FormalPara Key Summary Points

Why carry out this study?

In HAWK and HARRIER, brolucizumab was injected q12w or adjusted to q8w based on the presence of disease activity (DA). However, due to the study design, brolucizumab-treated eyes adjusted to a q8w interval could not subsequently extend to a q12w interval.

This analysis was conducted to assess subsequent DA in the subgroup of eyes with DA at Week 16 to determine if there was potential for treatment interval extensions during the first year of treatment.

What was learned from the study?

In eyes that still had DA 8 weeks after the final dose of loading phase, brolucizumab-treated eyes had improved fluid resolution and therefore a higher potential for treatment interval extension compared with aflibercept-treated eyes during the first year of treatment.

Introduction

Age-related macular degeneration is one of the leading causes of vision loss [1], affecting ~ 200 million people globally [2]. With the introduction of anti-vascular endothelial growth factor (VEGF) agents, the treatment of neovascular age-related macular degeneration (nAMD) has been revolutionized [3, 4]; however, significant unmet needs still exist for many patients with nAMD, including unresolved fluid [5], high injection burden [6], and poor adherence [7], which can result in inadequate treatment and subsequent avoidable vision loss [8].

The Phase 3 HAWK (NCT02307682) and HARRIER (NCT02434328) studies evaluated the efficacy and safety of brolucizumab versus aflibercept in treatment-naïve eyes with nAMD. The results of these trials demonstrated that brolucizumab 6 mg (administered in a every 12 weeks/every 8 weeks [q12w/q8w] regimen) achieved robust vision gains and superior fluid resolution versus aflibercept q8w; a majority of brolucizumab-treated eyes were maintained on a q12w regimen immediately after loading through Year 1 [9].

In both studies, following a matched loading phase, brolucizumab was injected q12w unless disease activity (DA) was identified resulting in permanent adjustment to q8w; aflibercept was dosed q8w throughout. Due to the study design, brolucizumab-treated eyes adjusted to a q8w interval could not subsequently extend to a q12w interval. The primary aim of this post hoc analysis was to assess subsequent DA in the subgroup with DA at Week 16 to determine if there was potential for treatment interval extensions during the first year of treatment.

Methods

HAWK and HARRIER were 96-week prospective, randomized, double-masked, multicenter Phase 3 trials comparing the efficacy and safety of brolucizumab 3 mg (HAWK only) and 6 mg with aflibercept 2 mg in eyes with nAMD [9]. The study protocol and all amendments were reviewed and approved by the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for each center, as listed in the Table S1 in the electronic supplementary material. The studies were conducted in accordance with the principles of the Declaration of Helsinki, International Conference on Harmonization E6 Good Clinical Practice Consolidated Guidelines, and other regulations as applicable and were compliant with the Health Insurance Portability and Accountability Act of 1996. All study participants provided written informed consent about the results of the study being reported to any national regulatory agency and be used in scientific publications and/or presentations, provided no personal details would be released. By signing the Information and Consent document, study participants are authorizing access to their records.

In both studies, all eyes received 3-monthly loading injections in the study eye; brolucizumab was then injected q12w or adjusted to q8w based on the presence of DA as assessed by masked investigators. Aflibercept was dosed q8w throughout the study.

DA was assessed by the masked investigator based on their expert judgement of efficacy parameters typically reflecting the presence of DA, e.g., a decrease in best-corrected visual acuity (BCVA) ≥ 5 letters, presence of intraretinal fluid (IRF), subretinal fluid (SRF), or sub-retinal pigment epithelial fluid, or increase in central subfield thickness (CSFT) ≥ 40 μm. The DA guidance criteria at Week 16 were as follows: A decrease in BCVA of ≥ 5 letters compared with baseline, a decrease in BCVA of ≥ 3 letters and CSFT increase of ≥ 75 μm compared with Week 12, a decrease in BCVA of ≥ 5 letters due to nAMD DA compared with Week 12 and new or increased IRF/intraretinal cysts compared with Week 12. Further DA assessments were conducted at Weeks 20, 32, and 44 in both studies by the masked investigator (Fig. 1). The DA guidance criterion at Weeks 20, 32, and 44 was: a decrease in BCVA of ≥ 5 letters due to nAMD DA compared with Week 12.

