High-resolution multimodal imaging is key in dry AMD therapeutic development, future management

Despite the great strides made in better treatments for patients with exudative age-related macular degeneration (AMD), similar progress for the dry form of the disease has remained elusive. However, several potential strategies working their way through the investigative pipeline are showing promise.

Investigators are assessing a variety of approaches to reduce disease progression. These include drugs with antioxidative properties, inhibitors of the complement cascade, neuroprotective agents, visual cycle inhibitors, gene therapy, and cell-based therapies.¹

Compounds that suppress inflammation by inhibiting the complement pathway have attracted significant attention, with 2 showing promising results in phase 3 trials: pegcetacoplan (formerly APL2-103; Apellis Pharmaceuticals) and avacincaptad pegol (Zimura; Iveric Bio).¹

Results from Allegro Ophthalmics’ phase 2a study of risuteganib, a small peptide oxidative stress stabilizer, showed that risuteganib can reverse vision loss and restore function.² Stealth BioTherapeutics announced top-line data from its phase 2 trial evaluating elamipretide, saying that although it did not meet its primary end points, a key secondary end point showed the agent categorically improved visual function for patients with geographic atrophy (GA).³

OCT: assessing end points, monitoring GA progression

Alongside the development of new therapeutics, high-resolution optical coherence tomography (OCT) for assessing end points in clinical studies, detecting early markers of the disease, and eventually tracking treatment efficacy is becoming increasingly important. Platforms such as Spectralis (Heidelberg Engineering) that provide high-resolution, high-density OCT scans with multiple simultaneous fundus imaging modalities provide the type of diagnostic detail necessary in this new era.

GA is considered an end-stage manifestation of AMD. Modern multimodal high-resolution OCT helps the study of atrophy, with fundus autofluorescence (FAF) imaging now being the gold standard for detecting, monitoring, and quantifying atrophic lesions. These technological advances in imaging capabilities have made it necessary to develop consensus terminology and criteria for defining atrophy based on multimodal fundus imaging combined with OCT findings that can now differentiate affected retinal layers.

The international panel for the Classification of Atrophy (CAM) program has introduced 4 new terms that signify the evolution of the atrophic process, recognizing that photoreceptor atrophy can occur without retinal pigment epithelium (RPE) atrophy and that atrophy can undergo an evolution of different stages. The terms are incomplete RPE and outer retinal atrophy (iRORA) (Figure 1), complete RPE and outer retinal atrophy (cRORA) (Figure 2), complete outer retinal atrophy (cORA), and incomplete outer retinal atrophy (iORA).^4,5

The program further defined cRORA, an end point for atrophy that occurs in the presence of drusen, by the following criteria: (1) a region of hypertransmission of at least 250 µm in diameter, (2) a zone of attenuation or disruption of the RPE of at least 250 µm in diameter, and (3) evidence of overlying photoreceptor degeneration, all occurring in the absence of signs of an RPE tear.^4,5 iRORA describes a stage of AMD where these OCT signs were present but did not fulfill all the criteria for cRORA. iRORA is defined (1) as a region of signal hypertransmission into the choroid, (2) a corresponding zone of attenuation or disruption of the RPE, and (3) evidence of overlying photoreceptor degeneration.⁵ As seen in Figures 1 and 2 from the same patient 2 years apart, iRORA eventually will develop into cRORA.

Relevant findings

Double layer signs (DLS) are an important OCT finding that, in some cases, may herald patients at higher risk for developing exudative disease. High-resolution imaging with Spectralis allows clinicians to fully assess the retina, RPE, and choroid in order to identify these changes. For example, smooth DLS could be indicative of extensive sub-RPE deposits, whereas irregular DLS may be more indicative of subclinical choroidal neovascularization (Figure 3). The quality and density of the OCT scans are critical to observing features such as the quantity and content of drusen and discerning the appearance of hyper-reflective cores (Figure 4).

A separation between the RPE basement membrane and Bruch membrane, a feature that can only be identified by OCT, is also associated with progression. Standard fundus photography cannot fully capture areas of cRORA. Spectralis OCT and FAF help identify and delineate these features that will become increasingly critical in identifying patients who are at risk for progression to advanced AMD. FAF, the accepted standard for quantitating GA or cRORA, is being used as an end point in clinical trials. When therapies become available, this will prove essential for selecting and monitoring patients who would potentially benefit from treatment.

Conclusion

Therapies for dry AMD are on the horizon. It is important to be prepared with multimodal OCT platforms that have the ability to accurately and precisely discern features associated with progression as well as to monitor treatment results. These platforms also will ensure specialists can monitor and treat patients with both wet and dry AMD on a practical, day-to-day basis.

Karl G. Csaky, MD, PhD

E: kscaky@retinafoundation.org

Csaky is a vitreoretinal specialist and is the T. Boone Pickens Senior Scientist at the Retina Foundation of the Southwest in Dallas, Texas. He is a consultant for Heidelberg Engineering.

References

1. Cabral de Guimaraes TA, Varela MD, Georgiou M, Michaelides M. Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions. Br J Ophthalmol. 2022;106(3):297-304. doi:10.1136/bjophthalmol-2020-318452

2. Boyer DS, Gonzalez VH, Kunimoto DY, et al. Safety and efficacy of intravitreal risuteganib for non-exudative AMD: a multicenter, phase 2a, randomized, clinical trial. Ophthalmic Surg Lasers Imaging Retina. 2021;52(6):327-335. doi:10.3928/23258160-20210528-05

3. Stealth Biotherapeutics announces data from RECLAIM-2 phase 2 trial of elamipretide in geographic atrophy. May 2, 2022. Accessed May 9, 2022. https://investor.stealthbt.com/websites/stealthbio/English/5200/us-press-release.html?airportNewsID=e06fe2cb-dcaa-4303-8630-94ee8ef714db

4. Sadda SR, Guymer R, Holz FG, et al. Consensus definition for atrophy associated with age-related macular degeneration on OCT: Classification of Atrophy Report 3. Ophthalmology. 2018;125(4):537-548. doi:10.1016/j.ophtha.2017.09.028

5. Guymer RH, Rosenfeld PJ, Curcio CA, et al. Incomplete retinal pigment epithelial and outer retinal atrophy in age-related macular degeneration: Classification of Atrophy Meeting Report 4. Ophthalmology. 2020;127(3):394-409. doi:10.1016/j.ophtha.2019.09.035