Real-World Safety Outcomes with Brolucizumab in Neovascular Age-Related Macular Degeneration: Findings from the IRIS® Registry.

INTRODUCTION: To assess real-world safety outcomes for adults with neovascular age-related macular degeneration (nAMD) treated with brolucizumab from the US-based IRIS® (Intelligent Research in Sight) Registry. METHODS: In this retrospective study, 18,312 eyes (15,998 patients) treated with ≥ 1 intravitreal brolucizumab injections between 8 October 2019 (US launch date for brolucizumab) and 7 October 2021 were followed up for ≤ 2 years after first injection (index date). The study assessed the predefined incident ocular adverse events of intraocular inflammation (IOI), retinal vasculitis (RV), and retinal vascular occlusion (RO). RESULTS: Overall, 614/18,312 eyes (3.4%) experienced any IOI, RV, and/or RO event. Median (interquartile range [IQR]) time to an event was 84 (42-167) days; 77.4% of events (475/614) occurred within 6 months after index date. Median (IQR) number of brolucizumab injections before an event was 2 (1-4). For eyes with an adverse event and visual acuity (VA) data (n = 406), median (IQR) change in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters from pre-event VA was 0 (- 7 to + 5) at the 6-month follow-up; 50 eyes (12.3%) had a VA loss of 10 or more ETDRS letters. Risk of an event (hazard ratio [95% confidence interval]) was decreased in eyes from male patients (0.61 [0.53-0.71]), from older patients (0.83 [0.76-0.90]), from treatment-naive patients (0.51 [0.38-0.69]), and from patients who started brolucizumab in the second year after launch (0.68 [0.53-0.86] vs. first year). CONCLUSION: In this large real-world brolucizumab safety study, 3.4% of eyes experienced an IOI, RV, and/or RO event. Among eyes that experienced an adverse event for which VA data were available, median ETDRS vision change was 0 letters (IQR - 7 to + 5).

Exploring the role of retinal fluid as a biomarker for the management of diabetic macular oedema.

Anti-VEGF therapies are associated with significant gains in visual acuity and fluid resolution in the treatment of diabetic macular oedema (DMO) and have become the standard of care. However, despite their efficacy, outcomes can be unpredictable, vary widely between individual eyes, and a large proportion of patients have persistent fluid following initial treatment, with a negative impact on visual outcomes. Anatomical parameters measured by optical coherence tomography (OCT), in addition to visual acuity, are key to monitoring treatment effectiveness and guiding retreatment decisions; however, existing guidelines on the management of DMO lack clear recommendations for interpretation of OCT parameters, or proposed thresholds of various markers to guide retreatment decisions. Although central subfield thickness (CSFT) has been widely used as a marker for retreatment decisions in clinical trials in DMO, and a reduction in CSFT has generally been shown to accompany improvements in best-corrected visual acuity with treatment, analyses of the relationship between these parameters show that the correlation is small to moderate. A more direct relationship can be seen between an increased magnitude of CSFT fluctuations over time and poorer visual acuity, suggesting that control of CSFT could be important in maximising visual outcomes. The relationship between visual outcomes and qualitatively assessed intraretinal fluid and subretinal fluid is also unclear, although quantitative assessments of fluid parameters suggest that untreated intraretinal fluid and subretinal fluid negatively impact visual outcomes. These findings highlight a need for clearer guidelines on the management of retinal fluid to improve visual outcomes for patients with DMO.

Potential for Treatment Interval Extension in Eyes with nAMD Disease Activity Post Loading Phase in HAWK and HARRIER.

INTRODUCTION: The HAWK and HARRIER studies evaluated the efficacy and safety of brolucizumab versus aflibercept in treatment-naïve eyes with neovascular age-related macular degeneration. Based on the study design, brolucizumab-treated eyes adjusted to a q8w regimen because the presence of disease activity (DA) at the end of the matched loading phase (Week 16) could not subsequently extend to a q12w interval. The aim of this post hoc analysis was to assess subsequent DA in this subgroup to determine the potential for interval extensions during the first year of treatment. METHODS: Pooled data from the brolucizumab 6 mg arms and aflibercept arms of HAWK and HARRIER were included. Presence of DA was determined by the masked investigator based on their assessment of functional and anatomical parameters measured by optical coherence tomography. DA was compared at DA assessments, conducted at Weeks 16, 20, 32, and 44; fluid was also assessed at the primary analysis at Week 48. RESULTS: Fewer brolucizumab- (22.8%) than aflibercept-treated (32.2%) eyes had DA at the first DA assessment at Week 16. In eyes with investigator-identified DA at Week 16, BCVA change from baseline to Week 96 was comparable between treatment arms. Fewer brolucizumab- than aflibercept-treated eyes had DA at each subsequent DA assessment in Year 1: 31.8% vs 39.1% (Week 20), 27.3% vs 43.5% (Week 32), and 17.3% vs 31.2% (Week 44). Fewer eyes treated with brolucizumab than aflibercept had intraretinal and/or subretinal fluid: 35.3% vs 43.5% (Week 20), 55.8% vs 69.6% (Week 32), 30.0% vs 43.1% (Week 44), and 48.6% vs 68.6% (Week 48). CONCLUSION: These findings indicate that, in eyes that still had DA 8 weeks after the final dose of loading phase, brolucizumab-treated eyes had improved fluid resolution and higher potential for treatment interval extension than aflibercept-treated eyes during the first year of treatment.

