Nonclinical Safety Assessment of FHTR2163, An Antigen-Binding Fragment Against HTRA1 for the Treatment of Geographic Atrophy

Abstract

FHTR2163 is an antigen-binding fragment of a humanized immunoglobulin G1 monoclonal antibody directed against high-temperature requirement A serine peptidase 1 (HTRA1) that is being developed as a potential intravitreal (ITV) treatment for patients with geographic atrophy (GA), an advanced form of dry age-related macular degeneration. The nonclinical toxicology program was designed to assess the safety and tolerability of HTRA1 inhibition following ITV administration of FHTR2163 to support ITV administration in patients with GA. FHTR2163 was well tolerated in a single-dose ITV-administered 8-day toxicity study in cynomolgus monkeys following a 50 µL high (>700 mOsm/kg) osmolality formulation up to 12.5 mg/eye; however, 100 µL (2× 50 µL injections) of a high-osmolality formulation resulted in transient retinal detachment. Repeat-dose ITV administration every 2 weeks of FHTR2163 was well tolerated in 8- and 26-week studies with ITV injection of 100 µL (2× 50 μL) of iso-osmolar formulation up to 15 mg/eye, or 50 µL of the high-osmolality formulation up to 12.5 mg/eye. Observed transient and reversible ocular effects included inflammation and perivascular infiltrates, consistent with an immune response attributed to the administration of heterologous (humanized) protein. Overall, FHTR2163 was well tolerated, and the nonclinical package supported the continued clinical development of FHTR2163 in patients with GA.

Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration

“…In conclusion, our study provides a detailed insight into the mode of inhibition of the trimeric serine protease HTRA1 by a clinical Fab fragment. Together with the reported safety, tolerability, and pharmacodynamics of Fab15H6.v4.D221 [31][32][33] , our findings provide an improved understanding of this Fab-based therapeutic approach for the treatment of GA. The therapeutic potential of Fab15H6.v4.D221 may not be limited to AMD, as HTRA1 has been implicated in other chronic diseases, such as osteoarthritis 54,55 .…”

“…Hybridoma screening identified Fab15H6, which strongly inhibits the activity of human HTRA1 protease. The humanized and affinity-matured Fab15H6.v4.D226 was studied in pre-clinical models and in a Phase I clinical study [31][32][33] . It is currently being investigated as a novel treatment option for GA in a Phase II clinical trial (NCT03972709).…”

Phase 1 Study of the Anti-HtrA1 Antibody-binding Fragment FHTR2163 in Geographic Atrophy Secondary to Age-related Macular Degeneration

“…Taken together, abnormal activity of HTRA1in the retina possibly induces breakdown and elimination of extracellular matrix proteins resulting in photoreceptor and RPE atrophy similar to those in AMD pathology. FHTR2163 (RO7171009) is an antigen-binding fragment (Fab) of a humanized monoclonal antibody directed against the HTRA1protein 14,18,19 Inhibiting HTRA1activity by administering FHTR2163 intravitreally could potentially represent a novel therapeutic option for the treatment of GA. The nonclinical pharmacokinetic (PK) behavior observed for FHTR2163 is comparable with other Fabs (e.g., ranibizumab 20 and lampalizumab 21 ) and shows acceptable ocular PK properties after an intravitreal injection in cynomolgus monkeys, with an observed ocular half-life (t 1/2 ) of 2.16-2.44 days.…”

“…The nonclinical pharmacokinetic (PK) behavior observed for FHTR2163 is comparable with other Fabs (e.g., ranibizumab 20 and lampalizumab 21 ) and shows acceptable ocular PK properties after an intravitreal injection in cynomolgus monkeys, with an observed ocular half-life (t 1/2 ) of 2.16-2.44 days. 19 Based on biological rationale implicating HTRA1 in the pathobiology of GA secondary to AMD, this study was conducted to investigate the safety, tolerability, PK, and immunogenicity of intravitreal injection of FHTR2163 in this patient population. Dickkop-related protein 3 (DKK3) was identified as a HtrA1-specific substrate and the level of cleaved DKK3 in aqueous humor was used in this trial as a pharmacodynamic (PD) biomarker of FHTR2163 inhibition of HTRA1protease activity.…”

“…Dickkop-related protein 3 (DKK3) was identified as a HtrA1-specific substrate and the level of cleaved DKK3 in aqueous humor was used in this trial as a pharmacodynamic (PD) biomarker of FHTR2163 inhibition of HTRA1protease activity. 19…”