Novartis announced further positive results from two phase 3 studies of brolucizumab versus aflibercept (Eylea). Results showed noninferiority in primary endpoint, superiority in key retinal health outcomes, and long-lasting effect in patients with neovascular age-related macular degeneration (nAMD), according to a company news release. The results of the head-to-head trials, HAWK and HARRIER, were presented at the American Academy of Ophthalmology (AAO) 2017 Annual Meeting.
At week 16, relative to aflibercept, 35% fewer brolucizumab 6 mg patients showed presence of intra-retinal fluid (IRF) and/or sub-retinal fluid (SRF) in HAWK, and 33% fewer in HARRIER (P<0.0001 for both). Again at week 48, relative to aflibercept, 31% fewer patients on brolucizumab 6 mg had IRF and/or SRF in HAWK, and 41% fewer in HARRIER (P<0.0001 for both). The absence of fluid for patients in the brolucizumab arm suggests the potential for a long-lasting effect and decreased treatment need.
Additionally, brolucizumab 6 mg patients demonstrated superior reductions in central subfield thickness (CST). In nAMD, an elevated CST-as measured by optical coherence tomography (OCT)-is a key indicator of abnormal fluid accumulation in the retina. Significantly improved CST reductions were evident at week 16 (P=0.0016 in HAWK and P<0.0001 in HARRIER) and at week 48 (P=0.0023 and P<0.0001, respectively).
Brolucizumab met the primary efficacy endpoint of noninferiority to aflibercept in mean change in best-corrected visual acuity (BCVA) from baseline to week 48 in both trials. These results were achieved while a majority of brolucizumab patients -- 57% in HAWK and 52% in HARRIER -- were maintained on a q12w dosing interval immediately following the loading phase through week 48, according to Novartis.
"HAWK and HARRIER demonstrated that brolucizumab has the potential to positively impact disease management and provide long-lasting treatment effect," Pravin U. Dugel, MD, Managing Partner, Retinal Consultants of Arizona; Clinical Professor, Roski Eye Institute, Keck School of Medicine, University of Southern California; and principal investigator of both trials, said in the news release. "HAWK and HARRIER showed that brolucizumab outperformed aflibercept on disease activity assessments, including key measures of disease progression seen on OCT, which forms the basis of a clinician's treatment decisions. Importantly, improvements in these key OCT measures were seen as early as week 16 and maintained at week 48, with a majority of brolucizumab patients on a 12-week treatment interval."
"Having delivered on our non-inferiority endpoint with a majority of patients on a q12 week interval, we're truly excited to share these data showing that brolucizumab clearly improves key anatomical outcomes that are biomarkers of disease," Vas Narasimhan, Global Head, Drug Development and Chief Medical Officer, Novartis, said in the news release. "Brolucizumab represents a major scientific and clinical advancement for patients, caregivers and retina specialists around the world."
With brolucizumab, significantly fewer patients had active disease at week 16 in a matched head-to-head comparison. Active disease was observed in 23.5% of brolucizumab 6 mg patients versus 33.5% of aflibercept patients in HAWK, and in 21.9% of brolucizumab patients versus 31.4% of aflibercept patients in HARRIER (P=0.0022 for both).
Brolucizumab safety was comparable to aflibercept with the overall incidence of adverse events balanced across all treatment groups in both studies. The most frequent ocular adverse events (greater than 5% of patients in any treatment arm) for brolucizumab 3 mg, 6 mg and aflibercept, respectively, in HAWK were reduced visual acuity (8.7%, 6.9% and 8.9%), conjunctival hemorrhage (8.4%, 6.4% and 5.6%), vitreous floaters (6.7%, 5.0% and 3.1%) and eye pain (5.9%, 4.4% and 4.2%). The incidences of these events for brolucizumab 6 mg and aflibercept, respectively, in HARRIER were reduced visual acuity (5.9% and 6.2%), conjunctival hemorrhage (1.9% and 3.3%), vitreous floaters (3.0% and 0.8%) and eye pain (2.7% and 3.3%). The most frequent non-ocular adverse events were typical of those reported in an nAMD population; there were no notable differences between arms. The incidence of arterial thrombotic events (ATE) was 3.9%, 2.5% and 5.5% (brolucizimab 3 mg, brolucizumab 6 mg and aflibercept respectively) in HAWK and 1.6% and 1.1% (brolucizumab 6 mg and aflibercept, respectively) in HARRIER.
About brolucizumab (RTH258)
Brolucizumab (RTH258) is a humanized single-chain antibody fragment (scFv) and the most clinically advanced, humanized single-chain antibody fragment to reach this stage of development. 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.
The proprietary innovative structure results in a small molecule (26 kDa) with potent inhibition of, and high affinity to, all VEGF-A isoforms. In preclinical studies, brolucizumab inhibited activation of VEGF receptors through prevention of the ligand-receptor interaction. Increased signaling through the VEGF pathway is associated with pathologic ocular angiogenesis and retinal edema. Inhibition of the VEGF pathway has been shown to inhibit the growth of neovascular lesions, resolve retinal edema and improve vision in patients with chorioretinal vascular diseases.
About HAWK and HARRIER study design
With more than 1,800 patients across 400 centers worldwide, HAWK and HARRIER are the first and only global head-to-head trials in patients with nAMD that prospectively demonstrated efficacy at week 48 using an innovative q12w/q8w regimen, with a majority of patients on q12w immediately following the loading phase. Both studies are 96-week prospective, randomized, double-masked multi-center studies and part of the phase 3 clinical development of brolucizumab.
The studies were designed to compare the efficacy and safety of intravitreal injections of brolucizumab 6 mg and 3 mg (HAWK only) versus aflibercept 2 mg in patients with nAMD. The primary efficacy objective of HAWK and HARRIER trials was to confirm that brolucizumab is noninferior to aflibercept in mean change in BCVA from baseline to Week 48. Secondary endpoints include average mean change in BCVA from baseline over the period week 36-48, the proportion of patients on a q12w interval at week 48 and anatomical parameters.
In both trials, patients were randomized to either brolucizumab or aflibercept. Immediately following the 3-month loading phase, patients in the brolucizumab arms received a q12w dosing interval with an option to adjust to a q8w dosing interval based on masked disease activity assessments at defined visits. Aflibercept was dosed bi-monthly according to its label.
Week 16 was an important pre-defined data point, as it represents a timepoint when the treatment assessment for brolucizumab and aflibercept were identical, providing an opportunity to observe how both drugs performed in a matched comparison.