Emerging Oral Pharmaceuticals for Dry Age-Related Macular Degeneration: Mechanism of Action, Current Clinical Status, and Future Directions

Abstract

Dry age-related macular degeneration (AMD) has been historically managed with lifestyle modifications, monitoring for conversion to wet AMD, and vitamins. Recently there has been a flurry of research focused on discovering new targets to prevent worsening of dry AMD. In 2023, the US Food and Drug Administration approved the first two intravitreal complement inhibitors to slow the rate of geographic atrophy progression. However, serial intravitreal injections for a chronic progressive disease are burdensome for patients and have procedural risks. Therefore, there is significant research to discover novel oral medications to manage dry AMD. Several oral medications are currently in phase 2 and 3 clinical trials for dry AMD, whereas others have had recent readouts on their clinical trials and efficacy. The purpose of this review is to describe the therapeutic pathways currently being investigated and to provide an update on the clinical status of novel oral medications for the management of dry AMD.

Injecting therapeutics into the eye is one of the most common approaches to treating retinal disease. This delivery method simplifies a variety of pharmacokinetic requirements, including overcoming the blood-retinal barrier. Intraocular injections deliver some of the most successful and impactful drugs in medicine. In particular, intravitreal anti-vascular endothelial growth factor (anti-VEGF) proteins to treat wet age-related macular degeneration (AMD) have shown that monthly injections are safe and effective for preventing retinal bleeding and degeneration. Treatment for the more common dry AMD has turned out to be more challenging. Dry AMD is a slow progressing disease occurring over decades and can lead to geographic atrophy (GA) with significant vision loss.^1,2 Two intravitreal agents for GA were approved in 2023; however, the injections required for years-long treatment are a difficult regimen to maintain for practitioners and patients.^3,4 Oral medications may provide a less burdensome option for therapy over this timeframe.⁵ AREDS and AREDS-2 are oral antioxidant formulations that have been demonstrated to reduce the 5-year rate of developing advanced AMD by 25% at 5 years.⁶ However, AREDS and AREDS 2 were not effective in reducing the rate of GA growth.⁷ In fact, until 2023, there were no pharmaceuticals available to treat GA. This review focuses on the therapeutic targets, promises, limitations, and future directions of oral medications for dry AMD. The review covers medications that have been previously evaluated to illustrate the challenges of oral medications as well as current oral medications under clinical investigation that promise to help patients. Pharmaceuticals are reviewed by class, starting with inhibition of the complement cascade, visual cycle modulation, reducing oxidative stress, and ending with protecting against amyloid beta.

COMPLEMENT INHIBITION

Inhibition of the complement cascade has been a target of numerous medications (Figure 1). Interruption of the alternative complement cascade at the C3 or C5 positions with intravitreal injections has been demonstrated to reduce GA progression by 14% to 27%.^8–11

Figure 1.

Alternative complement pathway inhibition. The alternative pathway is initiated with the spontaneous hydrolysis of C3 after exposure to microbial antigens. Factor B binds to C3H2O and factor D cleaves factor B to produce the first step in the pathway. A similar reaction occurs with C3b during the amplification loop. Danicopan and iptacopan are antagonists against factor D and factor B, respectively. United States Food and Drug Administration (FDA)-approved intravitreal inhibitors, pegcetacoplan, and avacincaptad pegol, act later in the pathway. Pegcetacoplan acts on C3 and the C3 convertase, inhibiting the production of C3b. Avacincaptad pegol inhibits the cleavage of C5 by C5 convertase to produce the C5b subunit, which then sequentially binds to C6, C7, C8, and molecules from C9 to form the membrane attack complex.

Iptacopan is an oral complement factor B inhibitor and is the first approved oral monotherapy for paroxysmal nocturnal hematuria (PNH).^12,13 A phase 2 trial expected to conclude in 2026 is evaluating iptacopan in patients with early to intermediate AMD in one eye and neovascular AMD in the other eye. The primary endpoints are new incomplete retinal pigment epithelial (RPE) and outer retinal atrophy or advancement to late AMD in the early to intermediate AMD eye. Secondary endpoints include adverse events, change in best-corrected visual acuity (VA), low luminance VA, and contrast sensitivity.¹⁴ Known drug side effects of iptacopan in PNH are susceptibility to various infections and encapsulated bacteria.¹²

Danicopan is a factor D inhibitor that was approved for use as an add-on treatment for PNH in 2024^15–17 and is being evaluated for GA in AMD. For ocular use, danicopan has been shown to concentrate in the retina and uveal tract compared with plasma in pigmented rabbits and rats.^18–20 After oral administration, it may concentrate in the retina and uveal tract to treat GA. Currently, danicopan is undergoing a dose-finding, phase 2 investigation for GA with a primary outcome of the square root of total GA lesion at weeks 52 and 104.²¹

INFLAMMATION

Inflammation is known to play a vital part in the pathogenesis of AMD on multiple levels. Inflammation-driven cell damage in the choriocapillaris and breakdowns in Bruch’s membrane are hallmarks of AMD.²² Targeting these pathways may rescue endothelial cells, reduce inflammatory components that promote drusen formation, and prevent RPE atrophy (Figure 2).

