Author: Ramin Tadayoni (France)
Co-authors: Charles Wykoff, Zdenka Haskova, David Silverman, Jane Ives, Karen Basu, Hugh Lin
Faricimab is a novel bispecific antibody designed to inhibit both angiopoietin and vascular endothelial growth factor (VEGF)-A, reduce vascular leakage and inflammation, promote vascular stability, and improve outcomes and durability beyond anti-VEGF monotherapy for diabetic macular edema (DME). The phase 3 YOSEMITE and RHINE trials aim to assess the efficacy, safety, and durability of intravitreal faricimab versus aflibercept in patients with DME.
YOSEMITE (NCT03622580) and RHINE (NCT03622593) are identical, randomized, double-masked, active comparator–controlled, 100-week, phase 3 trials of faricimab in treatment-naïve and previously anti-VEGF–treated patients with DME.
Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks (Q8W) after 6 initial Q4W doses, faricimab 6.0 mg per personalized treatment interval (PTI) after 4 initial Q4W doses, or aflibercept 2.0 mg Q8W after 5 initial Q4W doses. The PTI algorithm is a protocol-driven regimen based on the treat and-extend concept, with dosing intervals adjusted in 4-week increments (Q4W up to Q16W) using prespecified best corrected visual acuity (BCVA) and central subfield thickness (CST) criteria. The primary efficacy endpoint was mean change in BCVA from baseline at 1 year, averaged over weeks 48, 52, and 56. Noninferiority in the intention-to-treat (ITT) population, followed by superiority in treatment-naïve patients, was assessed for each faricimab arm against aflibercept. Secondary endpoints included the proportion of patients with ≥ 2-step Early Treatment Diabetic Retinopathy (ETDRS)-Diabetic Retinopathy Severity Scale improvement from baseline, the proportion of patients gaining or avoiding a loss of ≥ 15 ETDRS letters from baseline, change in CST from baseline, and the proportion of patients in the PTI arm on Q4W, Q8W, Q12W, or Q16W dosing at 1 year. Safety was assessed by the incidence and severity of ocular and nonocular adverse events.
In total, 1891 patients with DME were enrolled in YOSEMITE (N = 940) and RHINE (N = 951). Baseline characteristics were well balanced across treatment arms. Both trials met the primary endpoint; mean BCVA gains from baseline at 1 year with faricimab Q8W (+10.7 and +11.8 ETDRS letters in YOSEMITE and RHINE, respectively) or faricimab PTI up to Q16W (+11.6 and +10.8 ETDRS letters) were noninferior to aflibercept Q8W (+10.9 and +10.3 ETDRS letters). In treatment-naïve patients, mean BCVA gains at 1 year were consistent with the ITT population and no faricimab arm showed superiority to aflibercept. Mean change in CST over 1 year consistently favored faricimab over aflibercept. Similarly, absence of protocol-defined DME (CST < 325 µm) and absence of intraretinal fluid during year 1 were achieved by more patients treated with faricimab versus aflibercept. Notably, 52.8% (YOSEMITE) and 51.0% (RHINE) of patients in the faricimab PTI arm achieved Q16W dosing at week 52, while 73.8% and 71.1%, respectively, achieved ≥ Q12W dosing. In both trials, faricimab was well tolerated; intraocular inflammation event rates were low and no cases of vasculitis or occlusive retinitis were reported.
Faricimab Q8W or per PTI, a personalized regimen based on individual responses to treatment, offered noninferior vision gains compared with aflibercept Q8W, while demonstrating improvements in anatomic outcomes and the potential for extended (up to Q16W) dosing at 1 year.
Ramin Tadayoni: (Consultant) AbbVie, Alcon, Allergan, Apellis, Bayer, Genentech, Inc., Iveric Bio, KHB, Oculis, Roche, Thea; (Grant Support) Alcon, Bayer, Genentech, Inc, KHB, Novartis, Oculis, Roche, Zeiss. Charles C. Wykoff: (Consultant) Adverum, Allergan, Bayer, Chengdu Kanghong Biotechnology, EyePoint, Genentech, Inc., Kodiak Sciences, Novartis, Opthea, Regeneron, RegenXBio, Roche; (Grant Support) Chengdu Kanghong Biotechnology, Clearside Biomedical, Genentech, Inc., Graybug Vision, Kodiak Sciences, Novartis, Opthea, Regeneron, RegenXBio, Roche, Samsung Bioepis. Zdenka Haskova: (Employee) Genentech, Inc. David Silverman: (Employee) Roche Products Ltd. Jane Ives: (Employee) Roche Products Ltd. Karen Basu: (Employee) Roche Products (Ireland) Ltd. Hugh Lin: (Employee) Genentech, Inc.