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

Abstract

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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 – 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 .…”

“…This allosteric lock mechanism is consistent with the conformational selection model in that Fab15H6.v4 binding shifts the equilibrium from the competent to the non-competent state and thereby prevents substrates from sampling the active conformation. Consequently, Fab-bound HTRA1 is no longer able to process any substrates, as shown by functional cleavage assays in-vitro and was also observed in-vivo in a clinical Phase I study, in which intravitreal administration of the Fab15H6.v4.D221 completely blocked HTRA1-mediated cleavage of the biomarker DKK3 in the human aqueous humor samples of patients with GA secondary to AMD 31 , 33 .…”

“…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).…”

Neuroprotection for Age-Related Macular Degeneration

“…Although it has not been definitively proven that the HTRA1 gene is the gene within this locus that promotes AMD, HTRA1 activity has been suggested to be pathologic and contribute J o u r n a l P r e -p r o o f to AMD pathogenesis based on preclinical studies. In line with this, intravitreal delivery of FHTR2163/RO7171009/RG6147, an anti-HTRA1 antibody fragment (Genentech, San Francisco, CA), was shown to be safe and well tolerated in Phase 1 23 and is now being evaluated as a therapy for GA in the Phase 2 GALLEGO study (NCT03972709).…”

Association of Complement C3 Inhibitor Pegcetacoplan with Photoreceptor Degeneration Beyond Areas of Geographic Atrophy

“…14 Ultrahigh-resolution OCT technology would most likely provide more precise estimates of change-over-time in IS and OS thickness given the greater axial resolution. 52 Last, analysis of photoreceptor degeneration outside of RPE-atrophy in the larger phase 3 trials investigating the same drug is warranted (i.e., DERBY, OAKS) and across investigational drugs (including among other avacincaptad pegol, 53 IONIS-FB-LRx, 54 FHTR2163 55 ).…”