One-Year Brolucizumab Outcomes in Neovascular Age-Related Macular Degeneration from a Large United States Cohort in the IRIS® Registry.

PURPOSE: To evaluate visual acuity (VA) and injection intervals in patients with neovascular age-related macular degeneration (nAMD) after 12 months of brolucizumab therapy in clinical practice. DESIGN: Retrospective cohort study. PARTICIPANTS: Adults in the United States-based IRIS® Registry (Intelligent Research in Sight) with nAMD who received brolucizumab exclusively for 12 months (2308 eyes of 2079 patients). METHODS: Observational study of eyes with a first injection of brolucizumab (index), followed by 2 or more brolucizumab injections over the following 12 months without switching to another anti-vascular endothelial growth factor (VEGF) agent. MAIN OUTCOME MEASURES: Primary outcomes were change in best recorded VA and, for eyes receiving prior anti-VEGF therapy (treatment-experienced eyes), the difference between the brolucizumab injection interval at 12 months and the anti-VEGF injection interval before switching. The interval before switching was defined as the time between the prior anti-VEGF and index brolucizumab injections; brolucizumab interval was the time between the closest injection to day 365 and the preceding injection. Secondary outcomes included incident adverse events. RESULTS: Overall VA at index was 61.6 ± 18.4 Early Treatment Diabetic Retinopathy Study letters; 83.7% of treatment-naive eyes (184/220) and 86.1% of treatment-experienced eyes (1797/2088) showed stable (< 10 letters gained or lost) or improved (≥ 10 letters gained) VA at 12 months. Among treatment-experienced eyes receiving a prior anti-VEGF injection within 365 days before index, 29.5% (594/2015) showed an interval before switching of 8 weeks or more (mean, 7.6 ± 5.5 weeks), whereas 83.1% (1734/2015) showed a brolucizumab injection interval at 12 months of 8 weeks or more (mean, 10.3 ± 4.0 weeks). In all, 77.1% of treatment-experienced eyes (1554/2015) showed an interval extension of 1 week or more; of these, 55.4% (861/1554) showed an extension of 4 weeks or more. CONCLUSIONS: In this community-based study, at 12 months, brolucizumab treatment prolonged the interval between anti-VEGF injections for most treatment-experienced eyes, particularly those with shorter intervals before switching, while maintaining or improving VA. With careful balancing of the benefits and risks, switching to brolucizumab treatment may offer the advantage of extending the treatment interval for patients with a high anti-VEGF therapy burden. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Factors Linked to Injection Interval Extension in Eyes with Wet Age-Related Macular Degeneration Switched to Brolucizumab.

PURPOSE: To evaluate factors associated with anti-vascular endothelial growth factor (VEGF) injection interval extension in patients with neovascular age-related macular degeneration (nAMD) switched to brolucizumab treatment. DESIGN: Retrospective, observational cohort study. PARTICIPANTS: Adults in the United States-based IRIS® Registry (Intelligent Research in Sight) with nAMD who switched from another anti-VEGF agent to brolucizumab-only treatment for ≥ 12 months from October 8, 2019, through November 26, 2021. METHODS: Univariable and multivariable analyses examined associations of demographic and clinical characteristics with the likelihood of interval extension after switching to brolucizumab therapy. MAIN OUTCOME MEASURES: Eyes were classified as either extenders or nonextenders at 12 months. Extenders were eyes that achieved (1) an extension of ≥ 2 weeks in the brolucizumab injection interval at 12 months versus the interval before switching (time between the last known prior anti-VEGF injection and first [index] brolucizumab injection) and (2) stable (< 10 letters gained or lost) or improved (≥ 10 letters gained) visual acuity (VA) at 12 months versus VA at index injection. RESULTS: Of 2015 eyes among 1890 patients who switched to brolucizumab treatment, 1186 (58.9%) were extenders. In univariable analyses, demographic and clinical characteristics were comparable between extenders and nonextenders, except that extenders had shorter intervals before switching versus nonextenders (mean, 5.9 ± 2.1 weeks vs. 10.1 ± 7.6 weeks, respectively). In multivariable logistic regression modeling, a shorter interval before switching was associated significantly and positively with interval extension with brolucizumab therapy (adjusted odds ratio, 5.6 for interval before switching of < 8 weeks versus ≥ 8 weeks; 95% confidence interval, 4.5-6.9; P < 0.001), and eyes with an index VA of 40 to 65 letters were significantly less likely to be extenders than eyes in the higher (better) index VA categories. CONCLUSIONS: Length of the treatment interval before switching was the characteristic associated most strongly with successful interval extension with brolucizumab. Treatment-experienced patients who required more frequent injections (i.e., shorter intervals before switching) showed the greatest extensions when switching to brolucizumab. With careful consideration of benefits and risks, brolucizumab may be a valuable option for patients with higher treatment burdens because of the need for frequent injections. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Trends in the Cumulative Post-Marketing Reporting Rates of Retinal Vasculitis and/or Retinal Vascular Occlusion and Associated Vision Loss with Brolucizumab.

