Jessica Rousseau
email: jessica.rousseau@hmg.inpg.fr

Emmanuel Frangin

Philippe Marin

Laurent Daudeville

Damage prediction in the vicinity of an impact on a concrete structure: a combined FEM/DEM approach

published or not. The documents may come

Damage prediction in the vicinity of an impact on a concrete structure: a combined FEM/DEM approach

Introduction

The design of some civil engineering structures must take into account the risk of severe loadings due to natural or manmade hazards, such as rockfalls, aircraft or missile impacts. On a sensitive concrete structure, such loadings may have disastrous consequences, and an efficient and accurate prediction of damage proves to be of prime importance.

Generally speaking, these severe loadings lead to fractures and fragmentation localized in one part of the concrete structure. The Discrete Element Method (DEM) [START_REF] Cundall | A discrete numerical model for granular assemblies[END_REF] is appropriate for modeling such discontinuities. The model developed uses a disordered assembly of spherical elements of different sizes and masses in order to reproduce isotropic and homogeneous behavior at the macroscopic scale. This method does not rely on any assumption regarding where and how a crack or several cracks occur and propagate since the medium is naturally discontinuous and very well adapted to dynamic problems. In order to offer a predictive model, the DE model must properly depict concrete behavior.

The identification process of Discrete Element (DE) parameters, in both linear and nonlinear behavior, will first be described. Local model parameters are calibrated so as to reproduce macroscopic concrete behavior. This process is nearly the same as that described in Hentz et al. (2004a), and the proposed modifications have simplified the process and improved the reproducibility and accuracy of the macroscopic characteristics obtained. These improvements have also provided a reliable and fast calibration method for parameters of large structures.

Nevertheless, computation time increases with the number of DE, and the analysis of large structures with DEM proves difficult. A number of authors have pointed out that such a method is limited to small structures due to the computation cost of DEM. Use of the FE method further from the impacted area represents one way to minimize this constraint since in most cases, severe degradation phenomena are localized right in the vicinity of the impact. In addition, the FE method is widely used, and efficient mesh generation software can dramatically reduce modeling duration, with the potential for faster calculations than when applying a full DE approach thanks to the facility of handling various discretization sizes.

These facts naturally lead to proposing a coupled FE/DE approach. Such a coupling is based on partitioning the structure into two sub-domains: an initial FE domain where nonlinear phenomena may be neglected, and a second DE domain where severe nonlinear degradation phenomena due to impact loading may occur. The second section of this article will summarize the main features of the coupling method. Additional technical details can be found in another paper by the same authors (Frangin et al., 2006).

In the fourth section of this article, the coupling method will be used for modeling a rock impact on a concrete slab. This part is intended to illustrate, by way of example, the identification process, validation of the coupling method through a comparison between a DE model and a coupled FE/DE model, and the computation time-savings offered by the coupled model.

The Discrete Element model for concrete

Model description

Discrete methods can be split into two groups: lattice models and discrete element models. Lattice models use simple deformable elements like beams or bars organized into a structural network; these models are widely used to represent concrete at the microscopic or mesolevel scale [START_REF] Leite | Computer simulation of fracture processes of concrete using mesolevel models of lattice structures[END_REF][START_REF] Prado | Effect of particle structure on mode I fracture process in concrete[END_REF]. For example, [START_REF] Prado | Effect of particle structure on mode I fracture process in concrete[END_REF] modeled concrete material according to three phases: aggregates, mortar and interfaces. They used 2D Euler-Bernoulli beams with elastic and fully brittle constitutive behavior. Such models perform poorly when it comes to representing the contact between fractured areas, and a fine discretization scale is required. The extension to 3D models therefore is hardly feasible.

