MONTREAL — Complement inhibitors to treat geographic atrophy (GA) were associated with thickening of the retinal nerve fiber layer (RNFL), which could be helpful or pathologic, according to a study reported here.
Both FDA-approved complement inhibitors were linked to an increase in the RNFL, whereas untreated GA, or dry age-related macular degeneration (AMD), and anti-VEGF injections were associated with a reduction in RNFL thickness. RNFL thickness increased by 4.37 µm annually in patients on pegcetacoplan (Syfovre) and by 5.72 µm in those on avacincaptad pegol (Izervay). The highest rate of RNFL thickening occurred during the first year of anti-complement treatment, then leveled off after that but continued to increase.
RNFL thickening appears to be a class effect of complement inhibitors, and the difference between pegcetacoplan and avacincaptad pegol did not differ significantly, said David Brown, MD, of Retina Consultants of Texas in Houston, at the American Society of Retina Specialists meeting. Whether the thickening represents pathologic swelling or infiltrate or a neuroprotective response remains unclear.
“The scary part is that it never plateaus,” said Brown. “What you’re doing is thickening the nerve. You’re increasing ischemic optic neuropathy. Is this neuroprotection, edema, or infiltration? If it was neuroprotection it would go from [nerve fiber loss] to zero.”
“What’s happening?” he continued. “Polyethylene glycol [PEG] is vacuolized by macrophages. In preclinical data, you saw it in the nerve and it went all the way to the brain in the avacincaptad pegol data. I think you’re giving pegylated drugs that are driving macrophage vacuolization and becoming incorporated into the retina. We need to examine this further.”
Ongoing development of nonpegylated complement inhibitors for GA, such as ANX007, should provide some clarity to the question of whether PEGylation or complement inhibition causes RNFL thickening, he noted.
Questions Without Answers
At the conclusion of the late-breaking abstract session, Brown fielded questions for which he had few answers.
“Have you seen [RNFL thickening] in any of the prospective trials with the hundreds of patients that have been treated to date?” asked Charles Wykoff, MD, PhD, also of Retina Consultants of Texas and a co-investigator in the study. “And clinically, is this changing what you’re doing when you manage patients with anti-complement therapeutics?”
RNFL was not assessed in clinical trials, said Brown. As for the impact on clinical management, “It’s hard to say. Is this limiting visual acuity? Is this the reason that you didn’t have better vision with avacincaptad pegol? Is this the reason you didn’t have better vision with Macugen [pegaptanib, another pegylated drug]? I don’t know. We need to do a lot more work and we need a lot more data.”
“I don’t know what to tell patients now,” he added. “I think you’ve got to tell them. I think you’ve got to watch the RNFL. You’ve got to watch the optic nerve.”
John Thompson, MD, of Retina Specialists of Maryland in Towson, wondered whether the retinal thickening might be applicable to other types of injection therapy.
“When we raise the IOP [intraocular pressure] and put in this 0.1 mL, is this having some sort of effect? Is it possible that we’re damaging eyes when we put in this 0.1 mL?” said Thompson. “You see the optic nerve get kind of pale, and the artery is pulsing. Is this another source of damage that maybe is causing swelling of the nerve fiber layer?”
Brown and colleagues intend to look more closely at the effects of anti-VEGF injections.
“If you get swelling in the optic nerve fiber, then you kill off the nerve and it gets less,” said Brown. “If you get no injections, no RNFL ever gets thicker. In the [anti-VEGF] injection patients, about 8% got an increase in RNFL. That’s probably inflammation. If you got rid of that noise, you might have seen more loss of RNFL in the anti-VEGF group. We’ve got the patients and the numbers [to study that].”
Brown reiterated that he and others initially thought the RNFL changes might be beneficial, “and they still might be. It might not be harmful.” Observations from other clinical fields lend support to that point of view. For example, treatment with pegylated drugs has not been shown to affect renal filtration or hepatic function.
“But this is different. This is a nerve. It might make a big difference, whether you’re incorporating stuff in nerves as opposed to renal tissues,” said Brown.
Background, Key Findings
The study had its origin in the observation that some patients treated with the complement inhibitors developed ischemic optic neuropathy. Brown and colleagues performed a study to assess how intravitreal injections of complement inhibitors or anti-VEGF therapies affect RNFL compared with no injections. The study involved 331 eyes with AMD and 4,870 optical coherence tomography measurements of RNFL thickness before and during therapy with complement inhibitors or VEGF inhibitors.
The analysis included 77 eyes with dry AMD, followed for 3-5 years without any intravitreal injections, during which time RNFL thickness declined by 0.29 µm/yr. Among 52 eyes followed for a similar period of time and treated with anti-VEGF therapies, RNFL thickness decreased by 0.79 µm/yr, not significantly different from the natural history group.
In contrast, RNFL thickness increased in 159 eyes treated with pegcetacoplan, with an average of 4.37 µm/yr, including >1 µm/yr in 141 eyes. The 43 eyes treated with avacincaptad pegol had a 5.72 µm/yr average gain in RNFL, despite a ninefold lower PEG concentration in the therapy. Thickening reached a maximum of 9.1 µm/yr in the first 6 months after the start of treatment and then leveled off to 3.2-3.6 µm/yr thereafter.
Comparison of RNFL slope by treatment group showed a significant difference in complement inhibitors versus control (P<0.001).
Brown said neither complement inhibitor manufacturer had contacted him about the study (and neither had responded at publication to a request for comment from MedPage Today).
“Our group is doing more analysis on the ganglion cell layer [GCL] thickness in these eyes,” he told MedPage Today. “If the drugs are making the eye ‘healthier’ then thickening of the ganglion cell layer would occur in parallel with the RNFL. I suspect the GCL will be unchanged and this will prove that the thickening of the axons are pathologically affected.”
“To figure out whether this is related to PEGylation versus complement inhibition, I’m encouraging Regeneron to include RNFL and optic disc imaging in their systemic complement inhibitor trial,” Brown added. “Also, if C1q inhibition [target of ANX007] is effective, the trial, which reads out later this year, would help as it is not pegylated.”
