- Studies show mechanism of action and biodistribution of GEM103 and support continued development as a potential treatment for AMD
Gemini Therapeutics, Inc. (Nasdaq: GMTX), a clinical stage precision medicine company developing innovative treatments for genetically defined age-related macular degeneration (AMD), today announced one oral presentation and the presentation of three posters at the 13th International Conference on Complement Therapeutics held in Ioannina, Greece from September 8-13, 2021.
“The results presented today underscore the potential of GEM103 as the next class of complement therapeutic for the treatment of AMD by regulating complement. These results to date add to our understanding of GEM103’s mechanism of action, points of intervention in the pathway, duration and the ability of complement factor H to restore regulation of complement activity in the eye,” said Walter Strapps, Ph.D., Chief Scientific Officer of Gemini Therapeutics. “Additionally, these data contribute to the growing body of evidence that gives us confidence in this potential novel intravitreal treatment and the importance of the restoration of complement regulation, rather than indiscriminate inhibition, as a therapeutic approach.”
Gemini is currently conducting the ReGAtta study, an ongoing Phase 2a open-label, single-arm study of GEM103 in genetically-defined patients with geographic atrophy (GA) secondary to dry AMD. ReGAtta is designed to investigate the safety and tolerability, PK, and evidence of complement regulation through ocular biomarkers following repeat intravitreal administration of GEM103. Based on the previously announced initial results of the ReGAtta study, Gemini plans to advance GEM103 into late-stage studies that will be designed to assess efficacy and safety of GEM103 in the treatment of GA.
The oral presentation was given by Dr. Robyn Biggs, Associate Director – Research on September 10, 2021 at 9:35 am (GMT+3) and was titled “Mechanism of Action of Complement Factor H as a Therapeutic in AMD”. The presentation covered a study designed to understand the non-canonical complement pathway mechanisms of action (MOA) as it relates to the RPE cell health and homeostasis, and GEM103’s demonstration of several advantages as a potential therapeutic for the treatment of AMD. Notably, the study results show that GEM103 localized to “self cell” surfaces, including the RPE, using endogenous mechanisms and remained bound on the cell surface for an extended duration. GEM103 also inhibited inappropriate complement activation selectively on host cells by inhibiting deposition of C3-convertase while leading to a reduction in inflammation markers C3a and Ba levels.
Posters presented include the following:
“Recombinant Complement Factor H (GEM103) Ocular Biodistribution and Activity Following Intravitreal Administration in Cynomolgus Monkeys”
Prior to initiating its ongoing Phase 2a clinical program of GEM103, researchers studied the biodistribution and half-life of GEM103 in the ocular tissue of non-human primates following a single IVT dose. Results demonstrate that GEM103 rapidly biodistributed to key tissues of interest including the retina, choroid and retinal pigment epithelium (RPE), and was retained on the RPE cell surface for an extended duration and remains functionally active in the eye following IVT-administration. Additionally, the pharmacokinetic profile for GEM103 was consistent across retinal tissues, with 24-hour Cmax observed in the vitreous humor, retina, RPE, choroid and aqueous humor post IVT dose.
“Complement Factor H (CFH) Potentiating Antibody (PoAb) Enhances Cell Surface FH Localization and Activity and Maintains Fluid-phase Regulation in vivo”
In-vitro assays demonstrate the ability of a novel CFH PoAb to promote CFH localization to cell surfaces and thereby enhance CFH complement regulatory function at the activation site. Subsequent treatment of the PoAb in a preclinical renal disease model showed similar behavior in vivo leading to reduction in the pathologic C3 deposits on kidney while maintaining fluid phase regulation and endogenous complement driven encapsulated bacteria clearance mechanisms.
“AMD Associated Variants in Complement Factor I (CFI) Hinder CFI Expression, Function or Both”
In a preclinical study evaluating the AMD risk-associated CFI protein variants for their effect on CFI expression and function as compared to a non-risk form in a panel of in vitro assays, risk variants were observed to have insufficient functional activity, reduced expression level, or both. Overall, the level of CFI functional deficiency correlated with AMD disease risk for the variants studied.
