Investigational Drug Shows Signal to Protect Rods and Cones

CHICAGO — An investigational drug that would potentially be the third approved treatment for people with geographic atrophy has demonstrated a signal the two approved treatments have not: An ability to protect photoreceptors in the eye from further damage.

Geographic atrophy causes the loss of photoreceptors, the rod and cone cells that capture light and images and relay them to the brain. The phase 2 ARCHER trial found patients treated monthly with ANX007 had up to a 59% decrease in the ellipsoid zone (EZ) loss after a year of treatment, Rahul Khurana, MD, reported at the 2024 American Academy of Ophthalmology Annual Meeting.

“This study found consistent, significant, dose- and time-dependent protection from vision loss on multiple measures of visual acuity, and protection of photoreceptors, especially those in the central fovea, areas most closely correlated with vision,” Khurana, a retina specialist in the San Francisco Bay Area, told Medscape Medical News.

Novel Mechanism of Action

ANX007 is an antigen-binding fragment antibody that selectively inhibits C1q, a complement protein that can activate the classical pathway of the complement system, which can lead to photoreceptor damage. The therapy is administered by an injection into the eye.

The US Food and Drug Administration in 2023 approved two agents to treat geographic atrophy, an advanced form of dry age-related macular degeneration (AMD): Pegcetacoplan (Syfovre) and avacincaptad pegol (Izervay). However, while those agents slow the progression of vision loss by reducing the growth rate of lesions in the eye, they do not stop the progression of the condition.

According to Khurana, ANX007 protected recipients from vision loss.

“C1q inhibition has shown efficacy in many animal models of neurodegeneration, and in human diseases such as in dry AMD, as demonstrated in the ARCHER study, Guillain-Barré syndrome, and Huntington’s disease,” Khurana said in an interview. “This novel mechanism of action translated to protection of vision, which has not been demonstrated by other approved therapies for geographic atrophy.”

ARCHER Study Hits Early Marks

The ARCHER study enrolled 270 patients randomly assigned to receive sham treatment (n = 89), monthly injections of 5 mg of ANX007 (n = 89), or every-other-month 5-mg injections of the agent (n = 92).

Through the first year, 21.3% of the patients in the sham treatment group experienced a persistent vision loss of 15 letters or more compared with 5.6% of those in the monthly and 9.8% of those in the every-other-month treatment groups.

After treatment ended at 12 months, the patients in the sham treatment group had experienced more accelerated vision loss than the treated patients, Khurana said, with 14% of patients in the monthly treatment group having a loss of 15 letters or more at 18 months, about half that of the sham treatment group.

In eyes with less advanced disease, the results were even more profound, Khurana said. Among this subgroup, 16.9% of those in the sham treatment group had a vision loss of 15 letters or more compared with 0% of those in the monthly and 6.1% of those in the semimonthly treatment groups.

An analysis that pooled both treatment groups into one showed that EZ loss, a marker of photoreceptor protection, was lower for recipients of ANX007 in three regions of the macula at 12 months: 27% lower in the pan-macula, 48% lower in the central 2 mm, and 59% lower in the central 1.5 mm.

Another marker, total EZ loss based on degree of loss upon enrollment, also favored the pooled treatment group. Among those with

Khurana said ANX007 was “generally well-tolerated,” with comparable rates of choroidal neovascularization (3.4% in sham vs 4.5% and 4.3% in monthly and semimonthly treatment groups, respectively). However, the treatment groups had three cases of endophthalmitis and three cases of intraocular inflammation after injection, while the sham treatment group had none. No cases of retinal vasculitis were reported in any of the groups, he said.

“What’s most meaningful about this study is ANX007 protection from vision loss and its safety,” Khurana said. “As a physician, I know my patients want to preserve vision so that they can maintain their quality of life. The therapies we have today for geographic atrophy protect from retinal pigment epithelium loss and lesion growth, but do not protect against vision loss.”

The phase 3 ARCHER trial is currently enrolling to confirm these results, Khurana added.

David Boyer, MD, a retina specialist in Los Angeles, said the results were encouraging. “It’s very exciting to have a treatment that may stabilize or prevent further visual loss because all the other trials in this space that have reported data unfortunately also were associated with visual decrease,” he told Medscape Medical News. “The results at one year are extremely exciting, and if we can duplicate that in the second year, it would be great.”

He noted that the effect seemed to slow from months 6 to 12. “So people are asking, if you don’t stop that, will the photoreceptors still remain viable?” he said. “We’ll have to find out if that’s true.”

The ARCHER findings put more emphasis on the photoreceptors, he said, although the stronger effect of the monthly vs every-other-month dosing does not bode well for longer treatment intervals.

“I have a little bit of a problem with that,” he said. He noted the approved agents for geographic atrophy can be dosed at longer intervals — pegcetacoplan at up to every 8 weeks and avacincaptad pegol can be stretched out to 12 months — so convincing patients to get more frequent injections could be difficult.

“The phase 3 trial has to be bigger and get the 4-week and 8-week intervals to see how often we have to administer this drug,” he said.

The study was funded by Annexon Biosciences. Khurana disclosed financial relationships with AbbVie, Annexon, Apellis Pharmaceuticals, and REGENXBIO. Boyer disclosed financial relationships with AbbVie, Annexon, Apellis Pharmaceuticals, Iveric Bio, and REGENXBIO. 

Richard Mark Kirkner is a medical journalist based in the Philadelphia area.