DARPin molecule prolongs anti-VEGF activity in nAMD
A phase III study program investigating abicipar pegol (Allergan) for the treatment of neovascular age-related macular degeneration (nAMD) is underway based on promising efficacy and safety results in phase II studies.
A phase III study program investigating abicipar pegol (Allergan) for the treatment of neovascular age-related macular degeneration (nAMD) is underway based on promising efficacy and safety results in phase II studies.
“Abicipar pegol is the first-in-kind designed ankyrin repeating protein (DARPin) studied in the eye, and it is an exciting molecule,” said Pravin U. Dugel, MD. “Like ranibizumab (Lucentis, Genentech), abicipar pegol is an antagonist to all isoforms of VEGF-A, but the DARPin is smaller. (This) allows for good tissue penetration, and results of in vitro and animal studies show that it is a more potent inhibitor of VEGF-A, binds with greater affinity, and has a longer intravitreal half-life than ranibizumab.”
Dr. Dugel is managing partner, Retinal Consultants of Arizona, Phoenix, and clinical professor, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles.
“Furthermore, in a multidose phase II study, abicipar pegol showed potential for treating nAMD with less frequent injections compared with ranibizumab.”
Recombinant protein
DARPins are recombinant proteins that are genetically engineered to bind to a specific target. Besides being small, potent, and having high specificity and binding affinity, DARPins are stable, which translates into good shelf-life, and highly soluble, which could allow for mixing with other agents and formulation in novel drug delivery systems.
The phase II study program for developing abicipar pegol as a treatment for nAMD was comprised of 3 stages. Most relevant to clinical practice, the third stage was a double-masked study that randomized 64 treatment-naïve patients to abicipar pegol 1 mg (n = 25), abicipar pegol 2 mg (n = 23), or ranibizumab 0.5 mg (n = 16).
Abicipar pegol was administered at weeks 0, 4 and 8, while ranibizumab was injected every 4 weeks through week 16. Patients were examined every 4 weeks through week 20.
The primary endpoint was change in best-corrected visual acuity (BCVA) from baseline to week 16, and the analysis showed numerically greater improvement in the abicipar pegol 1 mg and 2 mg groups compared with the ranibizumab-treated controls (+6.3 letters and +8.2 letters versus +5.3 letters, respectively).
BCVA improved at week 20
At week 20, BCVA had improved further in the abicipar pegol groups and declined from week 16 in the ranibizumab group. Mean change from baseline was +7.1 letters in eyes treated with abicipar pegol 1 mg, +9.0 letters for abicipar pegol 2mg, and +4.7 letters for ranibizumab.
“Even though the last abicipar pegol injections were given at 8 weeks, visual acuity improvement was maintained or increased 8 to 12 weeks later,” Dr. Dugel said. “Abicipar pegol also demonstrated sustained benefit at 8 to 12 weeks post-injection in analyses of the percentage of patients with a BCVA gain ≥15 letters and the functional outcomes corresponded with reductions in central retinal thickness (CRT).”
There were no cases of endophthalmitis or other serious ocular adverse events in the study. In the abicipar pegol 2 mg group, 1 patient developed iritis and 1 patient developed choroiditis. Three cases of intraocular inflammation, representing single cases of iritis, vitritis, and uveitis, occurred in the abicipar 1 mg group.
“All of the cases of intraocular inflammation were mild to moderate in severity and resolved with treatment,” Dr. Dugel outlined. “Importantly, there was no evidence of a dose-response effect. There was also no imbalance between groups in reported systemic adverse events, and there were no Anti-Platelet Trialists’ Collaboration events in any group. This was, however, a small study.”
Pivotal trials
The ongoing phase III program consists of two 96-week trials that are known as CEDAR and SEQUOIA. Recruitment is ongoing in the trials that have a planned enrollment of about 900 patents each.
Eligible patients are being randomized to 3 groups to receive abicipar 2 mg at week 0, 4, and 8 followed by injections every 8 weeks; abicipar 2 mg injections at week 0, 4, and 12 followed by injections every 12 weeks; or ranibizumab 0.5 mg every 4 weeks.
The primary endpoint is the proportion of patients with stable vision (≤15 letters change from baseline BCVA). Secondary endpoints are: change from baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA, change from baseline in corneal retinal thickness, percentage of patients with a BCVA gain ≥15 letters, and change from baseline in the National Eye Institute Visual Functioning Questionnaire-25 composite score.
Pravin U. Dugel, MD
This article is based on a presentation deliver by Dr. Dugel at the 2017 Retina World Congress. Dr. Dugel is a consultant to Allergan.
