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AMD Drug Shows Benefits with Fewer Doses

— Brolucizumab noninferior to aflibercept with 12-week dosing

MedpageToday

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.

Action Points

  • Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

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.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined ľֱ in 2007.

Disclosures

The HAWK and HARRIER trials were supported by Alcon/Novartis.

Brown disclosed relevant relationships with Adverum, Aerpio, Alcon, Aldeyra, Allegro Pharmaceuticals, Allergan, Apellis, Astellas, Aura, Boehringer-Ingelheim, Chengdu Kanghong Biotechnology, Chiltern, Clearside Biomedical, Coda Therapeutics, DRCR, Envisia, Genentech, GlaxoSmithKline, Heidelberg, Iconic, INC Research, Jaeb Center for Health Research, Johnson & Johnson, KOWA, Merck, Nei, Notal Vision, Novartis, OHR, Optos, Pfizer, pSivida, Quantel Medical, Regeneron/Bayer, RegenxBio, Samsung Bioepis, Santen, SciFluor, Senju Pharmaceutical, Stealth BioTherapeutics, Stealth Peptides, Taiwan Liposome, ThromboGenics, Tyrogenex, and Zeiss.

Dugel disclosed relevant relationships with Abbott/AMO, Acucela, Aerpio, Alcon, Alimera Sciences, Allergan, Amgen, Annidis, ArcticDX, Avalanche Biotechnologies, Bausch &Lomb, Boehringer Ingelheim, Beyonics, DCR Life, Chengdu Kanghong Biotechnology, Clearside, Digisight, DOSE Medical, Genentech/Roche, Graybug Vision, Irenix, Kodiak Sciences, Lutronic, Lux Biosciences, MacuSight, NeoVista, Novartis, Oculis, OD-OS, Omeros, Ophthotech, Opthea, Optovue, ORA, PanOptica, Pentavision, Regeneron, Santen, SciFluor Life Sciences, Shire, Spark Therapeutics, Stealth BioTherapeutics, ThromboGenics, TopCon, TrueVision, and Zeiss Group.

Khanani disclosed relevant relationships with Aerpio, Alcon, Alimera, Allergan, Digisight, Genentech, Novartis, Ophthotech, Opthea, Santen, and ThromboGenics.

Primary Source

American Society of Retina Specialists

Khanani AM, et al "Phase III randomized, double-masked studies of brolucizumab versus aflibercept in nAMD: Expanded primary and secondary outcomes from HAWK/HARRIER" ASRS 2018.

Secondary Source

American Society of Retina Specialists

Dugel PU, et al "A comparison of the anatomical efficacy of brolucizumab versus aflibercept in nAMD patients: Matched 16-week results from the HAWK and HARRIER studies" ASRS 2018.

Additional Source

American Society of Retina Specialists

Brown DM, et al "Predictive analysis of the 12-week dosing status at week 48 for patients receiving brolucizumab in the HAWK and HARRIER studies" ASRS 2018.