ANTIBODY FRAGMENTS

Dominik Escher PhD 

A new anti-VEGF agent called brolucizumab (RTH258, Alcon), a single-chain antibody fragment, appears to provide gains in visual acuity (VA) equivalent to those of ranibizumab and aflibercept in eyes with neovascular age-related macular degeneration (AMD), but with a longer duration of action, according to the results of two phase II studies, said Dominik Escher PhD at the 15th EURETINA Congress in Nice, France.

“Phase III trials are currently ongoing. In case brolucizumab would come to market, this would represent the first single-chain antibody fragment and thus would open a new class of molecules,” said Dr Escher, who is the head of ESBATech, Switzerland, the Novartis company which developed brolucizumab.

PRIMARY ENDPOINT

He noted that the first of the phase II trials, which involved 194 eyes of 194 patients, reached its primary endpoint of non-inferiority of brolucizumab to ranibizumab in terms of VA and central subfield foveal thickness.

Moreover, after a dose escalation phase, the median time to a return to standard of care based on pre-defined criteria was 75 days in eyes receiving 6.0mg brolucizumab, compared to only 45 days in eyes receiving ranibizumab.

The second of the phase II trials, the OSPREY trial, involved 90 eyes of 90 patients. It compared brolucizumab and aflibercept. It reached the same endpoints in terms of VA, at week 12, and in terms of central subfield foveal thickness, at week 16. Furthermore, when the interval between injections was increased from eight weeks to 12 weeks, fewer patients needed rescue injections in the brolucizumab group.

NEW ADDITION TO PHARMACOLOGY

Brolucizumab is a humanised single-chain antibody fragment (scFv) which binds to all isoforms of VEGF-A. Dr Escher noted that scFvs are the smallest functional units of an antibody that can still bind to its target. Their molecular weight is only half that of Fab fragments like ranibizumab.

He added that the small size of scFvs gives them greater tissue penetration, and their high solubility means that larger amounts can be concentrated into a single intravitreal dosage. They also have faster systemic clearance.

Dr Escher noted that ESBATech developed brolucizumab using a novel technology for the selection of fully human, highly stable and soluble scFv frameworks, which are then grafted with antigen-specific regions.

Other single-chain antibody fragments ESBATech are now investigating for ophthalmic use include one that is directed against tumour necrosis factor and is now in proof-of-concept studies as a potential topical treatment for dry eye and uveitis.

Dominik Escher: Dominik.escher@novartis.com