Modified Manufacturing Process for Abicipar Shows Modest Improvement in IOI Incidence

David Callahan, MD

Credit: Texas Retina Associates

A modified manufacturing process for 2mg abicipar pegol in the phase 2 MAPLE study was associated with a moderately lower incidence and severity of intraocular inflammation (IOI) in eyes with neovascular age-related macular degeneration (nAMD).¹

However, despite the removal of pro-inflammatory impurities from abicipar, results from MAPLE suggest the rate (8.9%) of IOI remained higher than those reported in recent phase 3 trials of approved anti-vascular endothelial growth factor (anti-VEGF) therapies.

“The results showed only modest improvement in the safety of abicipar, and in June 2020, the US Food and Drug Administration (FDA) declined to approve abicipar for treatment of nAMD, citing an unfavorable benefit–risk ratio resulting from the rate of IOI,” wrote the investigative team, led by David Callahan, MD, of Texas Retina Associates.

A pooled analysis of the phase 3 CEDAR and SEQUOIA studies revealed abicipar every 8 weeks (Q8W) or every 12 weeks (Q12W) achieved noninferiority to ranibizumab every 4 weeks (Q4W) for the primary efficacy endpoint of the proportion of patients with stable vision, as well as secondary endpoints of best-corrected visual acuity (BCVA) and central retinal thickness (CRT) at week 52 with 6–8 injections of abicipar versus 13 injections of ranibizumab.² The overall incidence of treatment-emergent adverse events (TEAEs) was similar; however, while the incidence of IOI events in the Q8W (15.1%) and Q12W (15.4%) were similar, it compared with only 0.3% in the ranibizumab Q4W group.

Thus, to address these differences, the manufacturing process for abicipar was optimized and the drug substance was purified using a proprietary modified process. The phase 2, open-label, 28-week, MAPLE study was conducted at 40 sites in the United States between May 2018 - April 2019, enrolling 123 patients ≥50 years with active subfoveal and/or juxtafoveal choroidal neovascularization secondary to AMD in the study eye. Enrolled participants received 2 mg abicipar administered intravitreally at baseline (day 1), and weeks 4, 8, 16, and 24 and no control treatment or randomization was performed in the trial.

In the event of IOI, treatment was discontinued, and the patient was observed and exited from the study following resolution of the IOI. Events of special interest included any event related to IOI, increased intraocular pressure (IOP), decreased BCVA, events potentially related to systemic vascular endothelial growth factor (VEGF) inhibition, and any systemic adverse events potentially related to immunogenicity. Efficacy outcomes consisted of the proportion of patients with stable vision, defined as loss of <15 letters in BCVA from baseline, as well as the mean change from baseline in both BCVA and central retinal thickness.

A total of 106 (86.1%) patients completed the 28-week study, with 17 (13.8%) discontinuing due to an adverse event, lost to follow-up, progressive disease, or other reasons. Overall, 59.3% (n = 73) of patients experienced a treatment-emergent adverse event. The percentage of patients who discontinued due to adverse events was 11.4% (n = 14), with 8.9% (n = 11) discontinuing due to IOI. No cases of endophthalmitis or retinal vasculitis were reported in the study.

Of the 11 cases of IOI, 9 were assessed as mild (2.4%; n = 3) or moderate (4.9%; n = 6), while severe IOIs were reported in 1.6% (n = 2) of study eyes. At study end, IOI was considered resolved for 9 patients after topical and/or oral steroid treatment and ongoing for 2 patients. Those with ongoing IOI were treated with topical and/or oral steroids, followed for safety reasons after study exit, and were reported to have achieved full resolution of IOI within 2 months. Visual acuity in most patients with IOI (n = 8) recovered to baseline BCVA levels or better by end of the study.

Additionally, stable vision was maintained for approximately ≥95.9% (n = 118) of all patients at all study visits. Vision improvement, as determined by the proportion of patients who gained ≥10 or ≥15 letters from baseline, showed a trend of consistent results from week 4 through week 48, as did the proportion of patients with BCVA ≥70 letters.

At Week 28, the mean change in BCVA from baseline was +3.6 letters (95% CI, 2.24 - 5.01), with a numerically greater mean change in BCVA in those without prior anti-VEGF treatment (+4.4 letters vs. +1.8 letters). Moreover, the analysis found the CRT in study eyes decreased in both treatment-naive and previously treated eyes, but eyes without prior anti-VEGF treatment showed greater reductions in CRT (98.5 vs. 45.5 µm).

Given these results, Callahan and colleagues noted a further reduction of IOI should be achieved, in order to full understand the potential of abicipar as a treatment for nAMD.

“Use of abicipar produced through a modified manufacturing process was associated with favorable functional and anatomical outcomes, while lessening the treatment burden for patients maintained on a Q8 treatment regimen or those on a treat-and-extend regimen that may require more visits than a predictable fixed dosing schedule,” investigators wrote.

References

1. Callanan D, Khurana RN, Maturi RK, et al. Impact of Modifying Abicipar Manufacturing Process in Patients with Neovascular Age-Related Macular Degeneration: MAPLE Study Results. Clin Ophthalmol. 2023;17:1367-1384. Published 2023 May 11. doi:10.2147/OPTH.S405994
2. Kunimoto D, Yoon YH, Wykoff CC, et al. Efficacy and safety of abicipar in neovascular age-related macular degeneration: 52-week results of phase 3 randomized controlled study. Ophthalmology. 2020;127(10):1331–1344. doi:10.1016/j.ophtha.2020.03.035