LAUSR

PURPOSE FHTR2163 is a novel antigen-binding fragment (Fab) directed against high-temperature requirement protein A1 (HtrA1). HtrA1 inhibition may preserve retinal integrity and slow disease progression in geographic atrophy (GA) secondary to age-related macular degeneration (AMD). This study examined the safety, pharmacokinetics, immunogenicity, and changes in the HtrA1-specific substrate Dickkop-related protein 3 (DKK3) in patients with GA who received FHTR2163. DESIGN Phase I, open-label, single ascending dose escalation and multiple-dose expansion study Methods: Adults age ≥ 50 with GA secondary to AMD with best corrected visual acuity ranging between Snellen 20/125 and 20/400 were enrolled. In the first stage, a single intravitreal injection of FHTR2163 was given in 5 dose-escalation cohorts ranging from 1-20 mg (n=3 patients/cohort; n=15 total patients). The second stage evaluated the maximum tested dose of 20 mg administered every 4 weeks for 3 doses (n=13 patients). RESULTS No dose limiting toxicities or ocular serious AEs were reported; most frequently reported AEs in the study eye were conjunctival hemorrhage (n=7), conjunctival hyperemia (n=4), and eye pain (n=2). No non-ocular or ocular AEs were assessed as drug related. There were no clinically significant changes in ocular exams. A sustained pharmacodynamic effect of anti-HtrA1 was observed in the aqueous humor as measured by levels of cleaved DKK3. CONCLUSIONS FHTR2163, a novel Fab directed against HtrA1, was well tolerated with no DLTs or significant ocular AEs. The molecule when injected intravitreally for 3 doses, showed a sustained pharmacodynamic effect at the maximum tested dose of 20 mg.