Studies Yield Mixed Findings for Investigational Drug Abicipar in nAMD

By Scott Baltic

May 04, 2020

NEW YORK (Reuters Health) - The investigational drug abicipar pegol is noninferior to ranibizumab for achieving stable vision in people with neovascular age-related macular degeneration (nAMD), according to a pair of phase-3 trials.

Abicipar requires less-frequent administration, but the trials show it has more side effects than ranibizumab, and its potential role in nAMD treatment is unclear, experts say.

The drug, from Allergan plc and Molecular Partners AG, belongs to a new class of therapeutics called DARPins, or designed ankyrin repeat proteins. Their ability to be engineered by PEGylation or attaching additional DARPin domains, along with other characteristics, makes it possible to "achieve an optimized combination of affinity, molar dose, and half-life, resulting in a longer duration of effect," researchers note in Ophthalmology.

The two randomized trials (CEDAR and SEQUOIA) used identical protocols involving three study arms: abicipar 2 mg every eight weeks (Q8), abicipar 2 mg every 12 weeks (Q12) and ranibizumab 0.5 mg every four weeks.

They are the first phase-3 studies to successfully use a quarterly (after initial doses) regimen of an anti-vascular endothelial growth factor agent without regimen adjustment and demonstrate noninferiority of the regimen to monthly ranibizumab in patients with nAMD.

The studies randomized 1,888 patients 50 years and older (mean age, 76; 55.7% female; 81.4% white) with treatment-naive nAMD, in 32 countries. In each patient, one eye was designated as the study eye, typically the one with worse visual acuity.

The primary endpoint was the percentage of participants who lost less than 15 letters from baseline in the study eye, as measured by best corrected visual acuity (BCVA).

In all, 1,620 participants completed the first 52 weeks of the studies. The completion rates were lower in the abicipar arms because of substantially higher rates of discontinuation due to ocular adverse events.

In a pooled data analysis based on one-year results, the proportions of patients with stable BCVA at week 52 were 93.2% in the abicipar Q8 group, 91.3% in the abicipar Q12 group and 95.8% in the ranibizumab group. According to prespecified criteria, abicipar was considered noninferior to ranibizumab.

Medication-related adverse events were more frequent in the abicipar groups (16.8% in Q8 and 20.4% in Q12) than in the ranibizumab group (4.5%) because of the occurrence (usually early in the study) of intraocular inflammation, most commonly uveitis and vitritis.

Among patients with intraocular inflammation, the most severe instances (graded as 3+) were noted in 12 of 96 (12.5%) patients in the abicipar Q8 group, 27 of 96 (28.1%) in the abicipar Q12 group, and in no patients in the ranibizumab group.

Overall, 77 (12.3%) patients in the abicipar Q8 group, 75 (12.0%) in the abicipar Q12 group and 25 (4.0%) patients in the ranibizumab Q4 group dropped out of the study due to adverse events.

The authors note that since CEDAR and SEQUOIA were completed, the abicipar product used in these studies "has gone through a purification process to reduce host cell proteins in an effort to reduce the incidence of intraocular inflammation." This version was investigated in a newer study, "whose results are forthcoming," they add.

First author Dr. Derek Kunimoto of Retinal Consultants of Arizona, Phoenix, told Reuters Health by email, "As clinicians, we always weigh the benefits of a given therapy against its risks."

Abicipar lowers the burden of intravitreal injections, with more than 90% of patients achieving stability with quarterly, not monthly, injections, he said, adding that in nAMD, "the ability to extend patient treatment intervals without losing vision is a major benefit."

"The treatment related AEs, mainly inflammation (most of which was successfully treated with topical medication), are indeed higher than ranibizumab, and this is thought to be due in part to the purification process, which has since been improved," Dr. Kunimoto said.

Dr. Peter A. Campochiaro, a professor of ophthalmology and neuroscience at the Wilmer Eye Institute at Johns Hopkins University School of Medicine, in Baltimore, Maryland, said that based on the new findings and earlier reports, "it is safe to conclude that abicipar will have a longer duration of action than ranibizumab in clinical practice."

He pointed out in an email to Reuters Health, however, that ranibizumab is not widely used in clinical practice; the most common medications for wet (neovascular) AMD are bevacizumab (initially) and aflibercept (if response to bevacizumab is suboptimal).

Dr. Campochiaro said there could be a role for abicipar, but that he would be hesitant to use it instead of aflibercept because of abicipar's high incidence of inflammation. "I am not inclined to recommend it for any of my patients," he concluded.

The study was funded by Allergan plc. Dr. Kunimoto reports financial ties to and several of his coauthors are Allergan employees.

SOURCE: Ophthalmology, online April 9, 2020.