INTRODUCTION: Brolucizumab, a low-molecular weight anti-vascular endothelial growth factor, was approved in the USA in October 2019 for the treatment of neovascular age-related macular degeneration. Following post-marketing reports of vasculitis, including retinal occlusive vasculitis, a safety signal of retinal vasculitis (RV) and/or retinal vascular occlusion (RO) that may result in severe vision loss was confirmed. This brief communication reviews the trends in the cumulative reporting rates of RV and/or RO and associated vision loss from May 2020 to September 2022. METHODS: This is a descriptive analysis of the cumulative post-marketing reporting rates of RV and/or RO cases, and associated vision loss included in the Novartis safety database between May 2020 and September 2022, utilizing an enhanced pharmacovigilance program. RESULTS: The RV-alone rates demonstrated an upward trend, rising to 5.1 events per 10,000 injections by October 2020 and subsequently remained stable until July 2021. Thereafter, the rate for RV-alone events increased modestly until October 2021 and then remained stable until September 2022. The RO-alone rates increased to 3.4 events per 10,000 injections by January 2021 and subsequently remained stable until September 2022. The combined reports of RV and RO showed an upward trend until December 2020 (7.5 events per 10,000 injections), followed by a plateau until September 2021 and then a downward trend until September 2022. Vision loss associated with RV and/or RO progressively increased until December 2020 (5.9 events per 10,000 injections) followed by a declining trend until September 2022 to the most recent reporting rate of 4.1 events per 10,000 injections. CONCLUSION: The cumulative post-marketing reporting rates of vision loss associated with RV and/or RO, following brolucizumab treatment, have shown a declining trend after an initial rise in the reporting rates immediately after identification of the safety signal.

The Treatment Patterns with Brolucizumab in Germany (REALIZE) Study: A Retrospective Cohort Study Based on Longitudinal Prescription Data.

INTRODUCTION: This study describes real-world treatment patterns in Germany for brolucizumab, an anti-vascular endothelial growth factor (anti-VEGF) therapy for neovascular age-related macular degeneration (nAMD). METHODS: This single-arm retrospective cohort study used German patient-level prescription data. Patients aged ≥ 50 years, who received ≥ 1 brolucizumab prescription in one eye only (unilateral) and had a minimum of 12 months follow-up were included. Three cohorts were defined from the overall population: anti-VEGF treatment-naive patients ("treatment-naive"); anti-VEGF treatment-experienced patients ("treatment-experienced"); and of the treatment-experienced cohort, patients persistent on brolucizumab for 12 months ("treatment-experienced persistent"), i.e. who received ≥ 2 brolucizumab injections and did not discontinue or use other anti-VEGF agents in that period. Descriptive statistics were used to analyse patient characteristics and injection intervals. RESULTS: A total of 2089 patients with at least 12 months follow-up and one brolucizumab injection were analysed. Most were female (58.1%), aged 80+ years (54.7%). A total of 539 (25.8%) were treatment-naive, 1550 (74.2%) treatment-experienced and, of those, 787 (50.8%) were persistent. Overall, the median (interquartile range, IQR) number of brolucizumab injections during the 12 months follow-up was 5.0 (3.0-8.0). In the treatment-naive and treatment-experienced sub-cohorts it was 5.0 (3.0-8.0) and 5.0 (3.0-9.0) injections, respectively. In the treatment-experienced persistent cohort the median (IQR) number of injections was 8.0 (5.0-10.0). In this same cohort, the median (IQR) treatment interval between anti-VEGF injections before switch to brolucizumab was 5.1 (4.0-8.0) weeks, whilst the brolucizumab interval at 12 months after switch was 8.0 (6.0-11.9) weeks. Of treatment-experienced patients, 67% extended their treatment interval and those with pre-switch intervals less than 6 weeks (< q6w), in particular, had meaningful treatment interval extensions. CONCLUSION: Patients who switched to brolucizumab had a median treatment interval extension of about 3 weeks at 12 months. These results show that treatment with brolucizumab has the potential to reduce treatment burden in patients with nAMD in routine clinical practice.

