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Subspecialties Basic & Translational Research, Neuro-ophthalmology, Retina

Off the Beaten Pathway

The drug development process is long and arduous, which can be exasperating for both patients in need of a treatment – and the physicians charged with their care. But patients in the advanced stages of dry AMD known as geographic atrophy (GA) are more than frustrated by the lack of approved treatments as the progressive and irreversible loss of retinal photoreceptor cells leading to blindness.

And that’s why I was so excited to take part in the ARCHER clinical trial (1). Phase II has just begun and will assess both the efficacy and safety of the anti-C1q ANX007 treatment, assessing reduction in GA growth rates through non-invasive fundus autofluorescence (FAF).

A steep descent 
So how does ANX007 work? It inhibits C1q, thereby inhibiting the immune pathway that is believed to be causing most of the damage – the complement cascade. Typically, the complement cascade pathways should aid the clearance of any pathogens. However, certain genetic mutations can lead the complement cascade to cause intrinsic damage; if left unchecked, this can lead to GA. 

At present, the complement cascade is known to be involved in GA, but this was not always the case – even though some of the earliest mutations discovered were complement cascade factors; each mutation increasing the risk of developing dry AMD. Some of the early genome wide association studies (GWAS) exposed different complement factors – related to mutations – as increasing the risk of developing AMD. Moreover, complement factors have been found deposited in drusen around GA lesions. And that has paved the way to a much clearer knowledge of GA pathology. 

Better understanding of GA pathology has led to the idea of targeting this system to override the effects of the damaging mutations – preventing the degradation of retinal neurons. With C1q as the main activator of the classic complement cascade, being localized in both drusen and around GA lesions, it makes sense to look at using a C1q inhibitor to potentially prevent damage to photoreceptors and other neurons in the retina.

Which pathway to choose?

Inhibiting all three complement pathways would be inviting a higher risk of infection and other complications.

There are three different pathways to activate the complement cascade: classic, alternative, and lectin. The anti-C1q treatment selectively blocks the classic complement pathway, leaving the two other pathways to maintain their normal function. Although the complement cascade is clearly causing damage in GA, it has extremely important responsibilities for immune function elsewhere. Therefore, inhibiting all three complement pathways would be inviting a higher risk of infection and other complications. Another advantage of this single-pathway approach is reduced risk of off-target effects. It’s better to use a sniper rifle to target what’s really important, instead of using a bazooka to blow the whole thing up.

The path to targeting the complement cascade for GA has not previously been filled with success. There have been high profile clinical trials of therapeutics, aiming to inhibit the alternative pathway (anti-factor D), which failed in both Phase II and Phase III. However, there are C3 and C5 inhibitors, which block all pathways, that are currently in phase III testing and have shown some promise. 

Although we are at an early stage of our clinical studies, there have been no indications of drawbacks or safety concerns; intravitreal ANX007 was well tolerated and fully inhibited C1q in Phase I. These results obviously follow on from strong preclinical studies that, very excitingly, improved the health of neurons, protecting against photoreceptor loss – a major pathological feature of GA. Though the treatment has had fantastic results so far in both preclinical and Phase I studies, expectations must of course be checked; after all, we are talking about a new treatment and a new target. 

New paths? 
The promise of precisely targeting one complement pathway has also brought enthusiasm from other ophthalmologists. The neuroprotective effect observed has been exclusive to C1q complement cascade inhibition, and has translated into neurodegenerative disease models – giving insight into neurodegeneration pathology, and possibly an additional avenue for ANX007. This shared neuroprotection between anti-C1q in the eye and in the brain is exciting; what happens in Alzheimer’s disease is scarily mirrored in dry AMD – the parallel systems of pathology are fascinating.

What’s next for this therapeutic? Due to the slow progression of disease and regulatory requirements, it is likely to take 5–7 years before ANX007 can be brought into clinical practice. Although this wait will seem far too long for many, it should be worth it in the end. As GA prevention is one of the biggest unmet needs in ophthalmology, filling clinical trials with patients is extremely easy; they are desperate for anything that we as ophthalmologists can do to reduce their risk of going blind.

The future also looks bright for expansion of trials to other countries outside of the US – most likely focusing on regions with high GA prevalence, such as Europe. GA is a huge problem across the globe, and with the absence of any therapeutics to combat the disease, any breakthrough would be welcomed. 

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  1. Clinical Trials, “A study investigating the efficacy and safety of intravitreal injections of ANX007 in patients with geographic atrophy (ARCHER),” (2021). Available at:
About the Author
Peter Kaiser

Peter Kaiser is Professor of Ophthalmology at Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, and Senior Vice President of Product Development at Ohr Pharmaceutical.

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