In a recent article in Retina Specialist about investigative treatments in retina, 2023 was described as the year of geographic atrophy (GA). Given the recent FDA approval of pegcetacoplan (Syfovre, Apellis Pharmaceuticals), the first such approval for any treatment for GA, and the projected 2023 FDA action on avacincaptad pegol (Zimura, Iveric Bio), it seems like an apt designation. In addition to these two treatments, there are at least 10 other investigative programs in GA ongoing currently.1
WHAT IS GEOGRAPHIC ATROPHY?
Age-Related Macular Degeneration (AMD) is a common eye condition and a leading cause of vision loss among people aged 50 and over. This disease is primarily broken into two subtypes, Dry AMD and Neovascular or Wet AMD. According to the American Academy of Ophthalmology EyeWiki, GA can be seen as part of late-stage dry AMD and is a chronic progressive degeneration of the macula. The condition can lead to permanent loss of visual acuity.2 GA is estimated to affect more than one million people in the U.S. and five million people worldwide and is a leading cause of blindness.34
GEOGRAPHIC ATROPHY TREATMENTS CURRENTLY IN THE PIPELINE
GA treatments currently under study in clinical trials span phases from early Phase I PK studies to Phase III pivotal trials such as those recently submitted to the FDA for Syfovre. The treatments’ therapeutic targets or mechanisms run the gamut from complement inhibition, antioxidative stress, anti-inflammatory, visual cycle modulation, gene therapy, to stem cell-based therapy. This article provides a brief overview of treatments under development.5
Two of the early phase trials underway for GA are for potential stem cell transplantation treatments. Both focus on Retinal Pigment Epithelial (RPE) cells delivered subretinally via injection.
- OpRegen (Lineage Cell Therapeutics, Genentech/Roche). An active but no longer recruiting, Phase I/IIa dose escalation clinical trial (NCT02286089) examined the safety and tolerability of human embryonic stem cell-derived retinal pigment epithelial (RPE) cells delivered into the subretinal space. Another Phase II study (NCT05626114) is actively recruiting and will study the success and safety of subretinal surgical delivery as well as the preliminary activity of OpRegen in participants with GA.
- RPESC-RPE-4Q (Luxa Biotechnology). RPESC-RPE-4W consists of allogeneic RPE stem cell (RPESC)-derived RPE cells isolated from the RPE layer of human cadaveric eyes and then transplanted under the macula. The treatment is being examined in a currently recruiting, first-in-human Phase I/IIa open-label dose-escalation interventional study in 18 subjects (NCT04627428).
Another potential GA treatment that has completed Phase I studies is the Retinol Binding Protein 4 (RBP4) specific antagonist Tinlarebant/LBS-008 (Belite Bio) (NCT03735810). The oral, once-a-day treatment is designed to reduce and maintain the delivery of vitamin A (retinol) to the eye, with the intention of reducing the build-up of toxic vitamin A by-products in ocular tissue. Belite Bio’s web site states that Phase 2 or 3 clinical trials were planned for 20226; however, these studies are not yet listed on ClinicalTrials.gov. Tinlarebant/LBS-008 is also being studied as a treatment for Stargardt’s Disease.
A possible treatment that targets the ocular inflammation of GA is Xiflam (InflammX), which was targeted to enter clinical trials in Q3 2022. Xiflam is an orally administered, once-a-day small molecule that targets inflammasome mediated and recycling inflammation in the eye. InflammX licensed the small molecule and its preclinical IND-enabling data.7 No clinical trials are yet registered on ClinicalTrials.gov.
As mentioned above, toxic vitamin A aggregates have been implicated in GA. In the case of ALK-001 (Alkeus Pharmaceuticals), the treatment is designed to replace natural vitamin A with a form that creates vitamin A dimers more slowly and prevents toxic vitamin A dimer formation. An active but no longer recruiting Phase III trial is underway (NCT03845582). The double-masked, multicenter, randomized, placebo-controlled clinical trial is evaluating the efficacy and safety of ALK-001 in participants with GA secondary to AMD.
Complement inhibition is the therapeutic target with the most ongoing Phase II/III clinical trials in GA. With the recent FDA approval of Syfovre, a complement C3 inhibitor, it has also had the most success. There are still several treatments in development that focus on complement inhibition, and it appears likely that Syfovre will have competitors soon.
- ANX007 (Annexon Biosciences). This treatment is an C1q inhibitor that is under examination in a multicenter, randomized, sham-controlled safety and efficacy study of ANX007 administered by intravitreal Injection in patients with GA, also known as the ARCHER Study (NCT04656561). The study is active but not recruiting.