Fig. 1
figure 1

Design of post hoc analysis of data from the HAWK and HARRIER studies. Pooled data from eyes in the brolucizumab 6 mg and aflibercept arms of the HAWK and HARRIER were included. Eyes with DA at the first DA assessment following the matched loading phase at Week 16 were compared for DA and presence of IRF and/or SRF at subsequent DA assessments during Year 1 of the studies. DA disease activity, IRF intraretinal fluid, q8w every 8 weeks, SRF subretinal fluid

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This post hoc analysis included pooled data from the brolucizumab 6 mg arms and aflibercept arms of both studies. Brolucizumab- and aflibercept-treated eyes with DA at Week 16 were compared to evaluate DA at subsequent DA assessments during Year 1 of the studies; presence of IRF and/or SRF was also evaluated at each DA assessment and at the primary analysis at Week 48. An analysis of variance (ANOVA) model, with baseline BCVA categories (≤ 55, 56–70, ≥ 71 letters), age categories (< 75, ≥ 75 years), and treatment as fixed effect factors, was used to compare the endpoint of change from baseline in BCVA. Statistical model using logistic regression with baseline BCVA categories (≤ 55, 56–70, ≥ 71 letters), age categories (< 75, ≥ 75 years), and treatment as fixed effect factors, was used to compare the DA and presence of fluid. SAS version 9.4 was used to analyse the data.

Results

Pooled data from 730 study eyes in the brolucizumab 6 mg arms and 729 study eyes in the aflibercept arms of HAWK and HARRIER were included in this post hoc analysis. Mean age was 74.5 vs 75.2 years in the brolucizumab vs aflibercept arms, respectively. More patients were female than male in both the arms. Mean baseline BCVA and CSFT was 59.4 vs 61.6 letters and 532.1 vs 483.9 µm in the brolucizumab vs aflibercept arms, respectively. At the first DA assessment at Week 16, fewer brolucizumab- (22.8%; 161/730) than aflibercept-treated (32.2%; 226/729) eyes had DA. In these eyes with investigator-identified DA at Week 16, change in BCVA from baseline to Week 96 was comparable in the brolucizumab (4.1 letters) and aflibercept (2.5 letters) arms (Fig. 2). Fewer brolucizumab- than aflibercept-treated eyes with DA at Week 16 had DA at subsequent DA assessments: 31.8% vs 39.1% (Week 20), 27.3% vs 43.5% (Week 32), and 17.3% vs 31.2% (Week 44), respectively (Fig. 3). Fewer brolucizumab- than aflibercept-treated eyes with DA at Week 16 had IRF and/or SRF: 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), respectively (Fig. 4).

Fig. 2
figure 2

BCVA from baseline to Week 96 in brolucizumab and aflibercept eyes with investigator-identified DA at Week 16. LS mean (SE) estimates from a logistic regression model were adjusted for baseline BCVA and age categories. BCVA best-corrected visual acuity, BL baseline, DA disease activity, ETDRS Early Treatment Diabetic Retinopathy Study, LS least squares, n number of eyes, SE standard error

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Fig. 3
figure 3

DA in brolucizumab and aflibercept eyes with investigator-identified DA at Week 16 at scheduled DA assessments in Year 1 of HAWK and HARRIER. Proportions and odds ratio estimates are based on a logistic regression model adjusted for baseline BCVA and age categories. BCVA best-corrected visual acuity, CI confidence interval, DA disease activity, n number of eyes

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Fig. 4
figure 4

Presence of IRF and/or SRF in brolucizumab and aflibercept eyes with investigator-identified DA at Week 16 at scheduled DA assessments in Year 1 of HAWK and HARRIER. Proportions and odds ratio estimates are based on a logistic regression model adjusted for baseline BCVA and age categories. BCVA best-corrected visual acuity, CI confidence interval, DA disease activity, IRF intraretinal fluid, n number of eyes, SRF subretinal fluid

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Discussion

This post hoc analysis of data from the HAWK and HARRIER studies assessed the evolution of DA during the maintenance phase in brolucizumab eyes assigned to a q8w regimen following the loading phase to determine the potential for subsequent treatment interval extensions during the first year of treatment had the protocol theoretically allowed extension.