More recently, Berton and Bolander (2005) developed a lattice model with Voronoi discretization. This model, based on the Rigid-Body-Spring Model [START_REF] Kawai | New discrete models and their application to seismic response analysis of structures[END_REF], has been used to simulate mode I fracture in concrete. For more general loading conditions, such as compression, the work of Shlangen and Garboczi (1997) and [START_REF] Cusatis | Tow-scale study of concrete fracturing behavior[END_REF] merits recognition. [START_REF] Cusatis | Tow-scale study of concrete fracturing behavior[END_REF] have developed a new lattice model called the "Confinement Shear Lattice model". They only considered the largest aggregates and connected the centroids with structural elements. An associated behavior for each element takes mortar, smaller aggregates and the cement-aggregate interface all into account. For this reason, modeled systems may actually be larger than the [START_REF] Prado | Effect of particle structure on mode I fracture process in concrete[END_REF] systems; however, the calculation effort turns out to be sizable, especially in determining the constitutive behavior parameters.

The second group of methods, i.e. using discrete elements, is based on modeling the continuum by means of rigid particles. The interaction laws between discrete elements serve to determine the macroscopic constitutive behavior. During early developments for noncohesive materials like sands [START_REF] Cundall | A discrete numerical model for granular assemblies[END_REF], particle interactions were described by friction laws, but the interaction laws for cohesive materials have since become refined (Hentz et al., 2004a).

Particle shapes remain of great importance. With a circular-shaped contact, determination is very fast even though porosity gets introduced. Polyhedrons [START_REF] Issa | Numerical analysis of micromechanical behavior of granular material[END_REF] fill the space very well, yet contact determination requires a specific and expensive algorithm that is more complex than for spheres or ellipsoids.

To guarantee reasonable computation times, a model based on Distinct Elements [START_REF] Cundall | A discrete numerical model for granular assemblies[END_REF] with rigid spheres has been chosen herein. Two types of interactions are defined. The initial interactions between two elements are generally link interaction (the two elements are not necessarily in contact). Additional interactions of contact type can be added during the simulation. Interactions between two spheres are defined with normal K n and tangential K s stiffnesses characterizing the elastic behavior of concrete.

"Micro-macro" relations (Eq. 1) from the Young's modulus and Poisson's ratio yield the local stiffnesses K n and K s . These relations stem from homogenization models [START_REF] Liao | Stress-strain relationship for granular materials based on the hypothesis of best fit[END_REF] typically used for regular DE assemblies; they have been modified to take into account both the relative disorder and the interaction surface S int . Equation ( 1) shows the micro-macro relations applied to determining K s and K n between two elements a and b.

, ab init D stands for the initial distance between elements a and b, with R a and R b being the element radii. The α, β and γ parameters still need to be identified. , 1

K s ab K init n n K s int K n K s K n K s K n D EK S βγ α ν α ⎧ + ⎪ = ⎪ + ⎪ ⎨ ⎪- ⎪ = ⎪ + ⎩ or ( ) , 1 1( 1 ) 1 1 int n ab init sn S KE D KK α β νγ α ν αν ν + ⎧ = ⎪ ++ - ⎪ ⎨ - ⎪ = ⎪ ⎩+ with: 2 (m in( , )) int a b SR R π = Eq. (1)
Stiffnesses K n and K s are used to compute the normal and tangential forces, F n and F s .

The sign convention employed herein is a positive compression force. An equivalent contact point P c is used to calculate local tangential displacement and rotation. For an interaction between elements a and b, the distance between the centroid of element a and the equivalent

contact point P c is: , 1 (( ) ) 2 ab aa b D RDR R =+ - + . Eq. (2)
The aim of this study is to model very large structures or parts of structures. The interaction laws are therefore stated in order to best represent concrete behavior at the macroscopic scale. To model the nonlinear behavior of the material, a modified Mohr-Coulomb model with softening has been adopted (see Fig. The centroid positions are randomly generated through use of a special "disordering" technique (based on an algorithm described in [START_REF] Jodrey | Computer simulation of close random packing of equal spheres[END_REF] that provides a polydisperse assembly with a particular size distribution. The characteristic sizes of elements do have to be representative of concrete constituents, such as the granular or cement matrix, since the aim is to produce a macroscopic description. The number of discrete elements must therefore be as small as possible to maintain a reasonable computation time. The specimen however must contain enough elements to guarantee a minimum number of links along with a correct distribution.

