To our knowledge, the LUMINOUS subgroup analysis represents the first long-term study in Korean patients with nAMD assessing the real-world effectiveness and safety of ranibizumab 0.5 mg. The study findings demonstrated that ranibizumab 0.5 mg resulted in improved VA and CRT outcomes at the end of Year 2 in treatment-naïve patients. Also, by Year 1, patients who were treatment-naïve, those with worse baseline VA, and those who received loading dose achieved better VA outcome. In patients with PCV, better VA and CRT improvements were observed at the end of Year 1. Multivariate logistic regression analyses confirmed that younger age, worse baseline VA and those receiving a loading dose were associated with higher odds of having any gain in VA by Year 1. Overall, ranibizumab 0.5 mg was
well-tolerated with no new safety findings in the real-world setting, consistent with the findings of global LUMINOUS nAMD populations.
In the current study, 43.3% and 72.2% of patients discontinued by Years 1 and 2, respectively, with loss to follow-up and patient switching to another anti-VEGF being the main reasons for study discontinuation. This highlights poor compliance of patients returning to the clinic for follow-up, likely due to high treatment burden (12) or patient relocation and transfer to another healthcare facility. The high discontinuation rate was expected, and was aligned with real-world trends in Korea, that have also been reported in other real-world studies (13,14). In the current study, 28.9% of patients switched to
anti-VEGFs other than ranibizumab, and the majority were prior-treated. The 2019 Preferences and Trends Survey showed that 68.4% of Asia Pacific physicians would switch to another anti-VEGF when patients do not respond adequately to first-line anti-VEGF therapy (15). This switching is to potentially improve outcomes in patients who do not respond adequately to initial treatment, assuming potential differences in the molecular structure and biochemical properties of anti-VEGFs, and thus effect (16). In addition, when the LUMINOUS global study was conducted, the national health insurance system in Korea had set reimbursement limitations for ranibizumab injection. Thus, patients that required additional anti-VEGF treatment over and above the reimbursement limit might have switched to a more cost effective option, such as bevacizumab (off-label use) (10).
The proportion of male patients (67.3%) in the current study was consistent with the Korean
post-marketing surveillance (PMS) study which consisted of 62.5% of male patients with nAMD (10), and the nationwide population-based study which showed that prevalence of nAMD in Korea was higher in males in all age groups (3). Similarly, a real-world study in Japan showed a higher proportion of male patients with nAMD who were treated with anti-VEGFs (17). After comparing baseline characteristics of treatment-naïve patients in the Korean and global populations of the LUMINOUS study, it was observed that the former had a slightly lower baseline VA (43.1 letters vs 49.7 letters), higher baseline mean CRT values (400.3 µm vs 365.7 µm), a higher proportion of minimally classic/occult CNV lesion type (75.0% vs 55.4%), PED (69.7% vs 42.7%), and PCV (31.6% vs 9.2%) (11). In the current study, PCV was diagnosed in 28.6% of Korean patients with nAMD regardless of pre-treatment status. This observation is aligned with the finding that PCV prevalence was observed to be higher in the Asian population; PCV is shown to occur in approximately 22–55% of Asian and 4–14% of Caucasian patients with nAMD (18).
Both VA gain and reduction in CRT were most prominent at 3 months post-treatment in Korean patients, and this improvement was maintained up to 24 months. Both VA gain and CRT improvements were better in treatment-naïve patients compared with prior-treated patients. This result is consistent with findings from Levy et al (2009) (19), and the Korean PMS study (10), which demonstrated that prior-treated patients generally do not show as much response to anti-VEGFs as treatment-naïve patients.
Prior-treated patients had relatively better baseline VA and CRT, which would have likely benefitted from previous anti-VEGF treatment. Even though the VA gain and CRT reduction were better in treatment-naïve patients, both groups had comparable VA (61.6 vs 57.4 letters) and CRT (272.4 vs 292.0 µm) values at Year 1. The result was consistent with findings that ranibizumab 0.5 mg stabilises vision in nAMD patients with relatively good baseline VA (20,21). At Year 2, the greater VA gain of treatment-naïve patients than that of prior-treated patients was not maintained, which is likely due to large variations in VA between the low number of patients who remained in the study in both groups, and may not reflect the actual trend.