HAWK and HARRIER were pivotal trials in nAMD that used identification of DA by the masked investigator after the loading phase to determine a suitable maintenance dose interval based on individual treatment need. This approach differs from previous studies evaluating q12w dosing intervals [10, 11]. Once eyes were assigned to the q8w treatment interval due to DA, the protocol did not allow for their treatment intervals to be subsequently extended once DA had resolved. As this analysis only included eyes with DA at Week 16 in all treatment groups, it allowed for a direct comparison of brolucizumab q8w and aflibercept q8w in this hard-to-treat patient population.

At the first DA assessment at Week 16, fewer eyes in the brolucizumab arm had DA (~ 10% difference). Among eyes with investigator-identified DA at Week 16, robust and comparable mean BCVA gains were seen in the brolucizumab and aflibercept arms at Week 48. These results were maintained through to Week 96, although a trend towards a numerical advantage in the brolucizumab arm was observed towards the end of the study. While the BCVA gains within this subgroup were comparable between brolucizumab- and aflibercept-treated eyes, they were lower compared with the overall population in the primary analysis, indicating that this subgroup is a hard-to-treat patient population [9].

Fewer eyes in the brolucizumab arm with DA at Week 16 had DA with notable change in visual acuity at subsequent visits compared with aflibercept, most notably at Week 32, which was 8 weeks post-injection. This observation suggests that more brolucizumab-treated eyes had potential to extend their treatment intervals than aflibercept-treated eyes, or more aflibercept-treated eyes had potential to reduce their treatment intervals if allowed, in this hard-to-treat patient population.

Similar to our findings, post hoc analyses of other Phase 3 studies have suggested that fluid presence after loading phase can indicate a hard-to-treat population and be associated with worse outcomes. A post hoc analysis of data from the ALTAIR study demonstrated that patients with fluid at Week 16 were more likely to have fluid at Weeks 52 and 96. Moreover, patients without fluid at Week 16 also had numerically better BCVA throughout the study period [12].

In clinical practice, the presence of retinal fluid can be indicative of DA, which influences retreatment decision making [5, 13]. Fewer eyes in the brolucizumab arm with DA at Week 16 had IRF and/or SRF throughout Year 1, again showing notable differences between the treatment arms 8 weeks after the previous injection at Weeks 32 and 48. This result, coupled with the DA findings, suggests that brolucizumab’s superior drying ability plays a role in the higher potential for treatment interval extensions vs aflibercept in this cohort of eyes [9].

In this post hoc analysis of eyes with DA at Week 16, approximately half of brolucizumab-treated eyes had presence of retinal fluid at the Week 48 assessment compared with 69% of aflibercept-treated eyes. However, only 17% of brolucizumab-treated eyes were considered to have DA, based on investigator discretion by the Week 44 assessment (the closest assessment to Year 1 in this analysis) compared with 31% of aflibercept treated eyes. In clinical practice, retreatment decisions are influenced by a number of factors, including vision and anatomy at a given assessment and in the context of a patient’s treatment history, but also patient preference, including their willingness to undergo more frequent treatment. As per its label, brolucizumab should not be given at intervals more frequent than every 8 weeks because of increased intraocular inflammation risk. However, based on the findings of this analysis, including lower levels of DA and retinal fluid in brolucizumab-treated eyes, along with a numerical, although not statistically significant, improvement in vision towards Year 2, it is possible that eyes receiving brolucizumab at an 8-week interval could achieve similar outcomes to those receiving an alternative anti-VEGF treatment at a more frequent interval. Ultimately, however, the decision needs to be based on careful consideration of all factors and agreed between a physician and their patient on a case-by-case basis. Strengths of this analysis include a relatively large sample size, enabling a more precise estimation of the treatment effect and more generalizable results. The retrospective, post hoc design, however, limits the conclusions that can be drawn, and further studies are needed to confirm that eyes without subsequent DA can indeed be extended to longer treatment intervals while maintaining vision.

Conclusion

The findings of this post hoc analysis suggest that in eyes that still had DA 8 weeks after the final dose of loading phase, brolucizumab-treated eyes had improved fluid resolution and a higher potential for treatment-interval extension within the first year of treatment compared with aflibercept-treated eyes. Further studies are needed to confirm these findings.