Figure 2 shows the orientation distribution of the links present; this distribution is quasi-uniform for various DE samples, which ensures an isotropic macroscopic constitutive behavior for the concrete samples. Initially, two discrete elements interact if the distance between their centroids is less than a given radius of interaction. According to the authors' experience, this radius of interaction is to be chosen such that the average number of interactions per DE equals 12: this value is the average number of links present in a regular (Face-Centered-Cubic) assembly of elements. Another value may be chosen, but such a change would introduce a different set of parameters. Of course this number cannot be too small to keep an isotropic specimen where there are not privileged directions of interactions.

As part of the proposed identification process and in order to obtain reliable results, this average number of interactions is calculated with internal elements only (i.e. edges are not considered). Young's modulus can thus be predicted with a maximum relative error of 6%.

It should be noted that in all of the following simulations, both axial and radial strains reflect the sample averages. For stability reasons, only those DE far from the edges and far from the central axis will be taken into account (Fig. 3).

Fig. 3: DE taken into account when computing the average strain

Identification of linear parameters

Tests carried out using the α, β, γ values identified by Hentz et al (2004a) reveal an error of between 20% and 30% for Poisson's ratio and about 5% for Young's modulus. The α, β and γ values must be reestablished. First of all, for some values of K s /K n , the ratio E/E 0 and Poisson's ratio ν were computed (a K s /K n =1 yields the E 0 value), which produces the set of numerical points to be fitted. Figure 4 displays how Hentz's identification (dotted line) of α, β,γ does not fit the corresponding numerical points. The values of α, β, γ need to be changed. The best-fit approximation (solid line in Figure 4) is obtained with: With these new values of the α, β and γ parameters, the average uncertainty now stands at 2% (with a maximum error of 7%) for Young's modulus and at approx. 3%

(maximum error of 6%) for Poisson's ratio: these results are highly accurate. The process employed to set the elastic behavior is now simpler in comparison to Hentz's proposal (2004).

Hentz was required to conduct two uniaxial tensile or compressive tests, the first as a reference for calculating the energy correction applied during the second. With this new identification of α, β and γ, the energy criterion proposed by Hentz is no longer needed. A correctly-adjusted interaction radius, which neglects border elements, guarantees accurate measurements of both the Young's modulus and Poisson's ratio during the first computation.

Identification of nonlinear parameters

The focus in this section is to identify local parameters for modeling macroscopic values, such as compressive strength σ c and tensile strength σ t .

As a first step, we have studied the reproducibility of both the compressive and tensile strength. A simulation of these uniaxial tests has been performed on the same set of samples as those used previously (Table 1). The parameters introduced here had been chosen arbitrarily and they are not held to be representative of any specific concrete. The level of reproducibility for both compressive strength (Fig. 5) and tensile strength (Fig. 6) is quite high. The gap between highest and lowest values equals about 2.6 MPa (6%)

Compression Strength

for compression and 0.3 MPa (5%) for tension.

These results suggest model reproducibility regardless of sample geometry or size and independently of the size of element used. From the perspective of modeling large structures, this identification process would be very expensive in terms of time, due to proportionality With this identification process (Fig. 7), the Discrete Element Model can now accurately represent concrete behavior. As explained above, the identification time for a large structure would be reasonable when using a representative extracted part.

