Eye | 2019
Brolucizumab: is extended VEGF suppression on the horizon?
Abstract
Anti-VEGF therapy has revolutionized the management of neovascular age-related macular degeneration (nAMD) in the last few years [1, 2]. It has become the first line treatment option for nAMD [3]. However, monthly dosing regimen was being bogged by multiple hospital visits, financial burden to the patient and healthcare system [4]. The researchers have explored newer treatment strategies such as Pro-re-nata (PRN), Treat and Extend (TREX) and three monthly interval (PIER) to extend dosing intervals [4–6]. However, the need of a longer acting anti-VEGF agent was felt. Ranibizumab port delivery system, Abicipar, Faricimab and Brolucizumab are recent efforts to provide long term VEGF suppression. Amongst these, brolucizumab {Humanized single chain antibody fragment (scFv)} has reached closer to marketing approval [7–9]. Recently concluded phase 3 HAWK and HARRIER trials have proven its safety and efficacy in nAMD and the marketing approval has been sought from the FDA by Novartis [10, 11]. Brolucizumab was ideated by ESBATech (ESBATech AG—Schlieren ZH, Switzerland) as ESBA1008 as the smallest unit of a novel anti-VEGF monoclonal antibody i.e. an scFv molecule that binds to all isoforms of VEGF-A and blocks their action. ESBA1008 was developed by grafting complementarity-determining regions of the novel anti-VEGF antibody to a human scFv scaffold [12]. The pre-clinical data revealed that the retina had a 2.2 times higher exposure to the molecule when compared with ranibizumab. RPE/Choroid complex also had 1.7 times higher exposure. Higher tissue penetrance was attributed to the smaller molecular size (28 kDa, compared with 48 kDa of ranibizumab, 115 kDa of aflibercept) [13]. The higher penetrance was postulated to give better fluid control across layers of retina resulting in better visual outcomes, which was later proven in HAWK and HARRIER trials [10]. The smaller molecular weight has allowed a higher molar concentration of the drug to be fit into the 50 μl with formulations up to 120 mg/ml. 50 μl of 120 mg/ml formulation has 22 times molar excess than 0.5 mg/0.5 ml ranibizumab and 12 times more than 2 mg/0.5 ml of aflibercept [14]. The in-vitro studies have shown brolucizumab having affinity to VEGF similar to ranibizumab and higher than bevacizumab [15]. In-vivo studies in primates have revealed that the systemic exit of the drug is significantly less than ranibizumab or aflibercept, possibly due to better tissue uptake of the molecule. The reduced systemic exit can lead to less generation of anti-drug antibody, which play a major role in immunogenicity and treatment failure [16]. The phase 1/2 study evaluated the safety and efficacy of ESBA1008 with a new codeRTH258 and demonstrated non-inferiority of 4.5 mg and 6 mg dosing of RTH258 in central subfoveal thickness improvement compared to 0.5 mg ranibizumab, with the dosing interval safely being extended 30 days beyond the regular monthly interval making it a q8w dosing formulation [13]. Alcon Research (Ft. Worth, TX; Basel, Switzerland) took over further development of RTH258 in phase 2. The phase 2 OSPREY trial compared the molecule with aflibercept in a 56-week study duration on 89 eyes showed non-inferiority compared to aflibercept in a q8w dosing schedule and supported further development [15, 17]. Alcon Research initiated the phase 3 trials with 2 similarly designed HAWK and HARRIER trials in treatment naïve nAMD patients at 408 sites globally. 3 mg and 6 mg dosing of brolucizumab were compared with 2 mg of aflibercept in 1775 target eyes, whereas HARRIER trial was designed for head to head comparison of * Ashish Sharma [email protected]