Researchers at Newcastle University and Sunderland Eye Infirmary, UK, have reported that, to date, there is “no evidence that complement inhibition with any agent improves functional endpoints in advanced AMD”. Despite the review, both academia and industry will likely continue to invest significant resources to support complement research on a treatment for AMD. Evidence shows that an overactive complement system is a key driver of AMD progression and therefore research on novel therapeutics for AMD treatments will likely continue over the coming decade.
The complement system plays critical roles in both innate and adaptive immunity, contributing to immune surveillance, inflammation, and homeostasis via three different activation pathways in biology (classical, alternative, and lectin) and numerous effector molecules. The complement system was first implicated in AMD through the observation of drusen-like deposits in patients and subsequent research on the basic biology and then further aimed at novel approached to interfere with the complement cascade. Clinical research studies have primarily been funded by industry and three experimental medicines, in particular, lampalizumab (Roche, an anti-Factor D humanized mAb), pegcetacoplan (Apellis Pharmaceuticals, also known Syfovre, a PEGylated compstatin peptide analogue that prevents cleavage of C3), and avacincaptad pegol (IVERIC bio, also known as Zimura, an IVT delivered anti-C5, single-strand, PEGylated nucleic acid aptamer), have been in phase 2 and 3 over several years.
In the current systematic reported, ten RCTs were evaluated with 4,052 participants with geographic atrophy (GA) showing that all of the three experimental treatments, lampalizumab, pegcetacoplan and avacincaptad pegol, reported no meaningful changes on BCVA, and/or no clinically meaningful changes in BCVA. The efficacy of IVT (intravitreal) for lampalizumab, versus sham for GA, followed 1,932 participants in three studies, all of which showed no meaningfully change BCVA given monthly (+1.03 letters, 95% confidence interval (CI) −0.19 to 2.25) or EOM (every-other-month) (+0.22 letters, 95% CI −1.00 to 1.44). In addition, for 1,920 participants, lampalizumab did not meaningfully change GA lesion growth given monthly (+0.07 mm², 95% CI −0.09 to 0.23) or EOM (+0.07 mm², 95% CI −0.05 to 0.19), and; lampalizumab may have also increased (macular neovascularisation) MNV risk given monthly (RR 1.77, 95% CI 0.73 to 4.30) and EOM (RR 1.70, 95% CI 0.67 to 4.28).
Similarly, efficacy of IVT pegcetacoplan versus sham for GA, followed 242 participants in one study, showed that pegcetacoplan probably did not meaningfully change BCVA given monthly (+1.05 letters, 95% CI −2.71 to 4.81) or EOM (−1.42 letters, 95% CI −5.25 to 2.41). However, in contrast, for 1,208 participants across three studies, pegcetacoplan provided meaningfully reduced GA lesion growth when given monthly (−0.38 mm², 95% CI −0.57 to −0.19) and EOM (−0.29 mm², 95% CI −0.44 to −0.13). These reductions correspond to 19.2% and 14.8% versus sham, respectively.
And finally, the efficacy of IVT avacincaptad pegol versus sham for GA, followed In a study of 260 participants with extrafoveal or juxtafoveal GA, monthly avacincaptad pegol probably did not result in a clinically meaningful change in BCVA at 2 mg (+1.39 letters, 95% CI −5.89 to 8.67) or 4 mg (−0.28 letters, 95% CI −8.74 to 8.18). Despite this, the drug was still found to have probably reduced GA lesion growth, with estimates of 30.5% reduction at 2 mg (−0.70 mm², 95% CI −1.99 to 0.59) and 25.6% reduction at 4 mg (−0.71 mm², 95% CI −1.92 to 0.51). Also, avacincaptad pegol may have also increased the risk of developing MNV (RR 3.13, 95% CI 0.93 to 10.55).
According to the authors of the review, the researchers stated that “there is currently little to no evidence that complement inhibition with any medicine results in a meaningful benefit in any of our chosen functional and quality of life outcomes at one year. Ongoing research on pegcetacoplan and avacincaptad pegol is likely to have an important impact on these assessments.”