Model description of the coupled method

Coupling methods have been widely studied. The first ones developed concerned the topic of Molecular Dynamics and Finite Elements at the microscopic scale. [START_REF] Curtin | Atomistic/continuum coupling in computational material science[END_REF] offered an overview of these atomistic methods; they introduced important notions, such as edge-to-edge coupling or bridging domain and energy weighting. Edge-to-edge methods typically require each Discrete Element to be coincident with a Finite Element node, which seems to be rather difficult within a disordered assembly. For this reason, edge-to-edge methods are naturally set aside. The bridging domain may be defined as a zone where MD and FE are both present and where the energy of both models is weighted. However, the bridging domain developed at the microscopic scale cannot be directly applied to a coupled DE-FE problem at the mesoscopic scale. [START_REF] Xiao | A bridging domain method for coupling continua with molecular dynamics[END_REF] then developed a coupling method based on a bridging domain (Fig. 13) with energy weighting. Xiao's method proposes minimizing the Hamiltonian (H), which is the sum of the Hamiltonians of both the FE and DE. To guarantee kinematic continuity, the degrees of freedom of both domains within the interface zone must be linked. Several approaches could be considered. [START_REF] Xiao | A bridging domain method for coupling continua with molecular dynamics[END_REF] proposed directly linking the Discrete Element degrees of freedom with Finite Element degrees of freedom using Lagrange multipliers. Eq. ( 6) presents the kinematic conditions on bridging domain r, with d DE displacements and u FE displacements.

.

rr dk u = r r
Eq. ( 6)

The Arlequin method (BenDhia and Rateau, 2005) uses displacement and strain projections over shape functions, in assuming field continuity. This method enables a spatial relaxation of the kinematic conditions. With Discrete Element models, the displacement and strain are not known at all points and such projections are not simple to use. This method may be adapted to DE models, by approximating the displacement and deformation fields, although this would increase computation time.

The preferred method therefore calls for using rigid kinematic conditions, like those in [START_REF] Xiao | A bridging domain method for coupling continua with molecular dynamics[END_REF]. Complementary kinematic constraints must then be added to link the DE rotations. Equation ( 7) lists the kinematic conditions linking DE rotations ω and displacements d with FE displacements u over bridging domain r. Both numerical simulations This section will present an application of both the coupling method and DE identification process. The full DE model will be compared with the coupling method, and the identification process explained above will be used in the two cases to determine local DE parameters.

This application consists of a rock impact on a concrete slab. A cubic rock block with a 30-cm side length impacts a concrete slab 2.5 m long, 2.0 m wide and 0.28 m thick. The In both models, the DE identification process previously described has been applied. A representative cube of the slab is extracted for identification purposes. This sample is isotropic, as shown by the orientation of interaction directions (Fig. 15). Moreover, the interaction radius is adjusted in order for the average number of interactions per element to equal 12. Sets of compression and tension computations are also performed to identify the local concrete parameters. Such local parameters are determined so as to yield a tensile strength of around 3 MPa and a compressive strength in the vicinity of 20 MPa (Table 2).

  1). When the tangential force F s lies outside the yield surface presented in the right-hand part of Figure 1, F s is taken at its maximum value for the corresponding normal force F n . Local parameters are the tensile strength T, cohesion C o and softening factor ζ (both the friction Φ i and contact Φ c angles are not studied in this paper and have been assigned fixed values of 6°). These local parameters must be identified from global parameters, such as compressive and tensile strengths σ c and σ t . More sophisticated laws taking into account compaction phenomena can be elaborated but they are not necessary to model thin structures (like the slab we use in the last part) as flexion and tension effects are principally observed.

Fig. 1 :

 1 Fig. 1: Interaction laws for DE

Fig. 2 :

 2 Fig. 2: Distribution of contact orientations within the sample

Fig. 4 :

 4 Fig. 4: Comparison of Young's modulus and Poisson's ratio computed and derived by approximation

Fig. 5 :

 5 Fig. 5: Reproducibility of the compression limit Fig. 6: Reproducibility of the tension limit

Fig. 8 :

 8 Fig. 8: Tensile test: Comparison of experimental and numerical results

Fig. 10 :

 10 Fig. 10: Compressive test: Comparison of experimental and numerical results (complete graph and close-up)

  β are the weight parameter of the FE Hamiltonian and the DE Hamiltonian, respectively. α and β have been defined on Figure 13, which presents an example of the bridging domain with four FE layers.

