An analyses of US real-world and Phase III data was presented at the American Academy of Ophthalmology (AAO) 2020 Annual Meeting identified baseline patient characteristics potentially associated with the incidence of inflammation-related adverse events that may occur following treatment with wet age-related macular degeneration (AMD) [1,2].

In the analysis of data from the IRIS Registry, including 12,000 patients treated with brolucizumab, the highest observed risk for experiencing retinal vasculitis (RV) and/or retinal vascular occlusion (RO) in the six months after first treatment with brolucizumab was prior intraocular inflammation (IOI) and/or prior RO in the 12 months before first brolucizumab injection [1].Up to 6 months after first brolucizumab injection, no intraocular inflammation, retinal vasculitis, or retinal vascular occlusion was seen in 97.61% of patients. All forms of intraocular inflammation occurred in 2.39% of patients, and retinal vasculitis and/or retinal vascular occlusion occurred in 0.55%.  Against an observed overall RV/RO risk rate of 0.46% for all brolucizumab-treated patients in the registry, this increased to 3.97% in individuals with prior IOI and/or RO1.

Even with the great advancements made in treating wet AMD, data shows 50% of patients have unresolved fluid and a third require monthly injections, highlighting the persistent unmet need that brolucizumab may help address [3,4].

Brolucizumab (also known as RTH258) is the first advanced humanized single-chain antibody fragment (scFv) approved for clinical use [11,12,13]. Single-chain antibody fragments are highly sought after in drug development due to their small size, enhanced tissue penetration, rapid clearance from systemic circulation and drug delivery characteristics [13-15].

In a post-hoc unmasked assessment of the Phase III HAWK and HARRIER data, there was an observed trend toward increased incidence of RV/RO in patients with treatment emergent (boosted/induced) anti-drug antibodies (ADAs) [2]. Further analyses of the data presented and additional data collection are ongoing.

The proprietary innovative structure results in a small molecule (26 kDa) with potent inhibition of, and high affinity to, all VEGF-A isoforms [14].  Brolucizumab is engineered to deliver a high concentration of drug, thus providing more active binding agents [11,12,13]. In preclinical studies, brolucizumab inhibited activation of VEGF receptors through prevention of the ligand-receptor interaction [14-16]. Increased signaling through the VEGF pathway is associated with pathologic ocular angiogenesis and retinal edema [17]. Inhibition of the VEGF pathway has been shown to inhibit the growth of neovascular lesions and suppress endothelial cell proliferation and vascular permeability [17].

 

 

In this real-world study, Dr. Ip and colleagues looked at more than 12,000 patients treated with brolucizumab between October 2019 and June 2020. They found that 90.0% of these eyes had prior treatment with anti-VEGF, “suggesting unmet medical needs continue to exist for patients that have wet AMD that are treated with our current anti-VEGF therapies.” Additionally, the anti-VEGF used most immediately prior to the switch was aflibercept (73.9%).

 

 

HAWK and HARRIER Trials

With more than 1,800 patients across nearly 400 centers worldwide, HAWK (NCT02307682) and HARRIER (NCT02434328) are the first global head-to-head trials in patients with wet AMD that prospectively demonstrated efficacy of brolucizumab at week 48 using an innovative q12w/q8w regimen, with a majority of patients on q12w immediately following the loading phase [11,12]. Both studies are 96-week prospective, randomized, double-masked multi-center studies and part of the Phase III clinical development of brolucizumab [11 12]. The studies were designed to compare the efficacy and safety of intravitreal injections of brolucizumab 6 mg (HAWK and HARRIER) and 3 mg (HAWK only) versus  flibercept 2 mg in patients with wet AMD [11,12]. The most common adverse events (≥5% of patients) with brolucizumab were vision blurred, cataract, conjunctival hemorrhage, vitreous floaters and eye pain [11,12].