In Korean patients with VA assessed at Year 1, treatment-naïve patients received a higher number of injections (5.2) and recorded monitoring visits (9.2) by Year 1 compared with prior-treated patients
(3.4 injections, 6.8 visits). Compared with the global LUMINOUS treatment-naïve population, the Korean treatment-naïve patients reported comparable injection numbers (5.2 vs 5.0) and monitoring visits (9.2 vs 8.8), (11) yet with a relatively better VA outcome (VA gain of 10.1 vs 3.1 letters). The VA gain observed in prior-treated patients was consistent with that of the global population, whereby patients treated with ranibizumab maintained their vision at Year 1 (11,22). The better visual outcomes in treatment-naïve Korean patients compared with the treatment-naïve global population might also be attributed to a relatively younger age (72.2 vs 75.0 years), a worse baseline VA (43.1 vs 49.7 letters), and a shorter time from diagnosis to first treatment (4 days vs 12 days) (11,22). The VA gain reported in treatment-naïve patients in this subgroup analysis was comparable to those reported in the pivotal MARINA and ANCHOR studies (7.2 letters in MARINA (23) and 11.3 letters in ANCHOR (24)), but relatively higher than randomised controlled trials conducted in Korea and other real-world studies. Kim et al. (2016) demonstrated that treatment-naïve Korean patients with nAMD treated with a mean of 4.5 injections showed significant BCVA improvement (0.14 logMAR, P = 0.017) and CRT reduction (139.3 µm, P < 0.001) from baseline to Year 1 (7). In the REAL study conducted in Taiwanese patients with nAMD, the mean number of ranibizumab injections was 3.2, and the VA gain at 1 year was only 1.1 letters (25). The AURA study reported comparable injection numbers in Year 1 (5 injections) with VA gain of 2.4 letters (26). Similarly, the LUMIERE study reported a lower VA gain (3.2 letters) with a comparable number of injections (5.1) in Year 1 versus the current study (20). The UNCOVER study reported 4.2 injections and 7 visits per year with VA reduction of 0.7 letters in Year 1 (27). However, most of the pivotal trials and real-world studies did not stratify the results based on prior-treatment status. CRT reduction in treatment-naïve patients in this study (160.6 µm) was also better than other real-world studies of ranibizumab (51.5 µm in Providência et al, 2018) (28).
The median time from diagnosis to treatment in treatment-naïve patients in this subgroup analysis was relatively short (4 days) compared with the global LUMINOUS population (12 days) (11). Korean patients can easily visit retina clinics without referral from primary physicians, and the short distance from home to clinics or hospitals in Korea might enable early detection and timely treatment of nAMD patients. It has been established that delay from symptoms to anti-VEGF treatment is associated with reduced VA outcome (29). Timely initiation of anti-VEGF treatment might also explain the favourable visual outcome in the Korean nAMD population in the current study compared with the LUMINOUS global population, as well as other real-world studies.
Stratified by different baseline characteristics and treatment categories, it was demonstrated that in both treatment-naïve and prior-treated patients, those with worse baseline vision (< 23 letters and 23–<39 letters), those who received the loading-dose, and those with PCV achieved higher VA gain by Year 1. Although VA improvement at Year 1 was notably higher in treatment-naïve compared with prior-treated patients, univariate logistic regression analyses did not support the association of pre-treatment status to any gain of VA, but showed that treatment-naïve patients have higher odds of achieving a VA gain of ≥ 5 letters by Year 1. However, multivariate logistic regression analysis showed that only patients with younger age, worse baseline VA, and those who received a loading dose were associated with higher odds of any gain in VA by Year 1, while only patients with worse baseline VA was associated with VA gain of ≥ 5 letters in Year 1.
Younger age as a prediction factor for better response to ranibizumab treatment is in-line with the Korean PMS study (10) and several post hoc analyses of pivotal trials and studies assessing predictors of response to ranibizumab (30–35). Findings from the current study also strengthen the observation regarding baseline VA being an important factor in predicting visual outcome, consistent with the Korean PMS study, (10) the study by Pedrosa et al. (2016) (36), the LUMIERE study (20), and the global LUMINOUS study (11,22). These findings could be explained by the “ceiling effect” whereby patients with higher baseline VA have limited potential to gain more letters, while those with lower baseline VA have little possibility for further loss of vision. However, patients with higher baseline VA had relatively higher mean VA by the end of Year 1; i.e. the VA at Year 1 were highest in patients with baseline VA of ≥ 74 letters in both treatment-naïve and prior-treated patients. The result indicated that even though eyes with poor VA responded well to treatment, they did not catch up to eyes with better baseline VA.