Fig. 13 :

 13 Fig. 13: Bridging domain and bridging parameter

  velocity of the impacting object is set at 40 m/s. The two opposite sides are locked in the direction perpendicular to the medium slab plane. The slab is first divided into two parts: the center modeled by DE, and the sides modeled by FE with three bridging domain layers (Fig.14). In a second model, only the DE are used.

Fig. 14 :

 14 Fig. 14: Combined FE/DE model, and a side view of the DE part

Fig. 15 :

 15 Fig. 15: Orientation of interaction directions for the extracted sample

Fig. 16 :

 16 Fig. 16: DE displacement under the impacting object Fig. 17: DE displacement vs. FE displacementThe combined model also efficiently describes damage in the vicinity of the impacted

  This difference in computation time stems from two points. The coupled model enables proceeding with a coarse discretization (FE discretization) on four-fifths of the structure. The time-savings offered by the smaller number of degrees of freedom can be increased by using a multi-time step algorithm, which makes the computation cost of this part negligible in comparison with the total computation cost.Because of the DE contact check, the computation time in DE does not increase linearly with the number of DE. By reducing the simulation time, we are able to simulate larger or more complex structures and/or refine the discretization.

Fig. 18 :Fig. 1 :Fig. 2 :Fig. 3 :Fig. 4 :Fig. 5 :Fig. 8 :Fig. 9 :

 181234589 Fig. 18: Comparison of damage response between the full DE model (left) and coupled model (right)

Fig. 16 :

 16 Fig. 16: DE displacement under the impacting object ............................................................. 17

Fig. 17 :

 17 Fig. 17: DE displacement vs. FE displacement........................................................................ 17

Fig. 18 :

 18 Fig. 18: Comparison of damage response between the full DE model (left) and coupled model

number Length (m) Width (m) Height (m)

  Tests have been carried out on 16 samples, as presented in Table1. The first 10 of these have identical sizes but different disorders, nos. 11 through 16 also display different geometries. The characteristic element size is identical for all samples, except no. 16. Sample nos. 15 and 16 have the same geometries, but no. 16 contains fewer elements with a larger average radius(1,427 DE vs. 18,672 DE).

	3.7 2.198 w ith 3.79 = ⎪ =< α β ν γ ⎧ ⎨ = ⎩ ⎪	1 /	α	(0.27)	Eq. (3)
	Hentz's values amount to:
	2.5 2.0 w ith 2.65 =< ν = ⎪ = α β γ ⎧ ⎪ ⎨ ⎩	1 /	α	(0.4)	Eq. (4)
	Sample 1 through 10					0.5	0.25	0.25
	11					0.5	0.4	0.25
	12					0.25	0.25	0.5
	13					0.25	0.25	0.25
	14					0.4	0.4	0.4
	15 and 16					0.6	0.6	0.6

Table 1 :

 1 Sample dimensions

  Table 3).

	Model	DE	Coupled DE/FE
	Number of DE	120808	6588
	Number of FE node	0	5935
	Number of time step	100000	100000
	Duration of computation 42h50mn	3h39mn

Table 3 :

 3 Comparison of the duration of the simulation

Table 1 :

 1 Sample dimensions ......................................................................................................9

Table 2 :

 2 Local concrete parameters ......................................................................................... 17

Table 3 :

 3 Comparison of the duration of the simulation ........................................................... 18

Acknowledgments:

The authors would especially like to thank the R&D Division of France's EDF electric utility company for their financial support, especially Sergueï Potapov for his helpful advices.

with the number of elements. However, with reproducibility now demonstrated, a sample extracted from the entire large structure can yield the same results. The computation time required to determine behavioral parameters will therefore be reduced due to use of this extracted part. The sample must obviously be representative of the entire structure (i.e. not too small); in addition, it must be isotropic and attributed an adjusted interaction radius.

