Joseph Pecha, MD, MPH
Bascom Palmer Eye Institute, Miami, FL
Efficacy and Safety of Complement Factor B Antisense, IONIS-FB-LRx, in Geographic Atrophy due to Age-Related Macular Degeneration: Results of the Phase 2 GOLDEN Study
Dr. Charles Wykoff from Retina Consultants of Texas presented the results of the recent Phase 2 GOLDEN study that examined the antisense oligonucleotide sefaxersen in halting progression of geographic atrophy (GA) in age-related macular degeneration (AMD). Sefaxersen is an antisense oligonucleotide against complement factor B and subcutaneously administered monthly.
The GOLDEN trial was a double-masked, randomized, placebo-controlled trial comparing subcutaneous injections of placebo with two treatment arms of differing doses of subcutaneous sefaxersen. The primary endpoint was growth rate of GA from baseline to week 49, and secondary endpoints were factor B levels in the plasma as well as other measures of visual function. Baseline subject characteristics were similar between the groups, and the study had an exceptionally high treatment compliance rate of 90%. Unique to this medication, patients were vaccinated against encapsulated bacteria, such as Neisseria meningitidis or Streptococcus pneumoniae, based on regional health department recommendations as systemic complement inhibitors can increase the risk of these infections.
The results of this trial demonstrated no increased infection risk compared to placebo, and no serious adverse ocular or systemic effects. However, the primary endpoint was not achieved as there was no significant reduction in GA lesion growth nor in prespecified subgroup analyses. No effect on best-corrected visual acuity (BCVA) was observed either.
During the discussion, Dr. Wykoff described the difficulty in vaccinating subjects –about 80% of whom were unvaccinated at recruitment—partly due to significant regional differences in vaccination recommendations. A question was raised about whether the demonstrated 70% reduction of plasma complement factor B levels is insufficient to slow GA lesion progression, but Dr. Wykoff responded that he doubts this is the case based on results of other recent trials where higher rates of reduction did not lead to a positive response. The results of this study, while unfortunately not meeting the primary endpoint, do raise several important questions: Is systemic therapy less effective than intraocular therapy? And is complement factor B more related to incidence rather than progression of AMD?
EYP-1901 for Retinal Exudative Diseases: Phase 2 Davio 2 nAMD End-of-Study Results and Phase 2 Verona DME Results
Dr. Carl Regillo from Wills Eye Hospital presented on the results of two trials—DAVIO 2 and VERONA—which examined a controlled release bioerodible insert of the selective TKI inhibitor vorolanib in treating AMD (DAVIO 2) and diabetic macular edema (VERONA).
DAVIO 2 compared two doses of EYP-1901 to aflibercept therapy. In the all three arms, aflibercept injections were given monthly for the first 3 months, but in the treatment arms, the EYP-1901 injectable insert was administered at the 3rd monthly visit. Thereafter, subjects received sham injections every 8 weeks. The control arm continued to receive aflibercept every 8 weeks. In all study arms, certain criteria were prespecified wherein rescue aflibercept therapy could be administered. The primary endpoint was change in best corrected visual acuity (BCVA) at 24 weeks after EYP-1901 injection. Baseline subject characteristics were balanced across the three treatment arms.
DAVIO 2 met its primary endpoint (statistical noninferiority to aflibercept), and the final BCVA was nearly identical in all three arms. However, BCVA fluctuated more in the control arm, and rescue injections were much more frequent in this arm compared to the EYP-1901 treatment arms. 63% of subjects in the treatment arms were rescue-injection-free at 6 months, and the drug reduced treatment burden by 80% compared to pre-trial.
No serious ocular or systemic adverse effects (SAEs) were observed, and no episodes of insert migration into the anterior chamber or cases of occlusive vasculitis were noted.
The VERONA study examined EYP-1901’s efficacy for center-involving diabetic macular edema (DME). At time zero, the control arm received one aflibercept injection and the treatment arms received EYP-1901 injection at two different doses. The primary endpoint here was time to supplemental anti-VEGF injection at week 24. Prespecified criteria were in place to guide clinicians in rescue aflibercept administration. Baseline ocular characteristics were well balanced between groups, and no ocular or systemic SAEs were noted. Results demonstrated a dose-response reduction in supplemental injections in the treatment arms compared to control.
A question was raised by an audience member about why Dr. Regillo feels there is such variability in treatment response between patients. In the subsequent discussion, Dr. Regillo and others hypothesized that while unknown at this time, patient-specific enzyme regulation and variable disease severity may explain some of this variability.