestingly, the cohort showed early resolution of biomarkers (SRF, IRF, PED, and SHRM) at w4 in 81–92% of the eyes after only one IVT-B. At w16 SRF and IRF showed a slight increase, as effect of reactivation, confirming their role as main biomarkers of clinical activity [13–14].
The effect of therapy on the VA was observed as stability and improvement that accounted for 93% of the eyes, VA change being statistically increased however only at w16.
In accordance with the procedure followed when other anti-VEGF drugs had become commercially available, also in the case of Brolucizumab the first published clinical experiences were conducted on refractive or poor-responder cases [6–8].
A few publications focused on the effect of Brolucizumab on naïve patients with nAMD, but usually they were mixed in with patients who had already undergone treatments with other drugs.
Four naive eyes were treated in a retrospective case series in a tertiary clinical setting by Montesel et al. with an induction dose of 3 IVT-B and at least 4w of follow-up after the last IVT-B: the authors observed the improvement of BCVA, CMT, and retinal fluids but no detailed temporal data and no clinical results of the cohort of naïve eyes were reported due to the small sample size [25]. A similar clinical set and results can be found in the report from Enríquez AB et al. [26].
The BRAILLE study [27] was conducted retrospectively in India and included 94 eyes, 20 of which naïve (21.3%), with a mean follow-up of 7.3 ± 2.2 (range 5–30) weeks after the first injection. In the naïve subgroup, the BCVA improved but not in a statistically significant way, while the central retina statistically thinned from baseline (398.53 ± 61.38 µm) to the final visit (285.16 ± 15.14 µm; p < 0.0001). No regular protocol treatment was observed, and no data about response timing is available.
The REBA study is a real-world observational, retrospective, multicentre study (Germany-India) evaluating Brolucizumab in wet AMD. Out of 105 included eyes, 25 were naïve (26%), with a mean follow-up period of 10.4 ± 1.5 months (minimum 9): patients were treated with induction of 3 IVT-B followed by a q8w or q12w assessment. Both VA and CRT improved (p 0.01 and p 0.02, respectively); dry retina was observed in 76% of the eyes after induction, and 68% had been scheduled in a q12w protocol at the end of the follow-up [28].
Due to differences in the study design, a comparison with our results is only possible in a very generic manner. None of them adopted a well-defined protocol and/or evaluated the fluid-free condition according to a temporal strategy.
The PROBE study is an observational, retrospective, multicentre study conducted in India and its results were not comparable with ours either. The study evaluated a PRN regimen in 27 treatment-naïve eyes, with a mean follow-up of 11.2 ± 1.2 months. One mandatory injection of Brolucizumab was planned in the study, and subsequent treatment was performed only if retinal fluids were present at least eight weeks after the first injection, even if fluids were present at four weeks. No loading induction was therefore planned. Dry retina was reported in 25.9% of the eyes after 1 IVT-B, 48% after 2 IVT-B, and 26% after ≥ 3 IVT-B [29].
Rubsam et al. [30] recently published a prospective study on 10 naïve eyes affected by nAMD, assessed at w16 and w20 after a monthly loading induction of three injections. In their experience, 80% of the eyes showed fluid-free retina at w16, thinning of the CRT, and increasing in VA, like in the present work. At the end of the period of induction at w16, 80% of the studied eyes were enrolled in a w12 regimen, in agreement with the HAWK and HARRIER studies. Detailed data about the type of fluid and activity biomarkers were reported with results comparable to our experience.
The main limitations of our study are its small cohort and the inclusion of every MNV subtype except for polypoidal vasculopathy. This latter subtype of MNV is often treated with photodynamic therapy with Verteporfin associated with intravitreal antiVEGF drugs and the effectiveness of monotherapy with antiVEGF drugs is still under investigation [31]. Moreover, two devices were used for the study (SSOCT Triton and SDOCT Optovue), but this condition is present in most multicentred trials as well as in real-life experiences. Comparing B-scan evaluation between SD and SS-OCT showed different opinions either in agreement or in disagreement [32] but our study examined the eyes longitudinally with the same devices and did not propose any comparison between the results.
The main strength of our study is its real-world setting, the purity of the cohort, and the prospective design, with a detailed analysis of the temporal trend of the response strictly related to the therapeutic choice. Currently, no such data are available except for the post-hoc analysis of the HAWK and HARRIER studies. This analysis showed that, regardless of which antiVEGF drug was administered, the cohort of eyes with fluid-free retina at w12 had a better chance of improving vision and central subfoveal thickness at the 2-year follow-up, compared to the cohort with residual retinal fluid at the w12 evaluation [5].
This report strongly associated the effectiveness of the three-monthly induction treatment to a quick resolution of fluids in nAMD patients treated with Brolucizumab: fluid-free retina was achieved early (at w4) and maintained, which made it possible to consider the extension of treatment interval to q8w or q12w. Therefore, when treating nAMD, the stability assessment becomes a primary interest [23]. Setting such a goal when treating nAMD, is important because it opens up a better chance of achieving and maintaining long-term improvement in visual acuity [22, 33]. In addition, early fluid resolution and its maintenance can reduce the fluid fluctuations that are responsible for the development of fibrosis and atrophy, causes of long-term impairment in AV [17].
Finally, this different approach can also be evaluated in economic terms to guide therapeutic choices [34]: a longer fluid-free interval and a lower number of visits and treatments result in saving resources that can be allocated to a larger cohort of patients to be treated or to the implementation of services for early diagnostic.
Although our study was not designed to determine the incidence of intraocular inflammation, intraocular inflammation was not observed during the follow-up time.