After exhibiting model reproducibility, we will now apply this identification process to determine actual concrete parameters. Identification work will be based on the R30A7 concrete studied at the 3S-R laboratory by [START_REF] Gabet | Triaxial behaviour of concrete under high stresses: Influence of the loading path on compaction and limit states[END_REF]. This process will first involve uniaxial and quasi-static tensile tests to evaluate the local tensile strength T and softening parameter ζ. During a subsequent approach, compressive tests will lead us to the appropriate cohesion parameter C o (Fig. 7). Damage is evaluated as the ratio of broken links to initial links and remains proportional to sphere darkness. The black color corresponds to free DE. and experimental results [START_REF] Calvetti | Experimental Micromechanical Analysis of a 2D Granular Material: Relation Between Structure Evolution and Loading Path[END_REF] Eq. ( 7)

We have derived the solution by minimizing Equation ( 8), with the kinematic conditions being taken in account using Lagrange multipliers λ d for displacements and λ ω for rotations.

( ) ( )

Eq. ( 8)

The time discretization relies upon an explicit scheme:

Eq. ( 9)

Each degree of freedom value is calculated without taking in account coupling. Then a correction is applied using the Lagrange Multipliers (Eq. ( 8)). Further details on the method developed can be found in Frangin et al. (2006).

The difference in discretization size between FE and DE may induce wave reflection at the interface, an effect that can be mitigated in different ways, e.g. damping, yet the choice of damping coefficient is not straightforward. We have proposed a method to attenuate the reflection by introducing a reduction parameter for Lagrange multiplier influence. This method leads to a temporal relaxation of the kinematic constraints and is equivalent to a penalty method with an automatic process for optimizing the penalty parameter. All of these methods are discussed in Frangin et al. (2006). In the next section, the application presented introduces just such a relaxation parameter, which serves to divide the influence of Lagrange multipliers in reducing wave reflection.

A rock impact on a concrete slab

Conclusion

The Discrete Element model offers an efficient and reliable means to represent concrete. A simple and effective process is now available and has been validated to identify local parameters. The reproducibility of results indicates that shape or size of the sample used to identify parameters exerts no influence. The identification for a large sample could thus be performed on a smaller sample extracted from the larger one. In addition, the computation time for model identification is reduced.

In contrast, the coupled approach seems to facilitate modeling a large structure submitted to local damage such as an impact. Comparative results between a full DE model and a combined model demonstrate that the two methods yield similar output, yet with a computation time ten times faster for the coupled method. We can therefore apply the coupled method to simulate an impact on very large structures, in recognition of the quality with which DE describes fractures and discontinuities.

Keywords: Discrete Element, Coupling Method, Concrete, Impacts.


Larry W Esposito

Giada Arney

Michael Aye

Amanda Brecht

David Crisp

Mark Bullock

Jörn Helbert

Greg Holsclaw

Kandis Lea Jessup

Andrew Jones

Hyperspectral

Hyperspectral Observer for Venus Reconnaissance (HOVER) Larry W. Esposito, and the HOVER Team

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Hyperspectral Observer for Venus Reconnaissance (HOVER) Larry W. Esposito, and the HOVER Team.

LASP, University of Colorado, Boulder CO 80303-7820, USA , larry.esposito@lasp.colorado.edu

Abstract

The Hyperspectral Observer for Venus Reconnaissance (HOVER) is a Venus orbiter for remote sensing of its clouds, chemistry, dynamics and surface. Its main goal is understanding the mechanics of the Venus climate. HOVER has the following science objectives: Dynamic meteorology of the cloud layer; Determine distribution of key absorbers and parent gases of the clouds; Characterize super-rotation and solar to antisolar circulation and compare to observations; Regional rock mineralogy to infer the distribution of continental crust; Monitor for volcanic eruptions. The HOVER mission will address the following key questions:

1

  This proposed mission would address the Decadal Survey priority questions for aqueous environments and life; current habitable environments; understanding climate change on Earth; and Solar System processes.

