PMID- 36249705 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20221019 IS - 2666-9145 (Electronic) IS - 2666-9145 (Linking) VI - 2 IP - 2 DP - 2022 Jun TI - A Phase I, Single Ascending Dose Study of GEM103 (Recombinant Human Complement Factor H) in Patients with Geographic Atrophy. PG - 100154 LID - 10.1016/j.xops.2022.100154 [doi] LID - 100154 AB - PURPOSE: To establish the safety, tolerability, pharmacokinetics, and pharmacodynamics of an intravitreal injection of recombinant human complement factor H (CFH), GEM103, in individuals with genetically defined age-related macular degeneration (AMD) and geographic atrophy (GA). DESIGN: Phase I single ascending-dose, open-label clinical trial (ClinicalTrials.gov identifier, NCT04246866). PARTICIPANTS: Twelve individuals 50 years of age or older with a confirmed diagnosis of foveal GA in the study eye. METHODS: Participants were assigned to the increasing dose cohorts and received 1 50-mul intravitreal injection of GEM103 at doses of 50 mug/eye, 100 mug/eye, 250 mug/eye, or 500 mug/eye; dose escalation was dependent on the occurrence of dose-limiting toxicities. MAIN OUTCOME MEASURES: Safety assessments included ocular and systemic adverse events (AEs), ocular examinations, clinical laboratory and vital signs, and serum antidrug antibody levels. Biomarkers, measured in the aqueous humor (AH), included CFH and complement activation biomarkers factor Ba and complement component 3a. RESULTS: No dose-limiting toxicities were reported, enabling escalation to the maximum study dose. No anti-GEM103 antidrug antibodies were detected during the study. Four participants experienced AEs; these were nonserious, mild or moderate in severity, and unrelated to GEM103. The AEs in 2 of these participants were related to the intravitreal injection procedure. No clinically significant ophthalmic changes and no ocular inflammation were observed. Visual acuity was maintained and stable throughout the 8-week follow-up period. No choroidal neovascularization occurred. CFH levels increased in a dose-dependent manner after GEM103 administration with supraphysiological levels observed at week 1; levels were more than baseline for 8 weeks or more in all participants receiving single doses of 100 mug or more. Complement activation biomarkers were reduced 7 days after dose administration. CONCLUSIONS: A single intravitreal administration of GEM103 (up to 500 mug/eye) was well tolerated in individuals with GA. Of the few mild or moderate AEs reported, none were determined to be related to GEM103. No intraocular inflammation or choroidal neovascularization developed. CFH levels in AH were increased and stable for 8 weeks, with pharmacodynamic data suggesting that GEM103 restored complement regulation. These results support further development in a repeat-dose trial in patients with GA with AMD. CI - (c) 2022 by the American Academy of Ophthalmology. FAU - Khanani, Arshad M AU - Khanani AM AD - Sierra Eye Associates, Reno, Nevada. AD - University of Nevada, Reno School of Medicine, Reno, Nevada. FAU - Maturi, Raj K AU - Maturi RK AD - Midwest Eye Institute, Indianapolis, Indiana. FAU - Bagheri, Nika AU - Bagheri N AD - California Retina Consultants, Bakersfield, California. FAU - Bakall, Benjamin AU - Bakall B AD - Associated Retina Consultants, Phoenix, Arizona. FAU - Boyer, David S AU - Boyer DS AD - Retina Vitreous Associates Medical Group, Beverly Hills, California. FAU - Couvillion, Stephen S AU - Couvillion SS AD - California Retina Consultants, Bakersfield, California. FAU - Dhoot, Dilsher S AU - Dhoot DS AD - California Retina Consultants, Bakersfield, California. FAU - Holekamp, Nancy M AU - Holekamp NM AD - Pepose Vision Institute, Chesterfield, Missouri. FAU - Jamal, Karim N AU - Jamal KN AD - Retinal Consultants of Arizona, Phoenix, Arizona. FAU - Marcus, Dennis M AU - Marcus DM AD - Southeast Retina Center, Augusta, Georgia. FAU - Pieramici, Dante AU - Pieramici D AD - California Retina Consultants, Bakersfield, California. FAU - Aziz, Aamir A AU - Aziz AA AD - University of Nevada, Reno School of Medicine, Reno, Nevada. FAU - Patki, Kiran C AU - Patki KC AD - Gemini Therapeutics, Inc., Cambridge, Massachusetts. FAU - Bridges, William Z Jr AU - Bridges WZ Jr AD - Western Carolina Retinal Associates, Asheville, North Carolina. FAU - Barone, Samuel B AU - Barone SB AD - Gemini Therapeutics, Inc., Cambridge, Massachusetts. LA - eng SI - ClinicalTrials.gov/NCT04246866 PT - Journal Article DEP - 20220411 PL - Netherlands TA - Ophthalmol Sci JT - Ophthalmology science JID - 9918230896206676 PMC - PMC9559901 OTO - NOTNLM OT - AE, adverse event OT - AH, aqueous humor OT - AMD, age-related macular degeneration OT - Age-related macular degeneration OT - BCVA, best-corrected visual acuity OT - C3(a/b), complement component 3(a/b) OT - CFB, complement factor B OT - CFH, complement factor H OT - CFP, color fundus photography OT - Complement factor H OT - Complement regulation OT - FA, fluorescein angiography OT - FAF, fundus autofluorescence OT - GA, geographic atrophy OT - GEM103 OT - Geographic atrophy OT - IRC, image reading center OT - LLVA, low-luminance visual acuity OT - NI, near infrared OT - OCTA, optical coherence tomography angiography OT - RPE, retinal pigment epithelium OT - SD, standard deviation OT - nAMD, neovascular age-related macular degeneration EDAT- 2022/10/18 06:00 MHDA- 2022/10/18 06:01 PMCR- 2022/04/11 CRDT- 2022/10/17 05:27 PHST- 2022/02/15 00:00 [received] PHST- 2022/03/18 00:00 [revised] PHST- 2022/04/05 00:00 [accepted] PHST- 2022/10/17 05:27 [entrez] PHST- 2022/10/18 06:00 [pubmed] PHST- 2022/10/18 06:01 [medline] PHST- 2022/04/11 00:00 [pmc-release] AID - S2666-9145(22)00043-4 [pii] AID - 100154 [pii] AID - 10.1016/j.xops.2022.100154 [doi] PST - epublish SO - Ophthalmol Sci. 2022 Apr 11;2(2):100154. doi: 10.1016/j.xops.2022.100154. eCollection 2022 Jun.