David Lally, MD: Perspective on ANX007 for Geographic Atrophy

New data from the phase 2 ARCHER trial, presented at the 127th Annual American Academy of Ophthalmology (AAO) Meeting in San Francisco, California, suggest the potential of intravitreal ANX007, a complement C1q inhibitor, as a treatment for geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

The findings showed ANX007 missed the primary endpoint of reducing GA lesion growth in ARCHER. However, ANX007 demonstrated a significant, dose-dependent protection against vision loss in eyes with GA in the phase 2 trial.

“What ARCHER showed us is that C1q inhibition is a novel neuroprotective mechanism for GA. It has a different mechanism compared to the previous complement inhibitors that are now available for commercial use,” said David Lally, MD, the director of the Retina Research Institute at New England Retina Consultants, in an interview with HCPLive. “It appears promising to potentially fundamentally change the way we think about treating patients with GA and can offer new hope to these patients to preserve their vision.”

ANX007 is a fab antibody fragment that specifically targets C1q, an initiating molecule of the classical cascade of the complement system and a key driver in neurodegenerative diseases. The phase 2 ARCHER study randomized patients to ANX007 in a 5mg monthly or every-other-month treatment arm versus sham over a 12-month period, followed by an off-treatment period of 6 months. Its primary endpoint was the change in GA lesion area to month 12, with secondary endpoints including best-corrected visual acuity, low-luminance visual acuity, and low luminance visual deficits.

Monthly treatment with ANX007 showed a non-significant 6% reduction in GA lesion growth at 12 months, missing the primary endpoint. Lally noted treatment did show greater growth reduction in the second 6 months of the treatment period, suggesting longer therapy could lead to greater reductions in GA growth over time.

However, in the ARCHER findings, ANX007 demonstrated significant and dose-dependent protection against vision loss, defined as ≥15 letters lost at 2 consecutive visits or at month 12. In the sham arm, at month 12, approximately 20% of patients had 15-letter loss, compared to only 5% in the monthly treatment arm and 10.9% in the every-other-month group.

“That was a significant finding of potential protection from vision loss with complement inhibition only at month 12,” Lally said.

Safety signals indicated ANX007 was generally well-tolerated, with no difference in the rate of choroidal neovascularization between the treatment groups over 12 months. Lally noted this has not been observed with previous complement inhibitors, which can increase the risk of CNV development. There were 3 cases of endophthalmitis considered related to the injection procedure, but there were no reports of serious adverse events, including retinal vasculitis and ischemic optic neuropathy.

“Generally, we would say that this trial did not meet its primary endpoint – however, it has a different mechanism of action,” Lally said. “And I think that’s the important take home point, where it’s meant to preserve photoreceptor cell synapses and it allows the alternative and lectin pathways to continue with their normal homeostatic functions.”

For more insight into the analysis, watch the full interview with Lally in the video above.

References

_{Lally D. Treatment of Geographic Atrophy Secondary to Age-related Macular Degeneration with Intravitreal ANX007, a Selective Classical Complement Inhibitor: Results of the ARCHER Study. Presented at the 2023 American Academy of Ophthalmology Annual Meeting, November 3 – 6, 2023.}