Author: Raj Maturi (United States)
Co-authors: Prema Abraham, Andrew Antoszyk, Sunil Patel, Alia Rashid, Kiran Patki, Arshad Khanani
Purpose
Geographic atrophy is the most advanced form of dry AMD. Genetic variations coding for proteins in genes involved in the alternative complement pathway are strongly associated with risk of AMD. Based on the literature as well as data from Gemini natural history study, approximately 40% dry AMD patients have a loss of function variant in the CFH gene. GEM103 is a full length, recombinantly produced human CFH protein which provides a functional level of active CFH in AMD patients with loss of function mutations in the gene encoding CFH. CFH functions physiologically to restore complement activity and to restore retinal health. Results from the Phase 1 study of IVT GEM103 in subjects with central geographic atrophy (GA) secondary to non-neovascular (dry) age-related macular degeneration (AMD) show that single IVT doses from 50 to 500 µg were well tolerated, with no dose-limiting toxicities, GEM103-related adverse events, signs of ocular inflammation, or ADA. These results supported the enrollment of subjects into ReGAtta, a Phase 2a multiple ascending dose evaluation of GEM 103 in genetically selected subjects with geographic atrophy (GA) secondary to dry AMD for continued evaluation of the safety, supraphysiologic CFH maintenance over time, and effect on biomarkers of complement activation.
Setting/Venue
This is the first data presentation of an interim analysis from ReGAtta, a phase 2a, open- label, repeat dose, dose escalation study evaluating safety and total CFH levels and complement biomarkers through serial aqueous humor (AH) sampling following 6 months of IVT GEM103 at 250 or 500 µg, with 12 additional monthly 500 µg IVT doses in genetically selected subjects with geographic atrophy (GA) secondary to dry AMD (ClinicalTrials.gov Identifier: NCT04643886).
Methods
Genetically selected subjects with GA secondary to dry AMD Subjects, ≥50 years of age, total GA lesion size ≥1.25 and ≤17.5 mm2 (0.5- and 7-disc areas), best corrected visual acuity (BCVA) 24 to 83 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (equivalent to Snellen visual acuity of approximately 20/25 to 20/320), no exudative AMD or CNV in study eye, and who met other eligibility criteria, were enrolled. Subjects were assigned to study cohorts based on genetic profile (either the common CFH variant [CFH402HH], Rare missense variants of CFH or complete complotype; or neither of these profiles). Outcome measures include AEs, signs of ocular inflammation, ADA, total CFH levels in AH, exploratory biomarkers in AH, and clinical effects including changes from baseline in visual acuity and anatomical measurements including GA lesion size.
Results
As of March 2021, preliminary baseline data were available for 62 subjects dosed with IVT GEM103: 36 with common CFH variant [CFH402HH], 13 with rare missense variants of CFH or complete complotype; and 13 neither of these genotypic profiles. Mean age was 78.03 years, 62.9% of subjects were female. Overall baseline GA lesion size (mean ± standard deviation) was 8.01 ± 5.62 mm2 (n=62). Overall baseline BCVA and LLVA (mean ± standard deviation) was 60.77 ± 18.92 ETDRS letters and 37.80 ± 18.25 ETDRS letters respectively (n=62). Analyses of available data for safety, total CFH levels in AH and biomarkers in AH after repeat IVT dosing with GEM103 will be presented at the meeting.
Conlusions
Gemini uses a precision medicine strategy to identify and treat genetically defined dry AMD subjects who are likely to respond to GEM103 therapy. Phase 2a (REGATTA), repeat dose, dose escalation study evaluates safety, total CFH levels in AH, and measurement of complement biomarkers after repeat IVT dosing with GEM103. REGATTA study will confirm findings from Phase 1 single dose study relating to safety, achievement of supraphysiologic levels of CFH over time in AH and effect on biomarkers of complement activation in AH after repeat IVT dosing with GEM103 in genetically selected subjects with geographic atrophy (GA) secondary to dry AMD.
Financial Disclosure
CONSULTING: Consulting: Neurotech, Oxurion, Aiviva, ForwardVue, Allegenesys, Eli Lilly, Ownership: ForwardVue, Allgenysis DORC International BV Type of relationship: Advisory Board (A) Nature of compensation: Honoraria (H) Allegro Ophthalmics, LLC Type of relationship: Consultant (C) Nature of compensation: Honoraria (H), Grants (G) Neurotech USA Type of relationship: Consultant (C) Nature of compensation: Honoraria (H) Samsung Bioepis Type of relationship: Investigator (I) Oxurion NV Type of relationship: Investigator (I) Boehringer Ingelheim Pharma GmbH & Co. KG Type of relationship: Investigator (I) Santen Pharmaceutical Co. Ltd. Type of relationship: Consultant (C), Investigator (I) Roche/Genentech Type of relationship: Investigator (I) Gyroscope Therapeutics Type of relationship: Investigator (I) Astellas Pharma Inc. Type of relationship: Investigator (I) Glaxosmithkline Type of relationship: Investigator (I) kalvista Type of relationship: Investigator (I) Santen Type of relationship: Consultant (C), Investigator (I) Graybug Type of relationship: Consultant (C), Investigator (I) Nature of compensation: Grants (G) Aerpio Type of relationship: Investigator (I) Allergan Type of relationship: Investigator (I) Genentech Type of relationship: Investigator (I)
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