- NGM621 (NGM Biopharmaceuticals). Another treatment targeting C3 inhibition is NGM621. A Phase II clinical trial (NCT04465955) is active but no longer recruiting. Early results indicated the trial did not meet its primary endpoint, but the company reports a post hoc analysis has shown a subgroup with more robust response. Updated results may be available soon.8
- IONIS-FB-LRx (Ionis Pharmaceuticals/Roche). Ionis-FB-LRx targets the complement factor B gene and is a specific antisense oligonucleotide that is administered subcutaneously. A Phase II study (NCT03815825) is currently recruiting.
- ALXN2040 (Danicopan) (Alexion Pharmaceuticals). This treatment is an orally administered complement factor D inhibitor. The treatment is being examined in a Phase II dose finding study that will also evaluate its efficacy, safety, and pharmacokinetics (NCT05019521).
There are two GA treatments under study in Phase II/III trials that target retinal mitochondrial dysfunction in AMD and attempt to reduce oxidative stress.
- Elamipretide (Stealth BioTherapeutics). Elamipretide is a cell-permeating peptide that targets cardiolipin in mitochondria, thereby reducing reactive oxygen species production. A Phase II study was conducted in 2022 (NCT03891875). The company announced that while the trial’s primary endpoints were not met, further analyses were found to be promising enough to support and inform the continued development of elamipretide for dry AMD.9
- Risuteganib (Luminate, Allegro Ophthalmics). While Risuteganib is not specifically a treatment for GA, it has been studied in intermediate non-exudative AMD (NCT03626636) and the company says it is preparing a Phase IIb/II clinical trial in patients with intermediate dry AMD.10 The treatment is an anti-integrin small peptide designed to downregulate oxidative stress.
GT005 (Gyroscope Therapeutics/Novartis) is a gene therapy developed to rebalance an overactive complement system by expressing the complement factor I (CFI), a natural inhibitor of the complement system. It is a 1-time AAV-based therapy administered by subretinal injection. The treatment is under study in two Phase II trials (NCT04437368 actively recruiting, NCT04566445 active, not recruiting).
Phase III, Submitted to FDA
The next GA treatment that appears to be nearing approval and commercialization is Zimura (avacincaptad pegol) from Iveric Bio. Zimura is a complement C5 inhibitor that met its prespecified endpoint in the Phase II/III GATHER1 study (NCT02686658). Positive topline data from the Phase III GATHER2 study (NCT04435366) was announced in February and the company completed its NDA submission to the FDA in December 2022.
There are numerous potential treatments for GA that have shown promise, and some that have gained, or are near gaining, FDA approval. Continued development and testing of treatments is clearly necessary given the millions of people projected to be diagnosed with AMD and the devastating visual loss that can come with GA.
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1Kirkner RM. 2023: The year of geographic atrophy. A comprehensive look at 87 clinical programs for investigative treatments in retina. 14Feb2023, accessed 09Mar2023. https://www.retina-specialist.com/article/2023-the-year-of-geographic-atrophy
2Shah YS, Krogh Nielsen M, Do DV, Bhagat N, Lim JI. Geographic Atrophy. American Academy of Ophthalmology EyeWiki. Last edited 19Dec2021, accessed 09Mar2023. https://eyewiki.aao.org/Geographic_Atrophy#:~:text=Geographic%20atrophy%20(GA)%20is%20a,retinal%20pigment%20epithelium%20and%20choriocapillaris.
3Rudnicka AR, Jarrar Z, Wormald R, Cook DG, Fletcher A, Owen CG. Age and gender variations in age-related macular degeneration prevalence in populations of European ancestry: a meta-analysis. Ophthalmology. 2012 Mar;119(3):571-80. doi: 10.1016/j.ophtha.2011.09.027. Epub 2011 Dec 15. PMID: 22176800.
4Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, Wong TY. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014 Feb;2(2):e106-16. doi: 10.1016/S2214-109X(13)70145-1. Epub 2014 Jan 3. PMID: 25104651.
5Su D, Boyer D. Geographic Atrophy Treatments in the Pipeline for 2022. Ophthalmology Adviser. 04Feb2022. Accessed 14Feb2023. https://www.ophthalmologyadvisor.com/slideshow/retina-vitreous/potential-therapies-for-geographic-atrophy-in-amd/
8Kirkner, RM. Ibid.
10Kirkner, RM. Ibid.