Abicipar pegol: the non-monoclonal antibody anti-VEGF

Abstract

The introduction of anti-VEGF molecules has dramatically reduced blindness attributable to neovascular age-related macular degeneration (nAMD). These molecules however have a relatively short intraocular half-life, which requires frequent injections on a regular basis, typically ranging from 4 to 12 weeks when a treat and extend injection protocol is utilized [1]. The frequent dosing intervals can be a significant burden for the patient and their families, and can be a cause for discontinuation of the therapy. The anti-VEGF clinical trials have demonstrated that the visual gains attained with current anti-VEGF monotherapy are +8 to +10 ETDRS letters. However, this significant benefit does not appear to improve with increased dosage or frequency of injections, thus indicating a possible therapeutic ceiling [2]. Trials such as PrONTO and SUSTAIN tried to extend the dosing interval while retaining the efficacy and were able to reduce the number of injections to 5.6 for 12 months of study; however, vision was negatively impacted [3, 4]. HORIZON trial suggests that less frequent injections may have an incremental decline in best-corrected visual acuity (BCVA) when compared to monthly injections of ranibizumab [5]. The next generation of anti-VEGF molecules are designed to provide a better dosing regimen with a sustained duration of action. Recently, brolucizumab, an scFv molecule has been filed for biologics license application (BLA) from FDA [6]. Faricimab is a unique bispecific mAb being developed on crossmAb platform to simultaneously inhibit Ang2 and VEGF and has been shown superior to anti-VEGF monotherapy with ranibizumab [7]. The most novel of all the molecules in pipeline for intravitreal therapy is Abicipar Pegol. (Allergan Inc, Switzerland) [1]. Abicipar Pegol is an anti-VEGF molecule based on the designed ankyrin repeat proteins (DARPin) therapeutics (Molecular Partners AG, Switzerland). DARPins are derived from naturally occurring ankyrin protein repeats (Fig. 1). The repeats are usually limited to four to six in numbers and thus lead to a right-handed solenoid structure with hydrophobic core and a large, grooved, solvent accessible binding surface [8]. Libraries of DARPin molecules of varying repeats numbers have been generated by a patented technology of protein engineering and recombinant DNA technology. Early in-vivo and in-vitro trials identified few DARPin molecules that had the potential for ocular use. Intravitreal injections of DARPin in mouse models prevented retinal vascularization, while topical drops prevented corneal neovascularisation related to suture tracts in rabbits. It also reduced vascular leakage from retinal vessels in rabbits and prevented LASER induced choroidal neovascularisation in rats. It also had a favorable toxicity profile which led to the development of anti-VEGF DARPin molecule [1]. Abicipar was engineered as MP-0112 by Molecular Partners to have a longer ocular half-life with faster systemic clearance. Due to their low molecular weight and no immunoglobulin component, naive DARPins are rapidly cleared from the systemic circulation by kidneys. A polyethylene glycol tail was added to the repeat protein which helped the molecule to stay above renal clearance threshold [8, 9]. It was the first DARPin molecule that entered clinical development with an aim to reduce the number of intravitreal injections needed. Initial preclinical trials showed significantly longer half-life of the molecule (6 days) following intravitreal injections in rabbits compared with aflibercept (4.7 days) and ranibizumab (2.5 days). Phase 1 dose escalation study showed the maximum tolerated dose (MTD) to be 1 mg with visual gains over the 16 weeks of study period in patients of nAMD. The trial also showed that at 2 mg * Ashish Sharma [email protected]