Eye Implant Slowed Geographic Atrophy Growth 54% at Six Months in Small Phase II Trial

A new approach to geographic atrophy (GA), the advanced form of dry age-related macular degeneration, slowed lesion growth by more than half in an early clinical trial.

The implant slowly releases kamuvudine K8, a dual inflammasome inhibitor. Liangbo Shen, MD, of Duke University Medical Center in Durham, North Carolina, presented the results at the American Academy of Ophthalmology meeting.

What the trial found

The GA growth rate fell 54% after six months in treated eyes. The effect grew over time: 43% during the first three months, then 70% during months three to six.

Growth was slower in the treated eye than in the untreated eye in 25 of 30 patients.

Three dose levels were tested. The mid-level dose worked best, and the lowest dose showed no difference from control. Shen said no drug-related adverse events occurred at any dose.

The drug works differently from the two approved GA treatments, both of which are complement inhibitors. K8 is a nucleoside reverse transcriptase inhibitor that blocks activation of two inflammasomes, NLRP3 and NLRC4.

The convenience pitch

Shen pointed to practical advantages over current options. "K8 is a quarterly injection, requires no refrigeration, and comes in a preloaded injector," he said.

Based on the results, a phase III pivotal program has been planned. No start date or enrollment figures were given.

The limits Shen himself acknowledged

The study is small and short. Jay M. Stewart, MD, of the University of California San Francisco, pressed Shen on the design during the discussion.

Investigators pooled results from the untreated eyes, which Stewart said created "a lot of complexity that we're not used to seeing." His question: "To what extent do you think an outlier or two in one of those groups could sway the results and make us think that one of the groups is having better efficacy than the other?"

Shen agreed it was a fair concern. He said the team also ran a comparison of treated and untreated eyes within the same patients, and the results were similar after adjustment for sample size and other factors.

Vision is the harder question. The trial was not powered for visual acuity. Investigators still compared best-corrected visual acuity at baseline and at the end of the study and found an improvement favoring the K8-treated eyes.

Stewart noted that vision testing was not masked and asked how to interpret that. Shen acknowledged the limitation. He also said the treated eye was the one with more severe GA, which might have skewed the results.

"Obviously, we all want something that can slow GA progressing in terms of visual function," Shen said, "but I think we have to have a much larger study to answer that question."

Dose and duration remain unsettled

The dose data is murky. Shen agreed that six months of follow-up may have been too short to show a true dose effect. There was no significant difference between the middle and high doses.

"We need a longer, larger study to investigate the treatment efficacy," Shen said. "But it is encouraging to see a phase II trial with a significant reduction in GA growth rate."

A crowded field

GA drug development has been busy. Recent retina meeting programming has included the phase 3 ARCHER II trial of ANX007 in dry AMD and GA, 48-month results from the OAKS, DERBY and GALE open-label extension, and a phase 1/2 update on OCU-410 for geographic atrophy.

Against that backdrop, K8's pitch rests on a different mechanism, inflammasome inhibition rather than complement inhibition, and on dosing and storage convenience.

What comes next

The phase III design is the next test. Whether a pivotal trial can show a dose-response relationship, use masked visual function testing and hold the lesion-growth effect beyond six months will determine if the early numbers survive. Patients will want to know whether slower lesion growth translates into preserved sight, the question Shen raised himself.