Two-year results of the phase 3 randomized controlled study of abicipar in neovascular age-related macular degeneration
Khurana RN, Kunimoto D, Yoon YH, et al. Two-year results of the phase 3 randomized controlled study of abicipar in neovascular age-related macular degeneration. Ophthalmology. 2021;128(7):1027-1038.
Treatment options for wet AMD in 2019 included off-label use of bevacizumab or use of an FDA-approved agent, ranibizumab or aflibercept. Early 2020 saw another agent, brolucizumab, gain FDA-approval. It is expected that the port delivery system (PDS) and faricimab will also likely gain FDA-approval in the near future. With a variety of potential therapeutics available and under investigation for wet AMD, treatment approaches for wet AMD will likely be determined by a combination of factors including efficacy, durability, cost, insurance coverage and side-effect profile. Abicipar pegol (abicipar) is a DARPin anti-VEGF therapy which binds all isoforms of VEGF-A. In this study, the authors report on the 2-year safety and efficacy data of abicipar for the treatment of wet AMD based on the pooled analysis of two identical phase 3 clinical trials (CEDAR and SEQUOIA).
The pooled analyses included 1888 eyes with wet AMD randomized 1:1:1 to receive abicipar 2 mg q8 weeks after loading doses, abicipar q12 weeks after loading doses or ranibizumab 0.5 mg q4 weeks. Main outcome measures the proportion with stable vision (<15-letter loss from baseline), change in vision from baseline and change in central retinal thickness (CRT) from baseline. The 1-year data from the study was previously reported; key findings included that q8 and q12 week abicipar was non-inferior to q4 week ranibizumab and that intraocular inflammation (IOI) was higher in q8 and q12 abicipar than q4 ranibizumab (15.4%, 15.3%, 0.3% respectively).
Of the 1888 eyes enrolled, 1411 (74.7%) completed the 104-week study. This included ~70% of those randomized to one of the two dosing frequencies of abicipar and ~83% of those randomized to ranibizumab. Ocular adverse events, mostly abicipar-related IOI, led to discontinuation of abicipar in 8.9% of eyes in the first year of the study.
Key findings at week-104 for those receiving q8 week abicpar, q12 week abicipar and q4 week ranibizumab include:
- The proportion of patients with stable vision was 93.0%, 89.8% and 94.4% respectively
- Mean change in BCVA from baseline was +7.8 letters, +6.1 letters, and +8.5 letters respectively
- Mean change in CRT from baseline was −147 μm, −146 μm, and −142 μm respectively
- The majority of cases of treatment-related IOI occurred in the first year of the study. Incidence of IOI at baseline through week 52 was 15.4%, 15.3%, and 0.3% respectively and increased marginally to 16.2%, 17.6%, and 1.3% respectively. Thus the incidence of IOI between week 52 and week 104 was 0.8%, 2.3% and 1.0% respectively
This study has several takeaways. The positive treatment effect noted at week 52 for abicipar was maintained at week 104 even with q12 week dosing. This shows the potential of abicipar to significantly lower treatment burden in wet AMD. IOI led to discontinuation of abicipar in 7.5% of study eyes in each of the abicipar treatment arms as compared to only 0.2% in the ranibizumab arm. Subtypes of reported IOI in abicipar-treated eyes included “uveitis,” “vitritis,” or “iridocyclitis” in the majority of cases. Only 1.9% of eyes receiving q8 week abicipar and 1.6% of eyes receiving q12 week abicipar was specifically noted to have retinal vasculitis. The incidence of IOI between week 52 and 104 was similar between the study groups. The authors noted that the risk of IOI in abicipar-treated eyes was highest during the first 12 weeks of therapy with an estimated monthly IOI rate of 2.95% which then dropped significantly in subsequent weeks. Importantly, there were no cases of abicipar-related retinal vasculitis after week 52.
Overall, the 2-year data shows abicipar to be a compelling option to reduce treatment burden in patients with wet AMD. The incidence of IOI with abicipar is of concern but the data does suggest that if patients are to experience IOI with abicipar, it seems likely to occur early on and does not feature a retinal vasculitis in the majority of cases. While it is important not to extrapolate experiences with brolucizumab to abicipar, it is equally important to note that clinical trials for novel intravitreal therapeutics may not be optimally designed to detect, classify and treat cases of IOI. It is truly hard to gauge the presence and severity of inflammation without multimodal imaging including wide-field fluorescein angiography and the requirement to grade IOI using a standard grading system (such as the standardization of uveitis nomenclature “SUN” criteria). Use of general terms such as “uveitis” or “autoimmune uveitis” in AE reporting creates ambiguity in understanding the severity of IOI. This creates some concern that post-marketing data may tell a different picture than the actual clinical trial data but this remains to be seen.