	. How do convection and chemistry
	produce the global clouds?
	2. Where and how is solar energy
	deposited?
	3. How is energy transported by large-
	scale circulation?
	4. What does Venus climate tell us
	about past climates?
	5. How is Venus current climate
	impacted by current volcanism?
	LASP provides the Project Management,
	Project Systems Engineering, Mission
	Management, Orbiter, Payload Integration,
	Mission Ops, instruments; Science
	Leadership and Science Data Center. SwRI
	provides the Project Scientist; Uni-Köln
	provides the Radio Occultation investigation.


MD Tien Y Wong
email: wongtienyin@tsinghua.edu.cn

MD Zdenka Haskova

PhD Kemal Asik

MD Caroline R Baumal

MD Karl G Csaky

MD Nicole Eter

MSc Jane A Ives

MD Glenn J Jaffe

Jean-Francois Korobelnik

MD, MBA Hugh Lin

MD Jean-François Korobelnik

MD Toshinori Murata

MD Paisan Ruamviboonsuk

MD Patricio G Schlottmann

MD András I Seres

MSc, MBChB David Silverman

MD Xiaodong Sun

PhD Yannan Tang

MD John A Wells

MD Young Hee Yoon

MD Charles C Wykoff

Rhine Investigators

Apellis, Bayer, Carl J F K : Consultant -Abbvie

Zeiss Meditec

NanoRetina, Roche Thea ; Janssen

Novartis Speaker's Fees -Bayer

Zeiss P R : Santen

Consultant -Bayer

Faricimab Treat-and-Extend for Diabetic Macular Edema: 2-Year Results from the Randomized Phase 3 YOSEMITE and RHINE Trials

Keywords: PerceiveBio, Perfuse, PolyPhotonix, Ray, RecensMedical, Regeneron, RegenXBio, Resonance Alkahest, Allergan, Allgenesis, Amgen, Annexin, Annexon, Apellis, Asclepix, Angiopoietin-2, Diabetic macular edema, Faricimab, Vascular endothelial growth factor-A, Vascular stability

versus aflibercept Q8W through year 2. Overall, faricimab was well tolerated, with a safety profile comparable to aflibercept.

Conclusions: Clinically meaningful visual acuity gains from baseline, anatomic

improvements, and extended durability with intravitreal faricimab up to Q16W were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2/VEGF-A inhibition to promote vascular stability and provide durable efficacy for patients with DME.