Figure 2.

Tetracyclines and metformin for age-related macular degeneration (AMD). (A) A healthy retina is pictured versus dry AMD. In a diseased state, matrix metalloproteinases circulating the bloodstream accumulate into the Bruch’s membrane and disrupt the extracellular matrix, leading to the formation of drusen.^63–65 Minocycline and doxycycline have demonstrated metalloproteinase inhibition, serving as a possible therapeutic for AMD. (B) Metformin possesses antiangiogenic and antioxidant properties that make it appealing as a possible therapeutic agent, as oxidative stress is a major contributor in AMD and the inhibition of angiogenesis could prolong the onset of wet AMD.

As a group, tetracyclines cause matrix metalloproteinase inhibition and have neuroprotective properties^23,24 (Figure 2A). Both doxycycline and minocycline have demonstrated central nervous system and ocular penetration.²⁵ One phase 2⁄3 study has been completed for doxycycline 40 mg versus placebo (2013 to 2020), but results have not been posted.²⁶ Minocycline has been tested in a phase 2 single-arm, 45-month trial (2016 to 2023) with 37 patients with GA. This study had a 9-month run-in phase and 3 years of treatment with 100 mg given twice daily. No significant difference was found for the primary endpoint for mean square root of GA enlargement. The study was powered to detect a 13% difference.²⁷

Another anti-inflammatory drug is metformin, which has antioxidation, antiangiogenesis, and neuroprotective properties (Figure 2B). Although there are mixed results, several retrospective studies have shown an association between metformin use and decreased risk of AMD.^28–32 An exploratory prospective study of metformin’s effect on progression for GA in patients without diabetes (n = 66) was completed in 2023, but no statistical difference was seen. Limitations of the study included limited enrolment (planned for n = 100 to detect 33% reduction).³³

VISUAL CYCLE

The visual cycle regenerates 11-cis-retinal from all-trans-retinal. This cycle consists of multiple enzymatic steps in the rod photoreceptors and RPE cells (Figure 3). In Stargardt disease, a retinal degenerative disease caused by variants in the ABCA4 gene of the visual cycle, visual cycle inhibition may slow retinal degeneration, which has led to some of these therapeutics to be studied in AMD. One visual cycle enzyme, RPE65, is an RPE-specific protein that converts retinyl esters to 11-cis-retinol as a vital step in the regeneration of 11-cis-retinal. Because this enzyme is RPE specific, it is a desirable target for oral drugs.³⁴ Emixustat is a small-molecule inhibitor of RPE65, which is currently in clinical trials for Stargardt disease.³⁵ With oral administration, it distributes to the ocular tissues and inhibits the visual cycle.^36–38 Side effects include chromatopsia (dark or colored tint to vision), delayed dark adaptation, and reduced VA, which were seen in a dose-dependent manner between 86% to 100% of patients.³⁵ Emixustat went into phase 3 clinical trials in 2018. However, for AMD, phase 2b/3 trials for GA did not demonstrate a significant difference in growth rate of the GA.³⁹

Figure 3.

Schematic depicting the visual cycle as it occurs in the rod photoreceptors and retinal pigment epithelium (RPE) in (A) healthy and (B) diseased retinas. All-trans-retinol (at-ROL) is transported to the RPE by retinol binding protein 4 (RBP4). This transport is inhibited by tinlarebant and fenretinide. During the visual cycle, all-trans-retinal esters (at-RE) are converted to 11-cis-retinol (11c-ROL) by the RPE65 enzyme. Eximustat inhibits the activity of the RPE65 enzyme, slowing the visual cycle. As the visual cycle proceeds in the photoreceptor outer segments, byproducts such as A2E and bisretinoids are formed by visual cycle intermediates, which contribute to drusen. The dimerization of vitamin A and formation of A2E are reduced when supplemented with Gildeuretinol. Sigma-2 receptors, the targets of CT1812, are depicted as a yellow 4-transmembrane domain proteins in the RPE.

Another oral drug targeting the visual cycle is fenretinide, a synthetic derivative of vitamin A that acts as a competitive inhibitor of retinol uptake to the RPE.^40,41 However, when evaluated in a 2-year phase 2 trial for GA, there was not a statistically significant difference in growth rate of GA relative to control.⁴² This study had a 28% rate of attrition, with a large portion due to side effects from fenretinide. For a subgroup of patients taking 300 mg fenretinide who achieved serum retinol binding protein (RBP4) levels of ≤ 2 mg/dL, there was a 0.33 mm² reduction in lesion growth rate per year compared with placebo. However, this did not meet statistical significance.

