Results from two clinical trials testing a new anti-VEGF molecule against ranibizumab (trade name Lucentis) suggest that clinicians will still need to balance overall efficacy and adverse effects of treatments against patient compliance with more frequent dosing. A recent clinical study compared a new treatment, 2 mg abicipar pegol (a novel DARPin molecule) against 0.5mg ranibizumab. The abicipar study arm regimens involved dosing 8 and 6 times over a 1-year period, while ranibizumab patients received 13 doses over the same duration, according to the study’s sponsor, Allergan. While ranibizumab achieved the highest proportion of stable vision in the primary analysis (95.5% to 96.0%), abicipar achieved 91.3% to 94.8% and 91.2% to 91.3% stable vision in the 8 and 6 dose arms, respectively. However, inflammation appeared to be significantly higher in both abicipar groups compared to the ranibizumab group.
DARPins, short for “designed ankyrin repeat proteins” are derived from natural ankyrin, or adaptor proteins, which are a common binding protein functioning in cell signaling and receptor binding activities. DARPins may be modified for highly specific target binding, facilitating the specific attack on a single validated disease pathway, limiting off-target effects. In addition, due to their small size, potentcy and stability, the molecules may have the potential to overcome some of the drawbacks found with other therapeutic approaches that can either be too large for effective penetration, or too toxic in terms of side effects. However, the real-world evidence for such novel molecules have yet to be demonstrated.
Two phase III studies (“SEQUOIA” and “CEDAR”) were conducted to assess the efficacy and safety of the potentially new anti-VEGF treatment, abicipar pegol, compared with ranibizumab in treatment-naïve patients with neovascular AMD. The studies were multi-centered randomized Phase III trials with the primary endpoint based on the proportion of patients with stable vision at week 52. Stable vision was defined by the sponsor as the proportion of patients with vision loss of fewer than or equal to 15 letters in BCVA from baseline. According to the sponsor, three (3) treatment arms were used in the study: one comprising 2 mg abicipar pegol, given in 3 monthly doses, followed by a dose every 8 weeks, a total of 8 doses for the primary analysis; a second test arm comprising 2 mg abicipar pegol given in 2 monthly doses, followed by a dose after 8 weeks, followed by every 12 weeks dosing totalling 6 doses for the primary analysis, and, finally; 0.5 mg ranibizumab administered in monthly doses totalling 13 doses for the primary analysis. Taking the SEQUOIA and CEDAR studies together, the proportion of patients with stable vision at week 52 in the abicipar group dosed 8 times during the year was 94.8% and 91.7%, respectively; for patients dosed with abicipar 6 times during the year the proportion of patients with stable vision was 91.3% and 91.2%, respectively; while the ranibizumab treated patients in both studies had a highest proportion of patients with stable vision at 96.0% and 95.5%, respectively. Intraocular inflammation appeared to be a significant issue in both of the abicipar study arms, reported at between 15.1% and 15.7% in the SEQUOIA and CEDAR studies respectively, compared to between 0% and 0.6% for ranibizumab. Commentary from the study sponsor did not include confidence intervals and so the range of vision stability measurements are not known. In addition, the non-inferiority margin, or “delta” is not known or recorded on the clinical trials.gov entry (NCT02462486, NCT02462928) and so the absolute differences between the groups is not yet known.