TY - JOUR
T1 - Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE)
T2 - two randomised, double-masked, phase 3 trials
AU - YOSEMITE and RHINE Investigators
AU - Wykoff, Charles C.
AU - Abreu, Francis
AU - Adamis, Anthony P.
AU - Basu, Karen
AU - Eichenbaum, David A.
AU - Haskova, Zdenka
AU - Lin, Hugh
AU - Loewenstein, Anat
AU - Mohan, Shaun
AU - Pearce, Ian A.
AU - Sakamoto, Taiji
AU - Schlottmann, Patricio G.
AU - Silverman, David
AU - Sun, Jennifer K.
AU - Wells, John A.
AU - Willis, Jeffrey R.
AU - Tadayoni, Ramin
AU - Aaberg, Thomas
AU - Abbey, Ashkan
AU - Abdulaeva, Elmira
AU - Abengoechea, Santiago
AU - Abraham, Prema
AU - Ach, Thomas
AU - Adams, Serrhel
AU - Adan Civera, Alfredo
AU - Adrean, Sean
AU - Agostini, Hansjurgen
AU - Alam, Suhail
AU - Alezzandrini, Arturo
AU - Alfaro, Virgil
AU - Aliseda, Daniel
AU - Almony, Arghavan
AU - Amat, Pedro
AU - Amini, Payam
AU - Antoszyk, Andrew
AU - Arias, Luis
AU - Asaria, Riaz
AU - Avila, Marcos
AU - Awh, Carl C.
AU - Bafalluy, Joaquin
AU - Baker, Carl
AU - Bandello, Francesco
AU - Barakat, Mark
AU - Barraza, Karen
AU - Bator, Gyorgy
AU - Baumal, Caroline
AU - Belfort, Rubens
AU - Bergstrom, Chris
AU - Brown, David M.
AU - Chang, Emmanuel
N1 - Funding Information:
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.
Funding Information:
We sincerely thank the trial participants and their families, investigators, and staff at all YOSEMITE and RHINE clinical sites, and members of the independent data monitoring committee. We also thank Aaron Osborne for his contributions to the design of the YOSEMITE and RHINE trials. F Hoffmann-La Roche (Basel, Switzerland) provided support for the study and participated in the study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the paper for publication. Funding was provided by F Hoffmann-La Roche for third-party writing assistance, which was provided by Karina D Hamilton-Peel of Envision Pharma Group.
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/2/19
Y1 - 2022/2/19
N2 - 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.
AB - 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.
KW - Aged
KW - Angiogenesis Inhibitors/administration & dosage
KW - Angiopoietin-2/antagonists & inhibitors
KW - Antibodies, Bispecific/administration & dosage
KW - Diabetic Retinopathy/diagnosis
KW - Double-Blind Method
KW - Drug Administration Schedule
KW - Edema/drug therapy
KW - Female
KW - Humans
KW - Intravitreal Injections
KW - Macula Lutea/diagnostic imaging
KW - Male
KW - Middle Aged
KW - Receptors, Vascular Endothelial Growth Factor/administration & dosage
KW - Recombinant Fusion Proteins/administration & dosage
KW - Treatment Outcome
KW - Vascular Endothelial Growth Factor A/antagonists & inhibitors
KW - Visual Acuity/drug effects
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UR - http://www.scopus.com/inward/citedby.url?scp=85124662878&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(22)00018-6
DO - 10.1016/S0140-6736(22)00018-6
M3 - Article
C2 - 35085503
AN - SCOPUS:85124662878
SN - 0140-6736
VL - 399
SP - 741
EP - 755
JO - The Lancet
JF - The Lancet
IS - 10326
ER -