Brolucizumab Effectively Reduces Sub-Retinal Hyperreflective Material Thickness in nAMD

A posthoc analysis of the phase 3 HAWK and HARRIER revealed greater reductions in sub-retinal hyperreflective material (SHRM) thickness from baseline with brolucizumab 6mg treatment, compared with aflibercept 2mg, in patients with neovascular age-related macular degeneration (nAMD).¹

The investigative team, led by SriniVas Sadda, MD, from the University of California, Los Angeles, suggests post-loading SHRM thickness and variability in thickness over time may be important biomarkers for visual outcomes in patients with nAMD.

“By more effectively reducing SHRM thickness, brolucizumab could offer the potential for greater disease control in patients with nAMD,” Sadda and colleagues wrote.

The identification of SHRM on optical coherence tomography (OCT) is common in eyes with nAMD and often persists after treatment with anti-vascular endothelial growth factor (VEGF) therapies. It is considered a major risk factor associated with continued visual acuity loss in nAMD, despite continued anti-VEGF treatment. Primary findings from the HAWK and HARRIER trials reported the non-inferiority of brolucizumab 6 mg versus aflibercept 2 mg in mean change in best-corrected visual acuity (BCVA) at week 48 and week 96, as well as greater fluid reduction through week 96.

In a masked, subcompartment analysis, investigators assessed OCT images from patients treated with brolucizumab 6 mg (n = 700) and aflibercept 2 mg (n = 696) for the maximum SHRM thickness across the entire macula at baseline and through 96 weeks. SHRM thickness reduction was also measured in patients with disease activity at week 16 in both treatment arms in a matched subgroup.

A pooled, treatment-agnostic analysis was used to compare the 2-year BCVA outcomes in patients with varying SHRM thickness cutoff thresholds (100 µm and 200 µm) at week 12 –when the full impact of the loading phase is observed. The pooled treatment agnostic data were additionally used to assess the association between SHRM thickness variability and visual outcomes.

In the pooled data set, 79.3% of patients exhibited SHRM at baseline in HAWK and HARRIER (brolucizumab 6 mg: 79.4%; aflibercept 2 mg: 79.3%). SHRM thickness was shown to decrease rapidly from baseline after initiation of anti-VEGF treatment and was maintained up to week 96 in both the brolucizumab and aflibercept groups.

Upon analysis, investigators found brolucizumab-treated patients had greater reductions in SHRM thickness versus aflibercept-treated patients over the 96-week study period. Brolucizumab was associated with numerically higher reductions from baseline in SHRM thickness versus aflibercept in all patients (week 96: 54.5% vs. 47.6%) and in those with disease activity at week 16 (week 96: 51.6% vs. 33.8%).

The absence of SHRM at week 12 was also associated with better visual outcomes through week 96. Patients with greater SHRM thickness at week 12 experienced worse BCVA outcomes at Week 96 (≥200µm, +3.10 ETDRS letters), compared to those with lower SHRM thickness (<200µm, +6.47 ETDRS letters).

After a comparison of mean BCVA through week 96, investigators found higher fluctuations in SHRM thickness were linked to worse visual outcomes at week 96. Those with the lowest SHRM thickness variability from Week 12 to Week 96 had the greatest BCVA gains from baseline (Week 96: <12 µm, +7.42 ETDRS letters vs. >71µm, -2.95 ETDRS letters).

Sadda and colleagues noted the link between SHRM and poorer visual outcomes indicates SHRM may comprise fibrotic tissue that separates the retinal pigment epithelium (RPE) from the photoreceptors and eventually leads to dysfunction or loss. Further in-depth analyses of the OCT images could help identify an association between SHRM morphology and the presence of fibrotic tissue to explain the poorer visual outcomes of those with persistent SHRM.

“Nevertheless, this study clearly demonstrates the impact of SHRM on long-term visual outcomes irrespective of the location within the macula and emphasizes the importance of reducing SHRM thickness as much as possible early in the course of anti-VEGF treatment,” investigators wrote.

References

1. Sadda S, Sarraf D, Khanani AM, et al. Comparative assessment of subretinal hyper-reflective material in patients treated with brolucizumab versus aflibercept in HAWK and HARRIERBritish Journal of Ophthalmology Published Online First: 05 September 2023. Doi: 10.1136/bjo-2023-323577
2. Dugel PU, Singh RP, Koh A, et al. HAWK and HARRIER: ninety-six-week outcomes from the phase 3 trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology 2021;128:89–99. doi:10.1016/j.ophtha.2020.06.028CrossRefPubMedGoogle