Is the development of exudative AMD when inhibiting complement in GA a concern?
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The risk is not worth the reward
Dealing with new-onset macular exudation while treating geographic atrophy with the complement inhibitors currently undergoing investigation seems a risk not worth the reward.
Based on the best available data we have from Apellis, the treatment effect of APL-2 (pegcetacoplan) is not profound. We have an average of less than a 20% reduction in geographic atrophy (GA) lesion growth as a primary endpoint when the data from both trials are pooled. This means that we would be treating patients with high frequency injections every 4 to 8 weeks in exchange for a small clinical benefit, while exposing them to the risk of developing macular exudation. And if this happens, these patients would have to go on to a second high-burden treatment while they are receiving already one high-burden treatment that does not have a profound clinical benefit. That is the problem: Is the whole process really worth it?
If we look at the subgroup of patients with extrafoveal lesions, the reduction in the rate of lesion growth increases to 25%, a similar rate to what was achieved in the same population with Zimura (avacincaptad pegol, Iveric bio) in the GATHER1 trial. Whether the same degree of efficacy will be confirmed in GATHER2 is yet to be seen, but even then, is the 25% effect in these patients with exclusively extrafoveal GA lesions profound enough to warrant exposing them to the risk of increased macular exudation? I do not think we have a clear answer on that. My concern is that patients are going to receive multiple injections, suffer disease advancement and have an increased risk for exudation requiring treatment.
There are a variety of other complement therapies currently in trial that may not hold this risk, such as NGM621 (NGM Biopharmaceuticals), a monoclonal antibody that is another way of potentially inhibiting complement C3. It may be that the pegylation of Zimura and APL-2 is what induces the neovascularization. Even if we do see the biological effect from this class of drugs, these agent may not be the right avenue to start with because we have potentially better options right around the corner.
David E. Eichenbaum, MD, is from Retina Vitreous Associates of Florida in Saint Petersburg, Florida.
Exudative AMD can be successfully treated
In the near future, treatment of GA may involve the inhibition of the complement cascade. At present, inhibitors of C3 and C5 appear to be on the brink of pivotal clinical trial evidence that could lead to FDA and EMA approval. In the clinical trials of the two agents, pegcetacoplan and avacincaptad pegol, for which data have been released so far, there is a safety signal that treated eyes experience a higher rate of exudative AMD. This, however, does not concern me.
First of all, I consider it a positive biologic signal that these two investigational therapies are having an effect on the complement system, therefore altering the disease state we know as GA in age-related macular degeneration. We did not see any such signal in the failed trials of lampalizumab. Furthermore, this safety signal is dose related. In the DERBY and OAKS phase 3 clinical trials, the combined rates of exudative AMD across the studies were 6% in the monthly dose group, 4.1% in the every other month dose group and 2.4% in the sham group. If we include the cases not reported by the investigators but detected by the reading center, the rates were 6.4%, 5%, and 3.8%, respectively.
Secondly, the rates in DERBY and OAKS were lower than those seen in the FILLY phase 2 trial at 20.9% in the monthly dose group and 8.9% in the every other month dose group.
Phase 3 clinical trials allow us to better characterize this emergent exudative AMD, potentially assisting future management strategies. Patients with fellow-eye choroidal neovascularization were included, and this is a well-known risk factor. All cases with available fluorescein angiography showed occult macular neovascularization except for two classical cases in DERBY. Double-layer signs were also a risk factor. Affected patients were treated with anti-VEGF injections while continuing to receive the study medication according to their randomized arm, and no loss of visual acuity attributed to the exudation was reported.
In my practice, I am successfully treating exudative AMD only to watch my patients lose vision over time to GA. I welcome the opportunity to preserve vision in my patients with AMD even if it means giving injections for both forms of advanced AMD.
Nancy M. Holekamp, MD, is from Pepose Vision Institute in St. Louis.
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