Age-related macular degeneration (AMD) is a leading cause of severe vision loss in people over age 60.1 In recent years, there have been tremendous developments in treating the less common but more rapidly progressing neovascular (wet) form of AMD, but there are few options for treating dry AMD, the form of the disease affecting the vast majority (about 90%) of AMD patients.1
The natural history of early to intermediate dry AMD is typically stable or slow loss of vision (Figure 1).2 In the early stage, dry AMD is largely asymptomatic and the risk of progression to advanced AMD is low. But when patients reach the intermediate stage, they typically have decreased acuity and visual function, such as problems with color vision and dark adaptation, and are at risk of progressing to geographic atrophy (GA) or wet AMD. Lifestyle modifications such as smoking cessation, blood pressure control, and a healthier diet, can potentially reduce the risk of disease progression. The nutritional supplements studied in the landmark Age-Related Eye Disease Study (AREDS) were proven to reduce the risk of converting from dry to wet AMD, but they had no significant impact on progression of dry AMD, including to late-stage GA.3
IMPACT OF CELLULAR OXIDATIVE STRESS
The pathogenesis of dry AMD is multifactorial, which is one of the reasons it has been so difficult to devise effective treatments. The eye is highly biologically active, with frequent exposure to UV light, which produces oxidative damage in the cells. Oxidative stress causes a number of downstream effects that have been associated with dry AMD, including inflammation and neurodegeneration.4
In a young, healthy eye, cellular mitochondria in the retinal pigment epithelium (RPE) control the excess reactive oxygen species (ROS) produced by oxidation. With age, the level of ROS increases, making it harder for the mitochondria to maintain homeostasis. Mitochondrial dysfunction has been shown to increase the deposition of integrin receptors on the surface of cells.5 This upregulation of integrins launches a feedback amplification loop, producing even more ROS, accelerating oxidative damage, causing inflammation, and activating the complement system.6 The RPE cells begin to de-differentiate and lose the functions that support photoreceptor viability. Eventually, cellular apoptosis and loss of the RPE and photoreceptors occur.
THE ROLE OF INTEGRIN REGULATION
Integrins are cell adhesion and signaling receptors that interact with the extracellular matrix. Located on cell surfaces throughout the body, they play a major role in cell-to-cell interactions and are capable of transmembrane regulation, or sending instructions down into the cell itself, which makes them a compelling therapeutic target. There are 24 different types of integrin receptors, each named for its unique isoform, or combination of alpha and beta subunits.7 Regulating either subunit of an isoform regulates the entire isoform’s function.
Risuteganib is a synthetic RGD (arginyl-glycyl-aspartic acid)-class peptide that regulates the functions of multiple integrin isoforms. It has a molecular weight of less than 1.0 kD. After intravitreal administration, radiolabel studies have shown the compound has a half-life in the rabbit retina of around 21 days.
There is recent experimental evidence from multiple independent laboratories that suppression of integrin function has protective effects.8-10 For example, mouse model gene expression work conducted at California Institute of Technology by Kornfield and Johns Hopkins University by Campochiaro showed that risuteganib is anti-inflammatory.8 In the hypoxia-stressed retina, risuteganib specifically suppressed the expression level of genes related to cell adhesion, migration, and inflammation (including integrin αM and β2 genes, which form the complement receptor 3). This expression modulation suggests broad suppression of leukocytic attachment and transendothelial migration.
Researchers at Duke University in the laboratory led by Glenn J. Jaffe, MD, were able to demonstrate RPE cytoprotection and improvements in mitochondrial function with risuteganib.9 Work at the University of California, Irvine in the Kenney/Kuppermann laboratory, along with others, has shown that risuteganib improves mitochondrial health and decreases ROS production in retinal cells (Figure 2).10 The Quiroz-Mercado laboratory at APEC Hospital in Mexico City demonstrated that pretreatment with risuteganib increased survival of multiple types of retinal cells during exposure to cytotoxic agents.8
Collectively, this preclinical research is significant because it suggests a mechanism of action that is highly relevant to AMD. If regulation of integrin function can stabilize mitochondrial function and turn off the complement 3 pathway, it can potentially reinvigorate the retinal tissue, increase retinal cell survival, and improve vision, which we have not previously been able to demonstrate in patients with dry AMD.