Tinlarebant is a serum RBP4 antagonist, which lowers the levels of RBP4 and vitamin A, leading to reduced delivery of vitamin A to the visual cycle, thus decreasing toxic byproducts. In a 24-month phase 2 trial for Stargardt disease, participants treated with tinlarebant showed lower atrophic lesion growth compared to historical controls with similar baseline characteristics, and 42% of affected participants did not develop atrophic retinal lesions.⁴³ Tinlarebant is currently under a 104-patient phase 3 investigation for Stargardt disease.⁴⁴ The primary endpoint is a change in atrophic lesion size as measured by fundus autofluorescence relative to placebo. Side effects of tinlarebant include xanthopsia/chromatopsia and delayed dark adaptation.^45,46 In AMD, a phase 1 safety trial was completed for GA with an approved enrollment of 71 individuals with treatment endpoints at 28 days. There is currently an ongoing enrollment for a phase 3 trial for GA.⁴⁷

TOXIC BYPRODUCTS

During the visual cycle, a buildup of side-byproducts occurs. Bisretinoids, A2E, and lipofuscin disrupt retinal architecture and all of these side-byproducts contribute to macular degeneration. Different therapeutic approaches attempt to mitigate the negative effects of these toxic byproducts (Figure 3).

Gildeuretinol is a C20-D3-vitamin A pharmaceutical that does not slow the visual cycle but instead uses a modified vitamin A that reduces toxic byproducts from the visual cycle. Vitamin A dimerization is thought to play a role in lipofuscin formation and retinal degeneration.⁴⁸ The rate-determining step in vitamin A dimerization is the cleavage of a C20 carbon-hydrogen bond.⁴⁹ When the C20 hydrogen atoms are replaced with deuterium, the rate of cleavage is decreased and dimerization is reduced.⁴⁹ In Stargardt disease, the TEASE study saw 21% slower growth rates of square root of atrophic lesions compared to placebo.⁵⁰ In TEASE-3, which targets early-stage disease, the first three teenage patients remain asymptomatic over 2 to 6 years without disease progression.⁵¹ For GA, recruitment ended in 2021 in a phase 2/3 trial with 300 patients.⁵² Readout is planned in 2024 with a primary endpoint of GA growth rate.

CT1812 is a sigma-2 antagonist and acts by binding sigma-2 on RPE cells. Sigma-2 regulates oligomer receptors and displaces amyloid-β oligomers bound at neuronal receptor synapses.⁵³ Amyloid-β oligomers have been found in drusen, at the edges of GA, and are thought to contribute to the pathogenesis of macular degeneration.^54–56 Furthermore, many of the proteins disrupted in AMD have been found to be differentially expressed with CT1812 treatment.^57–59 CT1812 is currently being evaluated for Alzheimer’s disease and dementia with Lewy bodies.^60,61 In GA, a phase 2 clinical trial is currently enrolling patients. The primary endpoint is 2-year GA growth of CT1812 versus placebo. Secondary endpoints include safety and tolerability, plasma concentration, ellipsoid-zone area, and drusen volume.⁶²

CONCLUSION

Therapeutic approaches to dry AMD are evolving rapidly. A few years ago, the management of dry AMD consisted of management of oxidative damage by avoidance of hazards such as ultraviolet light exposure, smoking, dietary considerations, vitamin supplementation, and monitoring for conversion to neovascular AMD. Currently, there are a number of approaches to address the pathogenesis of dry AMD. These include complement cascade inhibition, visual cycle modulation, inflammation reduction, and reduction or removal of toxic byproducts of the visual cycle, as well as gene therapies and cell-based therapies.⁵ Methods of delivery include intravitreal injections of medication or gene therapies, subretinal injections of gene therapies, subretinal implantation of cell-based therapies, intravitreal implantation of cell-based therapies, intravenous infusion, subcutaneous injection, and oral delivery.

Intravitreal complement inhibition has been demonstrated to reduce the growth rate of GA lesions.^8,11 Several oral complement inhibitors are currently under investigation in phase 2 trials. Targeting inflammation has been evaluated with doxycycline and minocycline. Trial results for doxycycline have not been published to date, and minocycline did not meet GA growth reduction endpoints in a phase 2 trial.

Visual cycle modulation is used to reduce toxic byproducts of the visual cycle. Oral emixustat and fenretinide did not meet primary endpoints in phase 3 trials of GA, although there were high rates of discontinuation due to medication side effects. Tinlarebant is currently under phase 3 investigation for GA. Gildeuretinol reduces toxic byproducts by decreasing vitamin A dimerization and formation of A2E and lipofuscin with a phase 3 readout planned in 2024. CT1812 displaces amyloid-β oligomers, which are found in drusen, and patients are currently being enrolled in a phase 2 trial.

CHALLENGES AND FUTURE DIRECTIONS

Oral delivery of medication is used for many chronic, long-term diseases due to simplicity of delivery and ease of termination or altering dose. As the eye is easily accessible and is able to act as a reservoir, many ocular therapies are applied as eye drops or as intravitreal injections. This allows high, local therapeutic levels of medication while minimizing systemic effects. As oral medications are provided systemically, the side-effect profile of the medication needs to be balanced with the advantages of oral delivery. Several of the medications discussed have had adherence problems due to systemic and ocular side effects. For example, fenretinide trended toward efficacy with higher dosing; however, there were large levels of nonadherence due to ocular and systemic side effects.⁴² Overall, it did not meet primary endpoints in clinical trials. Future directions in this field include using these novel modalities for oral systemic medications that concentrate or locally target ocular tissue with low side-effect profiles, extended drug delivery through drug-eluting implants, or through safe cell-based or gene therapies.