CHICAGO — Patients with neovascular age-related macular degeneration (AMD) had significant vision improvement that was maintained for a year with a bispecific antibody dosed every 3 to 4 months, a phase II randomized trial showed.
Simultaneous inhibition of angiopoietin 2 (Ang-2) and vascular endothelial growth factor (VEGF) with faricimab led to mean gains of 10 to 11 letters at 52 weeks, as assessed by Early Treatment of Diabetic Retinopathy Study (ETDRS) methodology. Patients treated with ranibizumab (Lucentis) every 4 weeks also averaged a 10-letter improvement in best corrected visual acuity (BCVA). Two thirds of patients randomized to faricimab had no disease activity 12 weeks after the last of four loading doses.
The proportion of patients who gained ≥15 letters was similar across treatment groups, and only a few of the 76 patients in the trial had BCVA losses ≥15 letters at 52 weeks, as reported here at the American Academy of Ophthalmology (AAO) annual meeting.
“Combined inhibition of Ang-2 and VEGF can reduce vascular destabilization and leakage and shows potential for increased durability in neovascular AMD,” said Arshad Khanani, MD, of Sierra Eye Associates in Reno, Nevada. “These results support moving forward with larger trials to confirm the benefits of dual inhibition of Ang-2 and VEGF in neovascular AMD, and a global phase III program will start early next year.”
Other neovascular AMD data reported at the meeting included results of two phase III trials of the VEGF inhibitor abicipar pegol, which demonstrated noninferiority to ranibizumab for BCVA with 8- and 12-week dosing.
Although intravitreal VEGF injections have demonstrated effectiveness for neovascular AMD, monthly treatment regimens have proven to be burdensome for many patients. As a result, strategies to reduce treatment burden continue to be investigated. At the same time, multiple studies have shown that patients often do not maintain BCVA gains with fewer injections, Khanani noted.
Faricimab was engineered with the goal of achieving durable improvements in BCVA with a reduced treatment burden. Inhibition of Ang-2 helps stabilize blood vessels, whereas VEGF inhibition blocks vascular proliferation. The monoclonal antibody’s design also reduces systemic exposure and inflammation potential.
Khanani reported findings from the phase II stairway trial. Investigators randomized older patients (mean age 77-80) to two faricimab intravitreal injections every 16 or 12 weeks (q16w, q12w) or to ranibizumab every 4 weeks. At week 24 (3 months after the last loading dose), patients randomized to q16w injections were switched to q12w if they still had evidence of active disease (determined by assessment of central subfield thickness (CST), BCVA, fundoscopy, and investigator clinical opinion).
At week 24, a total of 36 of 55 patients assigned to faricimab had no evidence of active disease. The three treatment groups had similar improvement in BCVA at 40 weeks (primary endpoint), and the improvement was maintained at week 52. The 1-year assessment of BCVA showed a mean improvement of 11.42 letters in the q16w faricimab group, 10.08 letters in the q12w group, and 9.59 letters in the ranibizumab group.
Khanani said 37.5% of patients treated with ranibizumab gained ≥15 letters in BCVA versus 46.4% of the q16w faricimab group and 33.3% of the q12w group. Across all three treatment groups, one patient had a loss of ≥15 letters in BCVA (q16w group).
Average reductions in CST at 52 weeks did not differ significantly in the three groups (-122.5 to -138.5 µm), nor did improvement in choroidal neovascularization lesion size (-4.2 to -5.4 mm2).
The incidence, type, and severity of ocular and systemic adverse events were similar in the three treatment groups.
Extended Dosing Intervals
Results of two phase III trials (SEQUOIA and CEDAR) involving a total of 1,888 patients demonstrated noninferiority for the investigational VEGF inhibitor abicipar pegol administered every 8 or 12 weeks versus ranibizumab every 4 weeks. Both trials had stable vision at 52 weeks as the primary endpoint, said Rahul N. Khurana, MD, of Northern California Retina Vitreous Associates in Mountain View.
In the SEQUOIA trial, baseline BCVA averaged 56 to 57 letters and central retinal thickness (CRT) averaged 378 to 382 µm across the three treatment groups. At 52 weeks, the proportion of patients with stable vision was 94.8% with abicipar pegol q8w, 91.3% with abicipar q12w, and 96.0% with ranibizumab.
The change in BCVA (a secondary endpoint) averaged 7.3 to 8.3 letters and did not differ significantly between groups, nor did the mean change in CRT (-142 to -147 µm). Improvements at 16 weeks were maintained to 52 weeks in all three groups.
Patients in the CEDAR trial had baseline BCVA of 56 letters and mean CRT of 378 to 385 µm. Rates of disease stability at week 52 were 91.7% with abicipar pegol q8w, 91.2% in the q12w group, and 95.5% in the ranibizumab arm. The change in BCVA averaged 5.6 letters with abicipar q8w, 6.7 letters with abicipar q12w, and 8.5 letters with ranibizumab. The improvement did not change significantly from week 16 to week 52. The decline in CRT at 16 weeks averaged 112 µm with abicipar q8w, 131 µm with ranibizumab, and 141 µm with abicipar q12w, and the improvement was maintained to 52 weeks.
Rates of treatment-emergent adverse events were similar across the three treatment groups, said Khurana. A combined analysis of both trials showed that intraocular inflammation (all grades) occurred more often with abicipar pegol (15% versus <1%). Most cases of inflammation were mild or moderate in severity.
Khurana said follow-up in both trials will continue to 104 weeks.
The faricimab study was supported by Roche/Genentech.
Khanani disclosed relationships with Aerpio, Allergan, Clearside Biomedical, Genentech, Novartis, Ophthotech, Opthea, Oxurion, Verana Health, Alimera, Notal Vision, Oxurion, Polyphotonix, Recens Medical, Roche, and Santen.
The abicipar pegol studies were supported by Allergan.
Khurana disclosed relationships with Allergan, Clearside Biomedical, Genentech, Google, Regeneron, and Santen.