PHASE 2 CLINICAL TRIAL
Top-line results from a US phase 2a randomized, controlled, double-masked, multicenter clinical study evaluating risuteganib demonstrated meaningful improvements in visual acuity compared to sham in patients with intermediate dry AMD, providing clinical support for this proposed mechanism of action. The primary endpoint in the study was a gain in ETDRS vision of ≥8 letters. One patient (7.1%) in the control group and nearly half the patients (48%) in the risuteganib group (P=.013) achieved this endpoint.11 The drug demonstrated a good safety profile, with no drug-related serious adverse events. Additionally, risuteganib has been tested for other indications, providing good evidence of safety in more than 1,200 injections. Further analysis of the study results is ongoing and a larger trial to confirm these results is planned.
With an aging population, a large number of people have dry AMD, a condition for which currently there are no treatments to prevent progression, let alone restore visual function. Although dry AMD does not become sight-threatening in most cases, those who reach the intermediate stage lose visual function in ways that can dramatically affect quality of life, such as the ability to drive or read the paper, and are at higher risk of progressing to advanced AMD.
Preclinical investigations of risuteganib suggest that this drug is anti-inflammatory, has mitochondrial stabilization properties, and prevents cellular apoptosis. Positive early results from the clinical trial of risuteganib in patients with intermediate dry AMD corroborate the laboratory work, offering some hope for the treatment of this disease. RP
- BrightFocus Foundation. Age-related macular degeneration: facts & figures. https://www.brightfocus.org/macular/article/age-related-macular-facts-figures . Accessed September 3, 2019.
- Hsu ST, Thompson AC, Stinnett SS, et al. Longitudinal study of visual function in dry age-related macular degeneration at 12 months. Ophthalmol Retina. 2019;3(8):637-648.
- Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-1436.
- Blasiak J, Petrovski G, Veréb Z, Facsko A, Kaarniranta K. Oxidative stress, hypoxia, and autophagy in the neovascular processes of age-related macular degeneration. BioMed Res Int. 2014:e768026.
- Hung WY, Huang KH, Wu CW, et al. Mitochondrial dysfunction promotes cell migration via reactive oxygen species-enhanced β5-integrin expression in human gastric cancer SC-M1 cells. Biochim Biophys Acta. 2012;1820(7):1102-1110.
- Werner E, Werb Z. Integrins engage mitochondrial function for signal transduction by a mechanism dependent on Rho GTPases. J Cell Biol. 2002;158(2):357-368.
- Barczyk M, Carracedo S, Gullberg D. Integrins. Cell Tissue Res. 2010;339(1):269-280.
- Quiroz-Mercado H. Integrin inhibitor targeting multiple oxidative stress induced pathways in DME. Presented at: the 2018 Association for Research in Vision and Ophthalmology Annual Meeting; April 2018; Honolulu, Hawaii.
- Yang P, Neal SE, Jaffe GJ. Luminate protects against hydroquinone-induced injury in human RPE cells. Invest Ophthalmol Vis Sci. 2019;60(9):1944.
- Kenney CM, Chwa M, Cáceres-del-Carpio J, et al. Effects of anti-VEGF and ALG-1001 on human retinal cells in vitro. Presented at: the 2018 Association for Research and Vision in Ophthalmology Annual Meeting; April 29, 2018; Honolulu, Hawaii.
- Kaiser PK. Safety and efficacy of risuteganib in intermediate non-exudative age-related macular degeneration—first time results from a phase 2 study. Presented at: the 2019 American Society of Retina Specialists Annual Meeting; July 27, 2019; Chicago, Illinois.