AbbVie Withdraws Abicipar Pegol Marketing Applications in EU and Japan Following FDA Rejection Over Intraocular Inflammation Concerns

July 21, 2020 News /BioonBIOON/ -- AbbVie’s subsidiary Allergan recently notified its partner Molecular Partners that it would withdraw its application to the European Medicines Agency (EMA) and Japan’s Pharmaceuticals andMedical DevicesMarketing application submitted to the Pharmaceuticals and Medical Devices Agency (PMDA) for the ophthalmic drug abicipar pegol, a novel investigational DARPin therapy for the treatment of neovascular (wet) age-related macular degeneration (wet AMD, nAMD).

Regarding U.S. regulatory matters, on June 26, the FDA issued a Complete Response Letter (CRL) rejecting the application for abicipar pegol in the treatment of neovascular age-related macular degeneration (nAMD). In the CRL, the FDA noted that the rate of intraocular inflammation observed following administration of abicipar pegol (2 mg/0.05 mL) in patients with nAMD resulted in an unfavorable benefit-risk profile. AbbVie plans toFDADiscuss and determine the next steps.

Allergan entered into a strategic ophthalmology collaboration with Molecular Partners in 2011 to develop novel multi-DARPin products. DARPin (Designed Ankyrin Repeat Proteins) are a class of novel binding proteins derived from natural ankyrin repeat sequences (ANK). Ankyrins are the most common class of binding proteins in nature, responsible for diverse functions such as cell signaling and receptor binding. DARPin proteins offer numerous advantages, including low molecular weight, high potency, high stability, high affinity, and structural flexibility, making them highly valuable for clinical therapeutic applications.

Abicipar pegol is an anti-angiogenic drug based on DARPin technology, developed for nAMD andDiabetesTreatment of Diabetic Macular Edema (DME). Abicipar pegol is an antagonist of vascular endothelial growth factor A (VEGF-A) that potently inhibits all VEGF-A isoforms. Combining small size, high potency, and a long intravitreal half-life, abicipar pegol enables less frequent injections (compared with Lucentis, the current standard of care) and greater visual acuity gains.

Wet AMD (wet-AMD, image source: retinaboston.com)

Regulatory application documents for abicipar pegol, based on data from two head-to-head Phase III clinical studies (SEQUOIA, CEDAR), supported the quarterly dosing regimen of abicipar pegol versus Roche/NovartisLucentis (ranibizumab) demonstrated non-inferior efficacy in maintaining vision with a monthly dosing regimen, achieving more than a 50% reduction in the number of injections during the first year (6 vs. 13 injections).

The SEQUOIA and CEDAR studies compared the efficacy and safety of abicipar pegol versus ranibizumab in treatment-naïve patients with neovascular age-related macular degeneration (nAMD). The results confirmed that, at week 52, the fixed-dosing regimens of abicipar pegol every 8 weeks (Q8) and every 12 weeks (Q12) met the primary endpoint of non-inferiority to the ranibizumab every-4-weeks (RQ4) regimen in terms of vision stabilization (loss of ≤15 letters in best-corrected visual acuity [BCVA] from baseline).

Abicipar pegol administered via 6 injections (Q12 regimen) and 8 injections (Q8 regimen) achieved similar efficacy to ranibizumab administered via 13 injections (RQ4 regimen) over one year of treatment: In the SEQUOIA study, the proportions of patients achieving stable vision were 94.8%, 91.3%, and 96.0% in the Q8, Q12, and RQ4 groups, respectively; in the CEDAR study, the proportions were 91.7%, 91.2%, and 95.5% in the Q8, Q12, and RQ4 groups, respectively. Regarding safety, overall across the three treatment groupsAdverse ReactionsSimilarly, the abicipar pegol treatment group exhibited a higher incidence of intraocular inflammation: In the SEQUOIA study, the overall incidence rates of treatment-related adverse events in the Q8, Q12, and RQ4 groups were 78.3%, 78%, and 74%, respectively, while the incidence rates of intraocular inflammation events were 15.7%, 15.3%, and 0.6%, respectively. In the CEDAR study, the overall incidence rates of treatment-related adverse events in the Q8, Q12, and RQ4 groups were 73.7%, 81.1%, and 73.2%, respectively, while the incidence rates of intraocular inflammation events were 15.1%, 15.4%, and 0%, respectively.

In April 2019, Allergan announced the top-line safety results from another clinical study, MAPLE. This was a 28-week, open-label study that enrolled 123 patients with neovascular age-related macular degeneration (nAMD) to evaluate the safety of abicipar pegol produced using an improved manufacturing process. In the study, treatment-naïve patients or those previously treated with anti-vascular endothelial growth factor (VEGF) therapy received three monthly injections of 2 mg abicipar pegol, followed by 2 mg injections every two months, for a total of five injections through Week 28.

Due to improvements in manufacturing processes, the incidence of intraocular inflammation (IOI) in the MAPLE study was 8.9%, lower than that observed in previous Phase III studies. The majority of IOI events were mild to moderate in severity. The incidence of severe IOI was 1.6%, with one case reported as iritis and one as uveitis. No cases of endophthalmitis or retinal vasculitis were reported in the study. (Bioon.com)

Original Source:Allergan pulls back European and Japanese application for wet AMD drug