CFH serves as an important endogenous regulator of innate immune system activity, functioning to selectively bind and protect self-tissues and serving as an efficient inhibitor of the alternative complement pathway. Conversely, a wide and diverse range of literature implicates polymorphisms in the CFH genetic code in the development of age-related macular degeneration (AMD).1-4 Indeed, factor H functional insufficiency has been linked to impaired lipid trafficking on retinal pigment epithelium (RPE) cells5 and its chronic, dysfunctional amplification in geographic atrophy/AMD of membrane attack complex6 (the ultimate downstream effector molecule in complement activation that triggers pathways leading to cell lysis and death7). Furthermore, preclinical models suggest that insufficient CFH expression is strongly correlated with increased risk of AMD.8
Taken together, these data provide rationale for restoring function to CFH as a mechanism to thwart crucial pathways involved in AMD pathobiology. To date, Gemini Therapeutics is believed to be the first company to solve the manufacturing challenge in making a full-length human recombinant CFH molecule. Initial clinical study data show that its GEM103 therapeutic can safely be injected intravitreally, where it is distributed and retained within relevant ocular tissues at greater rates than endogenous levels.9
“The hypothesis is that GEM103 will provide regulation back to the system, as CFH is the endogenous complement regulator for the alternative pathway,” said Samuel Barone, MD, Chief Medical Officer of Gemini Therapeutics. “We’re restoring the system and allowing it to take care of itself.”
Intuitively, such an approach would seem highly advantageous for the 30% to 50% of AMD patients expressing common and rare loss of function polymorphisms in CFH.4 Yet, restoration of CFH may have additional non-canonical effects beyond its implications for regulating the alternative pathway, including restoring retinal homeostasis, supporting phagocytosis, and increasing lipid clearance. Thus, restoring CFH functionality, regardless of one’s genetic propensity for developing AMD, may be a case of “never having too much of a good thing”—relative to other approaches to inhibit or shut down complement activity, GEM103 may have a more acceptable safety profile as it aims to add back in physiologic activity rather than take away a complement activation product to induce therapeutic benefit.
Earlier this year, Gemini announced initial results from its phase 2a ReGAtta study, a dose escalation trial of GEM103, which is designed to evaluate safety and tolerability, as well as measures of intraocular pharmacokinetics and disease-relevant biomarkers, to inform the late-stage development program. The initial data show GEM103’s ability to regulate complement with immediate and sustained reduction of complement biomarkers (Ba and C3a) elevated in AMD. Intravitreal delivery of GEM103 was well-tolerated with no ocular serious adverse events and no serious adverse events related to GEM103; there was no increased risk of choroidal neovascularization. Furthermore, pharmacokinetics following GEM103 dosing supports every other month dosing.9,10
“We are very excited about these data. I think if we would have drawn the curves on a white board before we got the data to see what an optimal curve would look like in terms of the biomarkers, they would look pretty close to the actual results,” said Dr. Barone.
Every early data release involving virtually any drug or therapeutic comes with the usual caveat: further study will help substantiate the findings and give a better sense of safety and efficacy. Gemini is in the process of planning an adequate and well-controlled study to demonstrate clinical effect in the progression of geographic atrophy. The company is also in discussions to align with regulators and looks forward to initiating this study in the first half of 2022.
For a disease state like AMD in which there is no current therapeutic, restoring CFH functionality via a precision medicine approach offers tremendous potential to help a large subset of patients with unmet need. Additionally, what Gemini learns about its approach in the eye may have relevance for other disease states. Beyond its work in dry AMD, Gemini has already initiated preclinical studies investigating whether its precision medicine approach may be beneficial as an adjunct to anti-VEGF therapy in neovascular AMD, and it has also started studies of GEM307, a monoclonal potentiating antibody for CFH, in systemic renal disease.
1. Haines JL, Hauser MA, Schmidt S, Scott WK, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419-421.
2. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385-389.
3. Edwards AO, Ritter R 3rd, Abel KJ, et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421-424.
4. Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA. 2005;102:7227-7232.
5. Weismann D, Hartvigsen K, Lauer N, et al. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature. 2011;478(7367):76-81.
6. Radu RA, Hu J, Jiang Z, Bok D. Bisretinoid-mediated complement activation on retinal pigment epithelial cells is dependent on complement factor H haplotype. J Biol Chem. 2014;289(13):9113-9120.
7. Mullins RF, Schoo DP, Sohn EH, et al. The membrane attack complex in aging human choriocapillaris: relationship to macular degeneration and choroidal thinning. Am J Pathol. 2014;184(11):3142-3153.
8. Ding JD, Kelly U, Landowski M, et al. Expression of human complement factor H prevents age-related macular degeneration-like retina damage and kidney abnormalities in aged Cfh knockout mice. Am J Pathol. 2015;185(1):29-42.
9. Gemini Therapeutics. Based on initial data from its ongoing phase 2a study of GEM103 in patients with geographic atrophy secondary to dry age-related macular degeneration as of May 2021.
10. Gemini Therapeutics. Gemini Therapeutics announces initial data from its ongoing phase 2a study of GEM103 in patients with geographic atrophy secondary to dry age-related macular degeneration. June 22, 2021. Press release available at: https://investors.geminitherapeutics.com/news/news-details/2021/Gemini-Therapeutics-Announces-Initial-Data-From-Its-Ongoing-Phase-2a-Study-of-GEM103-in-Patients-With-Geographic-Atrophy-Secondary-to-Dry-Age-Related-Macular-Degeneration/default.aspx.
