Jovi C.Y. Wong, MD, MSc, DPhil
University of Toronto
The AAO 2023 Retina Subspecialty Friday afternoon session Late Breaking Developments (Part 1) continued with the exciting release of the ARCHER study results. Dr. David Lally (New England Retina Consultants) delivered a talk entitled, “Treatment of Geographic Atrophy Secondary to AMD With Intravitreal ANX007, a Selective Classical Complement Inhibitor: Results of the ARCHER Study.”
ARCHER is a Phase 2 trial studying intravitreal delivery of ANX007, a novel C1q inhibitor in patients randomized to 5mg monthly, 5mg every other monthly, or sham. Dr. Lally explained that C1q is the initiating molecule of the classical complement pathway and a key driver of neurodegenerative disease, which localises on photoreceptor synapses. He stated that blocking C1q will lead to blocking all downstream complement inflammatory processes. He then showed imunohistochemistry slices of retinal tissue and stated that photoreceptor synapses experience worse injury and loss compared to cell bodies in geographic atrophy.
Both foveal and nonfoveal GA patients were recruited and CNVM was permitted in the fellow eye. The primary endpoint was mean change in geographic area lesion size at month 12. Dr. Lally reported that monthly treatment with ANX007 showed a non-significant reduction in lesion growth in the first 12 months (6%, non-significant). However there was greater lesion growth reduction in the 6-12 month timeframe compared to previous months. Dr. Lally proposed that we could interpret this to mean that a longer duration of treatment could increase the effect size.
Vision loss was defined as at least 15 letter loss in two consecutive visits. ANX007 showed dose-dependent protection against vision loss. In time to event analysis, at Month 12 there was 72% risk reduction for at least 15 letter loss with monthly administration of ANX007, and 48% risk reduction with every other month administration. This effect was seen for both foveal and nonfoveal lesions.
When reviewing the proportion of subjects with >15 letter loss at each study visit in the first 12 months, the ANX007 treated group remained consistently low at 10% whilst the sham group continued to rise. Dr. Lally described this result as a neuroprotective effect on visual function.
Dr. Lally reported that ANX007 was generally well tolerated with no difference in choroidal neovascularization rates. There were 3 endophthalmitis cases attributed to the injection procedure. Other than this, there was one BRAO, one iritis, one vitritis and one vitreous debris. There were no reported cases of retinal vasculitis or NAION.
Overall, Dr. Lally described ANX007 as a neuroprotective therapeutic for GA with time- and dose-dependent vision protection that was independent of lesion growth.
Dr. Lally informed the session that Phase 3 preparations are underway.
The ensuing panel discussion raised concerns of complement pathway blockade and whether these could cause inadvertent risks. Dr. Lally describes that there are not any known risks from the preclinical animal model studies. He reiterated that this is the first complement pathway therapeutic without CNV rate increase nor effects on lesion growth, yet exerting effects on visual function. Others wondered why there was an effect between 6-12 months but not before. Dr. Lally proposed that blockade of C1q is upstream of other complement pathway targets, such C3 and C5, and therefore, a delay in effect could be observed.