Novartis have reported two new post-hoc analyses of the Phase III HAWK and HARRIER clinical trials in wet AMD at the EURETINA 2020 virtual congress. The first analysis demonstrated fewer brolucizumab patients had early persistent fluid, defined as the presence of intra-retinal fluid and/or sub-retinal fluid through week 12 of treatment, compared with aflibercept patients. For patients who did have early persistent fluid, those treated with brolucizumab achieved greater BCVA gains and greater reductions in central subfield thickness at week 96 versus those treated with aflibercept.
A further analysis showed brolucizumab was associated with better control of retinal fluid, as measured by achievement and maintenance of defined CST levels. In the study, more brolucizumab patients than aflibercept patients achieved CST control (80% vs. 69% at week 96 at a defined CST threshold of 320 µm, respectively). According to the company, “CST is a key indicator of fluid in the retina, and drying the retina is a core aim of treatment for wet AMD”.
Brolucizumab (or RTH258) was approved in the US in October 2019 and on February 13th 2020 by the EMA for the treatment of wet age-related macular degeneration (AMD), based on findings from the Phase III HAWK (NCT02307682) and HARRIER (NCT02434328) clinical trials. Known as RTH258, the drug is a clinically advanced humanized single-chain antibody fragment (scFv). The molecule is a 26 kDa with inhibition of, and high affinity to, all VEGF-A isoforms. The antibody inhibits activation of VEGF receptors through prevention of the ligand-receptor interaction. Inhibition of the VEGF pathway has been shown to inhibit the growth of neovascular lesions and suppress endothelial cell proliferation and vascular permeability. In clinical studies, brolucizumabdemonstrated non-inferiority versus aflibercept in mean change in best-corrected visual acuity (BCVA) at year one (week 48). The results of the study were achieved by two Phase III trials that recruited 1,817 patients at 408 sites in North, Central, and South America; Europe; Asia; Australia; and Japan. The results of the study were reported in the AAO journal (Ophthalmology) outlining that at week 48 of the study, each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline (least squares [LS] mean, + 6.6 [6 mg] and +6.1 [3 mg] letters with brolucizumab vs. +6.8 letters with aflibercept [HAWK]; +6.9 [brolucizumab 6 mg] vs. + 7.6 [aflibercept] letters [HARRIER]; P<0.001 for each comparison). Greater than 50% of brolucizumab 6 mg – treated eyes were maintained on q12w dosing through week 48 (56% [HAWK] and 51% [HARRIER]). At week 16, after identical treatment exposure, fewer brolucizumab 6 mg – treated eyes had disease activity versus aflibercept in HAWK (24.0% vs. 34.5%; P= 0.001) and HARRIER (22.7% vs. 32.2%; P= 0.002). Greater central subfield thickness reductions from baseline to week 48 were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean – 172.8 µm vs. -143.7 µm; P=0.001) and HARRIER (LS mean – 193.8 µm vs. – 143.9 µm; P< 0.001). Anatomic retinal fluid outcomes favoured brolucizumab over aflibercept. Earlier, overall adverse event rates were generally similar with brolucizumab and aflibercept.
Following the EURETINA conference, Dirk Sauer, Global Head Development, Novartis Pharma Ophthalmology, stated that, “the data presented at EURETINA suggests Beovu can better help patients who have persistent retinal fluid achieve disease control by reducing CST and improving their vision in the long term. These results further strengthen our confidence in Beovu as an effective and important treatment option for wet AMD patients aiming to improve their vision.”