Additionally, Korean patients who received the loading dose showed better VA improvement compared with those who did not, which is consistent with the BeMOc study (21), the real-world LUMIERE study (20), and the global LUMINOUS study (11). It should also be noted that in both
treatment-naïve and prior-treated groups, patients who received a loading dose had worse baseline VA compared with patients who did not. However, multivariate analyses adjusted for age and baseline VA confirmed that receiving a loading dose is associated with any gain in VA in Year 1. Findings from LUMINOUS highlighted the importance of the loading dose for VA improvements. This was not aligned with findings from the ARTIS study which showed that ranibizumab treatment regimens with 1 and 3 initial injections followed by a pro re nata regimen are equally effective in improving VA (37).
Treatment-naïve Korean patients with PCV showed a VA gain of 16.7 letters by Year 1, which is notably higher than patients without PCV (6.7 letters). Treatment-naïve patients with PCV also reported a greater reduction in CRT (–160.6 µm) compared with non-PCV patients (–99.0 µm). The findings were in line with those from the global LUMINOUS treatment-naïve population with PCV (38). VA gain and CRT reduction in the Korean treatment-naïve patients with PCV (16.7 letters and 160.6 µm) was better than the global treatment-naïve population with PCV (5.0 letters and 91.3 µm) (38). The better visual outcome in treatment-naïve Korean patients with PCV compared with the treatment-naïve global population with PCV might be due to a relatively younger age (68.4 vs 72.8 years) and a worse baseline VA (49.0 vs 53.8 letters) (38). However, due to a small sample size and large variance in the current subgroup analyses, no statistically significant difference was noted in the differences in changes in VA and CRT between treatment-naïve PCV and non-PCV patients (P > 0.05). Nonetheless, when VA and CRT were compared between patients with and without PCV in the overall group including both treatment-naïve and prior-treated patients, the differences in mean change was statistically significant for both VA (P = 0.0388) and CRT (P = 0.0293) at Year 1. In this subgroup analyses, PCV patients were relatively younger compared with patients without PCV (treatment-naïve: 68.4 vs 73.9 years, P = 0.0514; prior-treated: 68.7 vs 71.8 years; P = 0.8609); this is in line with previous studies that showed PCV tends to present in younger Asian patients compared with typical CNV (39–41). In fact, univariate and multivariate logistic regression analysis did not support an association of having PCV with any VA gain or gain of ≥ 5 letters at Year 1. The age difference between the PCV and non-PCV patients in this subgroup analyses might have driven the differences in the outcome at Year 1. It should be noted that fibrosis or haemorrhage in patients with PCV are usually observed with long-term follow-up, and might not be reflected over 1 year; thus it remained indefinite if the improved VA gain in PCV patients might be maintained beyond 1 year (42).
In both treatment-naive and prior-treated Korean patients with nAMD in this subgroup analyses, the frequency of ocular and non-ocular AEs over 1 and 5 years was low, and were consistent with the well-established safety profile of ranibizumab with no new safety findings identified (10,23,24). Ocular AEs related to ranibizumab treatment and/or ocular injection were rare. There was no significant difference in the rate of ocular and systemic AEs between the treatment-naive and prior-treated patients.
The current study had various limitations. The high discontinuation rate only allowed the treatment effectiveness to be meaningfully analysed up to 2 years. Being a real-life study, there was no comparator arm. There could be treatment bias due to patient’s access to treatment, physicians’ treatment decisions based on clinical judgement, local healthcare systems, and reimbursement policies, which limit interpretation of data to some extent. Besides, there were no strict criteria for disease diagnosis at the time of patient enrolment; hence, results may vary between study sites. Most of the limitations described are common to any real-world evidence study which collect real-world clinical practice data. The low number of patients with PCV also limits confirmation on the effect of ranibizumab in treatment-naïve Korean patients with nAMD and PCV, and requires to be validated in a prospective study with larger sample size and longer follow-up period.