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New Hope for Treating Age-Related Macular Degeneration

Joshua Dunaief, MD, PhD

Scheie Eye Institute, University of Pennsylvania

  • Expert Advice
Published on:
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Learn about a class of drugs currently in clinical trials, called complement inhibitors, which may provide new treatment options for people who have macular degeneration.

The Complement Cascade and Macular Degeneration

The complement cascade is a part of the immune system that has been strongly connected to age-related macular degeneration (AMD). It is a series of proteins present in the blood and the retina that can activate one another in a chain reaction, leading to inflammation and cell death. The connection to AMD has been established through genetic studies and by the finding of complement protein deposits in AMD retinas.

Learning from Previous Clinical Trials

Yet, several clinical trials testing complement inhibitors in AMD patients have been unsuccessful. The latest is an anti-factor D antibody called lampalizumab, which, in late 2017, failed two phase III trials for the advanced form of dry AMD, called geographic atrophy (GA). Other trials targeting complement factor C5 with drugs given intravenously or injected into the eye also failed to slow the progression of GA.

Despite their failures, these trials helped to pinpoint a complement protein that remains the best hope as a target for AMD therapy: complement factor C3. One of C3’s activated fragments, called C3a, can recruit white blood cells and also signal retinal cells, two factors that could worsen AMD.

Promising Results with Complement Inhibitors


Results from a recently reported phase II trial of the C3 inhibiting drug APL-2, made by Apellis Pharmaceuticals, showed a significant slowing of the growth of GA (protecting retinal cells near areas of GA). The drug, which inhibits activation of C3, was injected into the eye monthly. The study enrolled 246 patients at 40 clinical sites and documented their progress during one year of monthly injections followed by six months of observation. The drug is now being tested in a larger, phase III clinical trial. Patients wishing to enroll in the study would typically be referred by their ophthalmologist, who can help them determine whether they may be eligible. In addition, another complement-inhibiting drug called Zimura also showed significant slowing of GA in a phase II trial and is progressing to phase III. A difference between the two drugs is that APL-2 inhibits the complement protein C3, while Zimura inhibits a protein downstream of C3 in the complement cascade, called C5.


Complement inhibitors are also being tested for wet AMD, but these trials are generally smaller and in earlier stages than those for GA. The complement inhibitors are being tested in combination with anti-VEGF injections (Lucentis, Eylea, or Avastin). So far there is a hint that complement inhibitors may decrease the frequency of anti-VEGF injections, but these results are very preliminary.


Results from ongoing clinical trials with complement inhibitors should be available within a couple of years. For now, patients may be eligible to receive these treatments by enrolling in clinical trials. The advantages of enrolling are earlier access to a potentially effective treatment and contributing to our understanding of how to best treat the disease. The disadvantages are that some patients will be randomized to receive the placebo, which is necessary to determine whether the drug works, and that some experimental treatments in clinical trials may prove harmful.

Intensive, ongoing basic and clinical research on AMD has yielded helpful treatments, especially anti-VEGF drugs, and this research is likely to provide improved drugs in the future.

About the author

Headshot of Dr. Joshua Dunaief

Joshua Dunaief, MD, PhD

Scheie Eye Institute, University of Pennsylvania

Joshua Dunaief, MD, received his BA magna cum laude in Biology from Harvard (1987), MD/PhD from Columbia College of Physicians and Surgeons (1996), completed ophthalmology residency at the Wilmer Eye Institute, Johns Hopkins in 2000, and medical retina fellowship at Scheie Eye Institute, University of Pennsylvania in 2004.

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