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Clinical Trial
. 2022 Feb 19;399(10326):741-755.
doi: 10.1016/S0140-6736(22)00018-6. Epub 2022 Jan 24.

Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials

Charles C Wykoff  1 , Francis Abreu  2 , Anthony P Adamis  2 , Karen Basu  3 , David A Eichenbaum  4 , Zdenka Haskova  2 , Hugh Lin  2 , Anat Loewenstein  5 , Shaun Mohan  2 , Ian A Pearce  6 , Taiji Sakamoto  7 , Patricio G Schlottmann  8 , David Silverman  9 , Jennifer K Sun  10 , John A Wells  11 , Jeffrey R Willis  2 , Ramin Tadayoni  12 ; YOSEMITE and RHINE Investigators
Collaborators, Affiliations
Clinical Trial

Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials

Charles C Wykoff et al. Lancet. .

Abstract

Background: To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody.

Methods: YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).

Findings: 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]).

Interpretation: Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.

Funding: F Hoffmann-La Roche.

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Conflict of interest statement

Declaration of interests CCW reports research support from Adverum, Aerie, Aldeyra, Alimera, Allergan, Amgen, Apellis, AsclepiX, Bayer, Boehringer Ingelheim, Chengdu Kanghong, Clearside, Gemini, Genentech, Graybug Vision, Gyroscope, Ionis, iRenix Medical, Iveric Bio, Kodiak, Lowy Medical Research Institute, Neurotech, NGM Bio, Novartis, Oxurion, RecensMedical, Regeneron, Regenxbio, Roche, SamChunDang Pharm, Samsung Bioepis, Taiwan Liposome Company, and Xbrane BioPharma, outside the submitted work. CCW reports consulting fees from Adverum, Aerie, Aerpio, Allergan, Allgenesis, Apellis, Arrowhead, Bausch and Lomb, Bayer, Bionic Vision Technologies, Chengdu Kanghong, Clearside, EyePoint, Genentech, Gyroscope, Iveric Bio, Janssen, Kato, Kodiak, Long Bridge Medical, NGM Bio, Novartis, OccuRx, Ocular Therapeutix, ONL Therapeutics, Opthea, Oxurion, Palatin, PolyPhotonix, RecensMedical, Regeneron, Regenxbio, Roche, Santen, Surrozen, Takeda, Verana Health, and Vitranu, outside the submitted work. CCW reports other personal fees from Regeneron, stock or stock options from ONL Therapeutics, PolyPhotonix, RecensMedical, and Visgenx, and has served on advisory boards for Kato, outside the submitted work. CCW has served as a board member of the American Society of Retina Specialists and the Vit-Buckle Society, outside the submitted work. FA is an employee of Genentech. APA was an employee of Genentech during the course of this study and reports stock or stock options from Roche. KB was an employee of Genentech during the course of this study and is a current employee of Roche Products (Ireland). DAE reports research support from Alkahest, AsclepiX, Bayer, Chengdu Kanghong, EyePoint, Gemini, Genentech, Gyroscope, Ionis, Iveric Bio, Kodiak, Mylan, NGM Bio, Novartis, Ocular Therapeutix, Opthea, RecensMedical, Regeneron, and Regenxbio, outside the submitted work. DAE reports consulting fees from Alimera, Allergan, Apellis, Bausch and Lomb, Dutch Ophthalmic, EyePoint, Genentech, Gyroscope, Iveric Bio, KKR, Kodiak, Notal Vision, Novartis, RecensMedical, Regeneron, and Regenxbio, outside the submitted work. DAE reports other personal fees from Allergan, Apellis, Bayer, Dutch Ophthalmic, EyePoint, Genentech, and Novartis; stock or stock options from Boston Image Reading Center, Clearside, Hemera, and Network Eye; and has served on advisory boards for Genentech, Iveric Bio, and RecensMedical, outside the submitted work. DAE has served as a board member of the Florida Society of Ophthalmology, outside the submitted work. ZH is an employee of Genentech, and reports stock or stock options from Genentech. HL is an employee of Genentech, reports personal fees and stock or stock options from Roche/Genentech, and is a coauthor on patent application WO202123804 involving the PTI algorithm. AL reports research support from Notal Vision and Novartis, and consulting fees from Allergan, Bayer, Beyeonics Surgical, and Syneos Health, outside the submitted work. SM is an employee of Genentech, and reports stock or stock options from Genentech. IAP reports consulting and other personal fees from Allergan, Bayer, Novartis, and Roche, and has served on advisory boards for Bayer, Novartis, and Roche, outside the submitted work. TS reports research support from Bayer, Chugai, Novartis, Santen, and Senju; consulting and other personal fees from Bayer, Novartis, and Senju; and has served on advisory boards for Bayer, Novartis, and Roche, outside the submitted work. PGS reports personal fees and has served on advisory boards for Roche, outside the submitted work. DS is an employee of Roche Products, reports personal fees and stock or stock options from Roche, and is a coauthor on patent application WO202123804 involving the PTI algorithm. JKS reports research support from Boehringer Ingelheim, Jaeb Center for Health Research, Juvenile Diabetes Research Foundation, KalVista, Novartis, Optovue, and Physical Sciences; personal fees from Merck, Novartis, and Novo Nordisk; and equipment loans from Adaptive Sensory Technology, Boston Micromachines, and Optovue, outside the submitted work. JAW reports research support from Adverum, Alimera, Bayer, Clover Therapeutics, Genentech, Iveric Bio, Kodiak, Lowy Medical Research Institute, NIH National Eye Institute, Neurotech, Opthea, and Regeneron, and consulting fees from Genentech, outside the submitted work. JRW is an employee of Genentech, reports stock or stock options from Genentech, and is a coauthor on patent application WO202123804 involving the PTI algorithm. RT reports consulting and personal fees and has served on advisory boards for AbbVie, Alcon, Allergan, Apellis, Bayer, Chengdu Kanghong, Genentech, Iveric Bio, Novartis, Oculis, Roche, and Thea, and reports equipment from Zeiss, outside the submitted work.

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