AQUILA is one of the first observational, real-world studies of anti-VEGF agents in Latin America, and the first to assess the use of IVT-AFL in routine clinical practice in Latin America. Patients with nAMD who received IVT-AFL at the direction of the treating physician had improved functional and anatomic outcomes after 12 months of treatment, regardless of previous treatment status. Improvements in BCVA were numerically greater at 12 months in treatment-naïve patients (+ 5.2 letters) than in previously treated patients (+ 3.1 letters). CRT decreased from baseline to month 12 by 107 μm in treatment-naïve patients and by 81 μm in previously treated patients. Despite many patients in AQUILA not receiving the label-recommended number of injections, visual outcomes still showed improvement following 12 months of treatment, although not to the extent observed in randomized controlled trials. Patients who received three or more initial monthly injections had numerically greater improvements in BCVA than those who received fewer than three initial monthly injections. No new safety concerns were observed.
VIEW 1 and VIEW 2 were two similarly designed, global, phase 3 studies of IVT-AFL in treatment-naïve patients with nAMD . VIEW 1/2 were designed to assess IVT-AFL treatment noninferiority to ranibizumab; patients received IVT-AFL treatment for 12 months in one of three fixed dosing regimens (2q4, 0.5q4, and 2q8 [after three initial monthly injections]) or they received 0.5 mg ranibizumab monthly). Patients receiving anti-VEGF treatment according to their regimen achieved similar gains in BCVA (+ 9.3, + 8.3, + 8.4, and + 8.7 letters in patients receiving 2q4, 0.5q4, 2q8, and ranibizumab, respectively) by month 12. Patients in AQUILA, treated outside of the strictly controlled clinical trial environment, received fewer injections than patients in VIEW 1 and VIEW 2 (4.4 ± 2.2 injections by month 12 overall). Visual gains were clinically relevant, though lower than those achieved in VIEW 1 and 2. The AQUILA visual outcomes were consistent with previous observational studies of IVT-AFL (and indeed other anti-VEGF agents) treatment in routine clinical practice and have highlighted the disparity between label-recommended number of doses in clinical trials, and number of doses received during routine clinical practice [7,8,9].
LUMINOUS was a global, prospective, observational study of ranibizumab in patients with nAMD (and also for patients with DME or retinal vein occlusion), providing real-world evidence of the effectiveness of anti-VEGF treatment for nAMD [10, 11]. LUMINOUS enrolled treatment-naïve (n = 6241) and previously treated (n = 16 167) patients globally (including from Argentina, Colombia, Costa Rica, and Mexico [10, 11]). Baseline BCVA was 49.7 letters in LUMINOUS treatment-naïve patients compared with 48.2 letters in AQUILA treatment-naïve patients, and 58.3 letters in LUMINOUS previously treated patients compared with 47.7 in patients who previously received IVT-AFL in AQUILA [10, 11]. The baseline BCVA of previously treated patients in AQUILA is low when compared with other observational anti-VEGF studies including a previously treated patient arm [7, 11]. In AQUILA, the median time between diagnosis and first injection of IVT-AFL was 1.2 months in treatment-naïve patients, compared to 19.5 months in patients who received previous treatment; taken together, this may indicate a lack of efficacy of patient’s previous therapy (therefore their physician switched the patient’s therapy to IVT-AFL, allowing the patient to enroll in AQUILA; Additional file 1: Table S1), and therefore a comparably low baseline BCVA. Treatment-naïve patients (n = 3379) gained + 3.1 letters with an average of 5.0 ranibizumab injections up to month 12 of LUMINOUS . Despite treatment-naïve patients in AQUILA receiving fewer IVT-AFL injections (4.2 injections over 12 months), gains in BCVA were numerically higher (+ 5.2 letters). Patients who previously received therapy for nAMD in LUMINOUS lost an average of 1.6 letters after 1 year of ranibizumab treatment; LUMINOUS patients who received more frequent injections over 12 months had more positive visual outcomes. In comparison, previously treated patients in AQUILA gained 3.1 letters after 12 months of IVT-AFL treatment. However, previously treated patients in AQUILA had a lower mean BCVA at baseline than patients in LUMINOUS, and patients in AQUILA received a numerically higher number of injections than those enrolled in LUMINOUS (5.2 in AQUILA vs 4.7 in LUMINOUS) .
The Pan-American Collaborative Retina Study Group (PACORES) investigated 1-year outcomes following bevacizumab treatment for primary choroidal neovascularization secondary to nAMD in 60 patient eyes . The number of injections received by patients in the trial was fewer than in those enrolled in AQUILA, with similar visual outcomes. Despite most patients in AQUILA not receiving the label-prescribed number of injections, many patients achieved improvements in both functional and anatomic outcomes, although not of the magnitude reported in prior clinical trials . This suggests that if patients received the label-prescribed number of injections during AQUILA, they may have achieved larger gains in visual outcomes. This is consistent with data from longer-term studies suggesting that more frequent injections during the first year of treatment result in higher gains in VA .
In AQUILA, > 60% of patients with nAMD received three or more initial monthly doses of IVT-AFL, but < 20% received seven or more injections in the first year of treatment. Despite the intention to treat according to the label, many patients were treated reactively over the course of AQUILA. The decision to treat reactively may be linked to issues of treatment reimbursement. Treatment reimbursement in Latin America varies by country. In Argentina, anti-VEGF reimbursement depends on the payer, and patients pay for the treatment that they can afford. In Colombia, treatment costs are covered by self-paid insurance. Costa Rica’s national health care system is funded by taxpayers through employment taxes, with contributions from both the payer and employer; however, bevacizumab is the only anti-VEGF agent available via the national health care system. Patients from Costa Rica and Mexico who enrolled in AQUILA paid out of pocket for their treatment; these costs were reimbursed if patients had private health insurance. Indeed, the AQUILA data should be taken in context with treatment availability as dictated by the different Latin American health care systems. As over 70% of patients in the nAMD cohort of AQUILA come from Argentina, the Argentinian health care system largely influences the treatment pattern data in this study.
The safety profile of IVT-AFL was consistent with that of previous clinical and observational studies [4, 7, 14, 15]. No incidences of endophthalmitis were reported.
Reliance on BCVA as the key efficacy parameter is one limitation of this study; furthermore the data in this study may not give the full picture of treatment patterns and the landscape within Latin America, as it does not include Brazil, the country with the largest population in this region. A large proportion of CRT and fluid data are missing at month 12; this could be due to country-specific reimbursement for OCT testing, limiting the number of patients willing to pay for the examination, or due to availability of fluid measurement equipment. Furthermore, the BCVA results observed for patients with a certain number of IVT-AFL injections, and those without, were determined post-baseline and post hoc, and any interpretation must therefore consider their relation as associative, rather than causative.