Anatomical and functional outcomes following switching from aflibercept to ranibizumab in neovascular age-related macular degeneration in Europe: SAFARI study.

BACKGROUND/AIMS: Prospective data on switching anti-vascular endothelial growth factors in patients with neovascular age-related macular degeneration (nAMD) who have previously shown no/partial response are limited. This prospective study assessed the effect of switching from aflibercept to ranibizumab on anatomical and functional outcomes in patients with persistent/recurrent disease activity. METHODS: SAFARI (NCT02161575) was a 6-month, prospective, single-arm study conducted in the UK and Germany. Patients, meeting strict eligibility criteria for one of two subgroups (primary treatment failure or suboptimal treatment response), received 3 monthly intravitreal ranibizumab injections (0.5 mg). Thereafter, ranibizumab was administered pro re nata at monthly visits. The primary endpoint was change from baseline (CfB) to day 90 in central subfield retinal thickness (CSRT). Best-corrected visual acuity (BCVA) and retinal morphology parameters were assessed. RESULTS: One hundred patients were enrolled (primary treatment failure, 1; suboptimal treatment response, 99). In the overall population, there was a significant CfB in median CSRT of -30.75 µm (95% CI -59.50,-20.50; p<0.0001) to day 90. Improvements were also observed in other quantitative and qualitative optical coherence tomography parameters. In Early Treatment Diabetic Retinopathy Study letters assessed by category, 55% and 59% of patients gained 0-≥15 letters versus baseline at day 90 and day 180, respectively. However, mean improvements in BCVA (CfB) to each time point were small (≤2 letters). No new safety signals were identified. CONCLUSION: Switching from aflibercept to ranibizumab led to a significant improvement in CSRT, with ~60% experiencing stabilised/improved BCVA. Therefore, patients with nAMD who have shown a suboptimal response to aflibercept may benefit from switching to ranibizumab.

Resource Use and Real-World Outcomes for Ranibizumab Treat and Extend for Neovascular Age-Related Macular Degeneration in the UK: Interim Results from TERRA.

INTRODUCTION: Ranibizumab is an inhibitor of vascular endothelial growth factor-A (anti-VEGF) approved for the treatment of neovascular age-related macular degeneration (nAMD). The treat and extend (T&E) regimen can potentially reduce the burden of clinic visits compared with a pro re nata (PRN) regimen. Retrospective, interim analyses of clinical effectiveness, treatment and resource use patterns were conducted using real-world data in England and Wales from the TERRA study. METHODS: Two cohorts, those switching from a PRN to a T&E regimen ('prior PRN') and those initiating ranibizumab on the T&E regimen as their first anti-VEGF therapy ('anti-VEGF-naïve') were enrolled in TERRA. Retrospective clinical assessments were gathered from medical records, while resource use patterns were collected via an operating cost questionnaire completed by each study site. RESULTS: At the interim analysis cut-off date (15 November 2016), 11 sites had enrolled 145 patients (prior PRN: n = 110; anti-VEGF-naïve: n = 35). Mean change from baseline (date of first injection) in visual acuity and central subfield retinal thickness to 12 months was +7.6 Early Treatment Diabetic Retinopathy Study letters [95% confidence interval (CI) 2.8, 12.4; p = 0.003; n = 27] and -67.7 µm (95% CI -106.5, -28.9; p = 0.001, n = 29), respectively, in the anti-VEGF-naïve cohort. Most T&E clinics were run as one-stop services (same-day monitoring and injection), whereas 4/10 PRN clinics were run as two-stop services (monitoring and injection on different days). In general, one-stop clinics used less staff resources and were likely to be shorter in duration for healthcare providers than the cumulative time spent for two-stop clinics. CONCLUSION: This is the first real-world observational study conducted in England and Wales demonstrating the effectiveness of the ranibizumab T&E regimen in anti-VEGF-naïve patients. T&E is compatible with one-stop clinic services, which these real-world data suggest to be less resource intensive than two-stop clinic services, possibly providing a dosing regimen beneficial to both patients and resource burden in UK clinical practice. FUNDING: Novartis Pharmaceuticals UK Limited.