Information on Gemini Therapeutics, including GEM103 and initial ReGAtta data, and posters and presentations made by the company at the 13th International Conference on Complement Therapeutics are available on Gemini Therapeutics’ website under the Investors & Media section: Events and Presentations.
About the Phase 2a ReGAtta Study
The ongoing Phase 2a, multi-center, open-label, multiple ascending dose study of GEM103 in genetically-defined patients with GA secondary to dry AMD is designed to investigate safety and tolerability, PK, exploratory ocular biomarkers, and measures of retinal anatomy and function and not assess GA efficacy of GEM103. GEM103 is delivered monthly by an intravitreal injection and PK and biomarkers of complement regulation are determined from aqueous humor sampling. To date, the study has enrolled 62 patients with gene variants that have been linked to the progression of dry AMD from early to late-stage. The study’s design allowed for imbalances in GA baseline characteristics and does not inform GA efficacy and does not allow comparisons with uncontrolled fellow eye with similar imbalances.
Gemini’s lead program, GEM103, is a pioneering precision medicine approach, targeting trial enrichment with genetically defined patients. GEM103 targets a genetically defined subset of age-related macular degeneration (AMD) patients with complement dysregulation. Of the 15 million dry AMD patients in the United States, approximately 40% (or six million) have variants in the complement factor H (CFH) gene. Such loss of function variants are associated with increased dry AMD disease risk. GEM103 is believed to be the first ever recombinant complement regulator and is a full-length and human, recombinant complement factor H (rCFH) protein. When delivered by intravitreal injection, we believe GEM103 has the potential to address unmet medical need in genetically defined AMD patients by circumventing the complement dysfunction resulting from CFH loss of function variants and slowing the progression of their retina disease. The U.S. Food and Drug Administration (FDA) granted Fast Track Designation for GEM103 for the treatment of dry AMD in patients with CFH loss of function gene variants.
About Dry Age-Related Macular Degeneration (AMD)
Age-related macular degeneration (AMD) is a progressive retinal disease affecting millions of older adults, and the leading cause of irreversible blindness in the western world. Symptoms, which include blurry vision, loss of night vision and loss of central vision, make activities of daily living such as reading, driving and even recognizing faces progressively more difficult. Third-party reports indicate there are approximately 16 million patients with AMD in the United States alone. Dry AMD, which results from an interaction of environmental and genetic risk factors, represents about 90% of that population (or about 15 million) in the US compared to about 1.4 million with wet AMD. Genetic risk of developing dry AMD is significant, with approximately 70% attributable risk of advanced disease to heritability, while aging and smoking confer the strongest non-genetic risk. CFH risk variants occur in approximately 40% of patients with dry AMD and these patients have a significantly increased risk of developing the disease as well as progression from intermediate AMD to GA. The complement system, of which CFH is a regulator, is dysregulated in patients with these risk variants, and results in amplification of aberrant inflammatory responses in the eye. Over time, this dysregulation leads to damage to the macular region of the retina.
About Gemini Therapeutics
Gemini Therapeutics is a clinical stage precision medicine company developing novel therapeutic compounds to treat genetically defined age-related macular degeneration (AMD). Gemini’s lead candidate, GEM103, is a recombinant form of human complement factor H protein (CFH) and is designed to address both complement hyperactivity and restore retinal health in patients with AMD. GEM103 is currently in a Phase 2a trial in dry AMD patients with a CFH risk variant and a Phase 1/2a study in patients with neovascular age-related macular degeneration with or at risk for macular atrophy. Gemini has generated a rich pipeline including recombinant proteins, gene therapies, and monoclonal antibodies and is advancing a potentiating antibody for CFH, GEM307, into clinical development for treatment of systemic diseases.
For more information, visit www.geminitherapeutics.com.
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Joshua R. Mansbach