乌鸦传媒

VANCOUVER -- An investigational anti-VEGF drug proved noninferior to a current standard of care for neovascular age-related macular degeneration (AMD) and superior for key secondary endpoints with fewer treatments, according to updated results from two phase III trials.

The and trials met the primary endpoint of noninferiority for brolucizumab (formerly RTH258) versus aflibercept (Eylea) for best corrected visual acuity (BCVA) at 48 weeks, as previously reported (P<0.0001 for both trials). Patients treated with the higher (6 mg) dose of brolucizumab had significantly less retinal fluid accumulation and less retinal thickening, benefits initially observed after 16 weeks.

A majority of patients in both trials could be treated with brolucizumab every 12 weeks as compared with the 8-week schedule for aflibercept, researchers reported at the American Society of Retina Specialists meeting.

"The goal of AMD therapy is to gain vision, and I think the best way to gain vision is to maintain a fluid-free state," said David M. Brown, MD, of Retina Consultants of Houston. "So far, the phase II and phase III brolucizumab data have shown best-in-class drying ability of what I care most about -- intraretinal fluid (IRF), subretinal fluid (SRF). I truly feel that predictable, superior retinal drying could translate into improved outcomes with fewer injections."

Both trials involved patients ages ≥50 with untreated AMD and associated choroidal neovascularization and BCVA of 78 to 23 letters. In HAWK, 1,078 patients were randomized to two doses of brolucizumab (3 mg or 6 mg) administered every 12 weeks or to aflibercept administered every 8 weeks. HARRIER involved 739 patients randomized to 6 mg of brolucizumab or aflibercept. In both trials, investigators had the option of 8-week dosing with brolucizumab, said Arshad M. Khanani, MD, of Sierra Eye Associates in Reno, Nevada.

Analysis of the primary endpoint showed no significant difference between treatment groups in either trial. In the HAWK trial, mean change in BCVA was 6.1 ETDRS letters with brolucizumab 3 mg, 6.6 with brolucizumab 6 mg, and 6.8 with aflibercept. In the HARRIER trial, the mean change from baseline to 48 weeks was 6.9 letters with brolucizumab and 7.6 letters with aflibercept.

The proportion of patients who gained ≥15 letters with brolucizumab 6 mg and aflibercept were 33% and 26% in HAWK, and 29% and 30% in HARRIER, respectively. The proportion of patients who lost ≥15 letters in BCVA was about 5%-6% in both trials, regardless of treatment assignment.

Khanani reported that about a third fewer patients treated with brolucizumab had IRF or SRF at 48 weeks in the HAWK trial, and the proportion of patients with retinal fluid was 41% lower with brolucizumab in the HARRIER trial. Central subfield thickness (CST) by optical coherence tomography (OCT) also was significantly reduced with brolucizumab versus aflibercept in both trials (P=0.0023, P<0.0001).

With regard to the key secondary endpoints, the superiority of brolucizumab 6 mg was evident at 16 weeks and maintained to 48 weeks, said Pravin U. Dugel, MD, of Retinal Consultants of Arizona in Phoenix. In the HAWK trial, CST decreased by an average of 161.4 µM at week 16 with brolucizumab versus 133.6 µM with aflibercept (P=0.0016). In HARRIER, the mean CST reduction at 16 weeks was 174.4 µM with brolucizumab and 134.2 µM with aflibercept (P<0.0001).

With respect to presence of IRF/SRF, 35% fewer patients in the brolucizumab 6 mg group had retinal fluid 16 weeks in the HAWK trial, and 33% fewer patients had retinal fluid with brolucizumab at 16 weeks in the HARRIER trial as compared with aflibercept (P=0.0001 for both trials). Additionally, 30% and 33% fewer patients in the HAWK and HARRIER trials, respectively, had subretinal pigment epithelium fluid at 16 weeks when treated with brolucizumab (P=0.0021, P=0.0041).

The proportion of patients who could be maintained on a 12-week dosing interval was another key secondary outcome of both trials, said Brown. In the HAWK trial, 57% of patients randomized to brolucizumab 6 mg remained on the 12-week dosing interval to 48 weeks, as did 52% of patients in the HARRIER trial. About 80% of patients who would require 8-week dosing were identified during the first 12-week dosing cycle in each trial.

Among patients who completed the first 12-week dosing interval, 87.4% in the HAWK trial and 82.5% in the HARRIER trial remained on the 12-week dosing interval to 48 weeks, said Brown.