"Brolucizumab - alterative for neovascular Age-related macular degeneration?", SHIFT study aswers
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in industrialised countries. With the advent of anti-vascular endothelial growth factor (VEGF) therapy, the visual outcome of patients with neovascular AMD (nAMD) has improved and measurable reductions of legal blindness is witnessed.
A study by Bulirsch LM reports on early experiences with real-world outcomes of switch to brolucizumab therapy in previously antivascular endothelial growth factor (anti-VEGF)-treated patients [SHIFT STUDY] as published in BMJ case reports.
"Burden for both patients and caregivers is high when managing patients with repetitive intravitreal injections and monitoring visits over a long period of time in a chronic disease. Various real-world studies have shown visual outcomes to be inferior compared with the results from prospective randomised clinical trials (RCTs)."
Brolucizumab (Novartis), a single-chain antibody fragment, was recently approved for the treatment of nAMD. Potential benefits of brolucizumab are assumed to be related to its low molecular weight with subsequent better tissue penetration as well as higher molar concentration.
Two pivotal trials have recently shown non-inferiority of brolucizumab to the comparator aflibercept with regard to visual outcome. The SHIFT study is a retrospective, observational, monocentre study of patients with exudative AMD who received 6mg brolucizumab intravitreal therapy between 16 March 2020 and 15 October 2020, at the Department of Ophthalmology, University of Bonn, Germany, in routine clinical care.
All patients were previously treated repetitively because of recalcitrant fluid accumulations on optical coherence tomography (OCT) despite frequent dosing with other anti-VEGF agents, including ranibizumab, aflibercept and bevacizumab. Recalcitrant fluid was defined as persistent fluid accumulations despite a high frequency of intravitreal injections of other anti-VEGF agents over a longer period of time prior to the switch to brolucizumab.
The day of the first intravitreal brolucizumab injection was regarded as the baseline visit. Morphological effects were quantified to assess structural efficacy of brolucizumab.
Three parameters were determined:
- Foveal centre point (FCP), defined as the distance (µm) between the internal limiting membrane (ILM) and Bruch's membrane (BM);
- Central subfield retinal thickness (CSRT), defined as the mean retinal thickness (µm) between ILM and BM of the circular area within 1mm diameter around the centre of the fovea;
- Macular volume, defined as the mean volume of the retina in a circular area within 3mm diameter around the fovea.
BCVA was measured in decimals and for the purpose of this analysis converted to the logarithm of the minimum angle of resolution (logMAR).
Sixty-three eyes of 57 patients with nAMD (52.6% females) with a mean (±SD) age of 79.5±6.7 years were included. Mean change of BCVA was −0.02±0.13 logMAR (p=0.322). Significant reductions were recorded for FCP with a mean (±SD) change of −66.79±72.64 µm, −66.76±60.71 µm for CSRT and −0.27±0.24mm³ for macular volume (all p <0.001). Intraocular inflammation was observed in seven eyes of seven patients, including one case of retinal vasculitis without occlusion.
A significant reduction on average of retinal thickness parameters, including FCP, CSRT and macular volume, was observed demonstrating a favourable response on morphological signs for disease activity.
When interpreting the functional outcome in this study, it is to be considered that the SHIFT cohort comprises previously treated patients only, with up to 126 previous intravitreal anti-VEGF injections.
This might not only impact the BCVA before initial injection of brolucizumab but may also explain the lack of BCVA improvement despite significant change in structurally defined efficacy outcome parameters. This phenomenon has been observed before in other switch studies.
"Given the longstanding ocular history of exudative AMD in our cohort, underlying structural, in part irreversible damage may contribute to a limited potential of visual recovery. The phenomenon of disconnect between morphology and function has been observed in other switch studies of patients with nAMD."
Since the approval of brolucizumab, safety signals of development of IOI following brolucizumab treatment, ranging from anterior chamber cells to retinal vasculitis with or without occlusion and with or without moderate and severe visual loss, have been reported.
The pathogenesis of the inflammatory events is not yet understood and needs further investigations which are ongoing. In the pivotal phase-III HAWK and HARRIER studies of treatment-naïve nAMD patients, an overall rate of 4.6% of any IOI was reported following a review by a safety review committee (SRC). The rate of the development of retinal vasculitis was reported to be 3.3% and that of concomitant retinal vasculitis and retinal vascular occlusion was 2.1% .The overall incidence of at least moderate vision loss due to IOI was <1%.
Various limitations need to be considered for this study. This is an observational study in a relatively small cohort of 57 patients. An important limitation of study was the short review period post switch to brolucizumab of 1 month. In this real-world study, a treat & extend scheme was applied immediately after the first injection and three fixed 4-weekly injections post switch to brolucizumab were not performed as proposed in other switch studies. Therefore, in this relatively small cohort, data analyses beyond 1 month would be based on a variable number of injections after switch and would not allow a meaningful analysis and comparison between patients.
In summary, the SHIFT study reports real-world early experiences outside RCTs with brolucizumab in previously anti-VEGF treated patients with nAMD. A beneficial morphological effect was recorded pointing towards a strong antihyperpermeability effect of this agent. Safety issues with regard to IOI remain a concern and require further investigations with regard to the underlying mechanisms as well as risk mitigation measures.
Source: Bulirsch LM, Saßmannshausen M, Nadal J, et al. Br J Ophthalmol