By Richard Mark Kirkner, Editor

At last count, 10 candidates are in the investigative pipeline to treat geographic atrophy in dry, or non-neovascular, age-related macular degeneration. GA holds a strong allure for drug developers, the most obvious because no approved treatment currently exists and an estimated 5 million people worldwide have it.1

The mechanisms of action of these candidates are diverse: for example, an oral formulation of modified vitamin A (ALK-001, Alkeus Pharmaceuticals); a complement factor C5 inhibitor (Zimura, avacincaptad pegol, Iveric Bio); and an anti-sense oligonucleotide that inhibits CB gene expression (IONIS-F-LRx, Ionis Pharmaceuticals).

Another entry is ANX007 (Annexon Biosciences), an investigational monoclonal antibody antigen-binding fragment injected intravitreally designed to bind to C1q early in the complement pathway and inhibit the deleterious but enable the beneficial properties of downstream complement factors. 

The ARCHER trial, a Phase II study evaluating ANX007 in 240 patients with GA commenced in February (NCT04656561). Completion is planned for December 2023. 

Here, David R. Lally, MD, an investigator receiving grant support from Annexon, answers questions about ARCHER and ANX007. Dr. Lally is the director of the Retina Research Institute at New England Retina Consultants, an attending surgeon at Baystate Medical Center in Springfield and an assistant professor of surgery and ophthalmology at the University of Massachusetts Medical School-Baystate.

 

Q: In your own words, please describe the mechanism of action of ANX007.

A: ANX007 is an immunoglobulin G antibody fragment—a Fab fragment that’s directed against C1q, the initiating molecule of the classical complement cascade. It’s a humanized recombinant monoclonal antibody with a single heavy chain of the IgG1 isotype and a single light chain of the kappa isotype. It has a molecular weight of approximately 48 kDa. Early pharmacokinetic testing showed ANX007 was able to inhibit C1q for at least 29 days in the aqueous humor following a single intravitreal injection.

Previous genome-wide association studies identified a genetic link between polymorphisms in complement pathway proteins and AMD suggesting that complement pathway activity may play a role in AMD disease risk. C1q is involved in the initial step of the classical complement pathway.  It also happens to be found accumulating in drusen and photoreceptor neuron synapses in the outer plexiform layer with aging.  

We also know that C1q is produced by retinal microglia and macrophages and that it can activate the inflammasome, leading to local inflammation and potentially retinal atrophy. These observations support investigational therapies aimed to inhibit C1q to be studied in AMD.

 

Q: What’s novel about this treatment pathway compared to other candidates to treat GA?

A: There are three distinct pathways through which complement can be activated: the classical; alternative; and lectin pathways. Each pathway follows a sequence of different reactions that result in the formation of a protease called C3 convertase. C3 convertase catalyzes the cleavage of C3 to C3a and C3b. From that point on, the complement system follows a single pathway culminating in the formation of C5a and C5b, resulting in activation of the inflammasome, formation of membrane attack complex, and ultimately cell death.  

Apellis Pharmaceuticals’ candidate, pegcetacoplan, or APL-2, is an inhibitor of complement factor C3 that’s in late-stage investigation. By blocking C3, APL-2 attempts to inhibit all three pathways to maximize suppression of the entire complement system. Zimura targets inhibition of complement factor C5, which is downstream from C3, so it also attempts inhibit all three complement pathways. 

ANX007, on the other hand, works upstream, inhibiting only the classical pathway, leaving the alternative and lectin pathways uninterrupted. The complement system plays an active role in the innate immune system, and it’s unknown at this time whether blocking all three complement pathways or blocking one pathway without interrupting the other two will lead to differences in safety and efficacy outcomes.

 

Q: What can you tell us about the Phase II ARCHER trial?

A: This study is a Phase II, multicenter, randomized, parallel-group, double-masked trial investigating the efficacy, safety, and tolerability of ANX007 in the treatment of GA. Patients are randomized to one of four treatment groups: intravitreal injection of ANX00 7 5-mg monthly for 12 months; intravitreal injection of ANX00 7 5-mg every other month for 12 months; and sham treatment groups either monthly and every other month. Randomization is 2:2:1:1 with approximately 80 subjects in each ANX007 treatment group and 40 in each of the sham groups. ANX007 is injected at a volume of 0.1 mL,  which is double that of standard anti-VEGF therapies.

The primary efficacy endpoint is the change from baseline to month 12 in the GA lesion area between each ANX007 arm and the pooled sham control arm. 

Inclusion criteria requires a GA lesion area between 1.5 and 17.5 mm2, and if the GA is multifocal, then at least one of the lesions must measure ≥1.25mm2. The study allows the GA lesion to be located either foveally or non-foveally. A history of exudative choroidal neovascularization in the fellow eye is also permitted. Other key inclusion criteria include best-corrected visual acuity between 24 and 83 letters, or approximately 20/25 to 20/320 Snellen equivalent.

At month 12, the treatment period concludes and subjects are followed for an additional six months off-treatment.  

 

Q: What are the key secondary outcomes for ARCHER?

A: Secondary outcome measures include the incidence and severity of ocular and systemic treatment-emergent adverse events, and change from baseline to month 12 in BCVA, low-luminance BCVA and low-luminance VA deficit. RS

 

REFERENCE

1. Tufail A. Objective measurement of reading speed and correlation with patient-reported functional reading independence. Paper presented at the 15th EURETINA Congress; Nice, France; September 17-20, 2015