Geographic atrophy is taking center stage

(Image Credit: AdobeStock/bukhta79)

Age-related macular degeneration (AMD) is a potentially vision-threatening disease, with more than 20 million Americans having received this diagnosis. Geographic atrophy and neovascular AMD are the end stages of AMD, and approximately 1.5 million individuals are living with these vision-threatening forms.

Although excellent therapies have been developed for neovascular AMD that can delay disease progression, the developmental process has been slower in the battle to control geographic atrophy.

Sruthi Arepalli, MD, a vitreoretinal surgeon and uveitis specialist at Emory University in Atlanta, Georgia, described the drugs that are in the pipeline for treating late-stage AMD and the various routes of administration that the drugs offer. She also discussed the current status of various treatments at the 2023 Women in Ophthalmology Summer Symposium in Marco Island, Florida.

Geographic atrophy has been a frustrating disease to watch evolve as there have not been effective treatments to prevent its progression. This has led scientists and clinicians to question what pathways can be intercepted to slow down the progression of dry AMD.

One pathway that has become popular in the past few decades is the complement pathway. Investigators evaluated the complement pathway in 2005 and reported that a polymorphism in the CFH gene (located on chromosome 1) is linked to the development of AMD.

“This polymorphism binds heparin and C-reactive protein,” investigators said in the report. “The CFH gene is…repeatedly linked to AMD in family-based studies.”¹

There are 2 therapies that are linked to complement therapy that have been approved and will be discussed at the end of this article. Additionally, there are other pathways currently under investigation that will also be discussed below. Arepalli provides a short summary of a few medications in development; the routes of administration include oral, subcutaneous, subretinal gene therapy, and intravitreal drug administration.

Oral route

Gildeuretinol(ALK-001; Alkeus Pharmaceuticals) is an oral form of vitamin A that was originally developed to treat Stargardt disease, for which results are expected in 2025, according to the company. A phase 3 study of 200 patients with geographic atrophy associated with dry AMD is also under way, and the results are expected in late 2023.

Danicopan (Alexion) is a complement factor D inhibitor that quiets the immune response. The drug is being evaluated in a phase 2 trial, and results are expected in 2025.

Tinlarebant (LBS-008; Belite Bio) is an oral treatment that reduces retinol. The drug is currently being studied in the phase 2 PHOENIX study, but a release date for the results is currently unknown.

Subcutaneous administration

Elamipretide (Stealth BioTherapeutics) targets mitochondria and is being evaluated in the phase 2 ReCLAIM-2 study (NCT03891875). The drug works by causing a reduction in ellipsoidal zone attenuation. No target date for release of the results has been announced.

IONIS-FB-LRx (Ionis Pharmaceuticals, Inc) targets complement factor B. It is being studied in the phase 2 GOLDEN trials (NCT03815825), and results are expected to be announced in late 2023.

Subretinal gene therapy

RG6501(Lineage Cell Therapeutics, Inc) is currently in a phase 2 study and RPESC-RPE-4W (Luxa Biotechnology) is in a phase 1/2a study (NCT04627428). Both studies are currently enrolling patients, and both therapies provide subretinal delivery of retinal pigment epithelial cells.

Intravitreal delivery route

NGM621 is a humanized IgG1 monoclonal antibody that inhibits complement C3. The drug was being investigated in the phase 2 CATALINA trial (NCT04465955), but it did not meet the primary end point (ie, reduction of geographic atrophy compared with sham treatment).

ANX007 (Annexon, Inc), an antigen-binding fragment to complement C1q is being evaluated in the phase 2 ARCHER study (NCT04656561). The results showed that the drug protected the vision in 72% of patients dosed monthly and in 48% of patients who were dosed every 2 months.

Approved therapies

Pegcetacoplan(Syfovre; Apellis Pharmaceuticals, Inc) is the first and only therapy approved by the FDA for the treatment of geographic atrophy. The formulation works by targeting C3.²

This drug has been evaluated in the phase 2 FILLY trial (NCT02503332), as well as the phase 3 OAKS and DERBY trials (NCT03525613; NCT03525600).

During FILLY, investigators reported that “local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of [geographic atrophy] compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.”²

The more recent OAKS and DERBY phase 3 studies included a total of 1258 patients with AMD and geographic atrophy. The participants were randomly assigned to monthly or every-other-month treatment, or to sham injection. The primary end point was the change in the total lesion size of the geographic atrophy at the 12-month examination, as evaluated based on autofluorescence.³

The results demonstrated that pegcetacoplan showed reductions in the growth of geographic atrophy lesions from baseline to 2 years in OAKS and DERBY, whereas only OAKS showed significant decreases in growth. The drug exhibited a good safety profile during the clinical trials.⁴ Recently, there have been safety reports regarding intraocular inflammation after the administration of the drug, but it remains to be seen what the true cause of inflammation is.

Avacincaptad pegol intravitreal solution(Izervay; Iveric Bio, Inc) is also approved to treat geographic atrophy based on the results of the phase 2/3 GATHER1 trial and the phase 3 GATHER2 trial (NCT02686658; NCT04435366).

In these trials, 734 patients with AMD and geographic atrophy that did not involve the fovea were included. The primary end point was the therapeutic effect on the geographic atrophy.

The results indicated that the end points were met and the lesions exhibited less growth and patients had higher preservation of vision.5

Arepalli explained that real-world clinical data are needed for both of these drugs.

“It’s an exciting time with multiple avenues under investigation for targeting geographic atrophy,” Arepalli said. “As always, it’s important to discuss the potential risks and benefits with each individual as we enter into the real-world use of these medications.”

Sruthi Arepalli, MD

E: sruthiarepalli@gmail.com

Arepalli is an assistant professor at Emory University in Atlanta, Georgia. She has no financial interest in this subject matter.

References

1. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385-389. doi:10.1126/science.1109557

2. Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. Ophthalmology. 2020;127(2):186-195. doi:10.1016/j.ophtha.2019.07.011

3. Steinle NC, Pearce I, Monés J, et al. Impact of baseline characteristics on geographic atrophy progression in the FILLY trial evaluating the complement c3 inhibitor pegcetacoplan. Am J Ophthalmol. 2021;227:116-124. doi:10.1016/j.ajo.2021.02.031

4. Khan H, Aziz AA, Sulahria H, et al. Emerging treatment options for geographic atrophy (GA) secondary to age-related macular degeneration. Clin Ophthalmol. 2023;17:321-327. doi:10.2147/OPTH.S367089

5. Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. Ophthalmology. 2021;128(4):576-586. doi:10.1016/j.ophtha.2020.08.027