J o u r n a l P r e -p r o o f

Over the past decade, intravitreal anti-vascular endothelial growth factor (VEGF) therapy has become the standard of care for patients with center-involving diabetic macular edema (DME) with visual impairment. [START_REF] Flaxel | Diabetic retinopathy preferred practice pattern ®[END_REF][START_REF] Tan | Diabetic macular oedema[END_REF][START_REF] Wong | Diabetic retinopathy[END_REF] However, studies frequently show that the efficacy associated with anti-VEGF therapies in clinical trials are not achieved nor maintained in real-world clinical practices. [START_REF] Ciulla | Real-world outcomes of anti-vascular endothelial growth factor therapy in diabetic macular edema in the United States[END_REF][START_REF] Ciulla | Visual acuity outcomes and anti-VEGF therapy intensity in diabetic macular oedema: a real-world analysis of 28 658 patient eyes[END_REF][START_REF] Massin | Real-world outcomes after 36-month treatment with ranibizumab 0.5 mg in patients with visual impairment due to diabetic macular edema (BOREAL-DME)[END_REF][START_REF] Shimura | Real-world management of treatment-naive diabetic macular oedema in Japan: two-year visual outcomes with and without anti-VEGF therapy in the STREAT-DME study[END_REF][START_REF] Sugimoto | Intravitreal aflibercept for diabetic macular edema in real-world clinical practice in Japan: 24-month outcomes[END_REF][START_REF] Van Aken | Real-world outcomes in patients with diabetic macular edema treated long term with ranibizumab (VISION study)[END_REF] Suboptimal real-world outcomes may be attributed to undertreatment associated with the burden of frequent monitoring visits and injections, and heterogeneity in anti-VEGF treatment response across patient populations. [START_REF] Van Aken | Real-world outcomes in patients with diabetic macular edema treated long term with ranibizumab (VISION study)[END_REF][START_REF] Ashraf | Predicting outcomes to anti-vascular endothelial growth factor (VEGF) therapy in diabetic macular oedema: a review of the literature[END_REF] Concurrently, it is increasingly clear that the pathophysiology of DME involves multiple biologic pathways [START_REF] Wong | Diabetic retinopathy[END_REF][START_REF] Daruich | Mechanisms of macular edema: beyond the surface[END_REF] ; therefore, multi-targeted treatment strategies may address additional sequela that can develop in patients treated with anti-VEGF therapy, and have the potential to improve durability and outcomes beyond targeting the VEGF pathway alone.

The angiopoietin (Ang)-1/Tie2 signaling pathway is a key regulator of vascular stability and controls vessel permeability, inflammation, and angiogenic responses. [START_REF] Heier | The angiopoietin/Tie pathway in retinal vascular diseases: a review[END_REF][START_REF] Joussen | Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data[END_REF] Under homeostatic conditions, the agonistic ligand Ang-1 binds to and activates Tie2, leading to downstream signaling that maintains vascular stability by promoting endothelial cell survival, pericyte recruitment, and improved endothelial barrier function. [START_REF] Heier | The angiopoietin/Tie pathway in retinal vascular diseases: a review[END_REF][START_REF] Joussen | Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data[END_REF] In DME and other retinal vascular diseases, Ang-2 is upregulated and acts as a competitive antagonist of Ang-1, binding to Tie2 and disrupting the vascular stabilization effects of Ang-1/Tie2 signaling, resulting in vascular permeability, instability, and remodeling. [START_REF] Heier | The angiopoietin/Tie pathway in retinal vascular diseases: a review[END_REF][START_REF] Joussen | Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data[END_REF][START_REF] Saharinen | Therapeutic targeting of the angiopoietin-TIE pathway[END_REF][START_REF] Yancopoulos | Vascular-specific growth factors and blood vessel formation[END_REF] Elevated levels of Ang-2 promotes retinal vessel sensitivity to proinflammatory mediators and the angiogenetic effects of VEGF, [START_REF] Yancopoulos | Vascular-specific growth factors and blood vessel formation[END_REF][START_REF] Benest | Angiopoietin-2 is critical for cytokine-induced vascular leakage[END_REF][START_REF] Murata | Vascular endothelial growth factor plays a role in hyperpermeability of diabetic retinal vessels[END_REF][START_REF] Murata | The relation between expression of vascular endothelial growth factor and breakdown of the blood-retinal barrier in diabetic rat retinas[END_REF][START_REF] Oshima | Angiopoietin-2 enhances retinal vessel sensitivity to vascular endothelial growth factor[END_REF] and drives inflammation by inducing expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which leads to leukocyte adhesion and transmigration. [START_REF] Fiedler | Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation[END_REF] Independently of Tie2, Ang-2 can have direct proangiogenic effects by signaling through integrins to promote vascular destabilization and apoptosis of pericytes and astrocytes. [START_REF] Felcht | Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling[END_REF][START_REF] Hakanpaa | Endothelial destabilization by angiopoietin-2 via integrin β1 activation[END_REF][START_REF] Park | Angiopoietin 2 induces pericyte apoptosis via α3β1 integrin signaling in diabetic retinopathy[END_REF][START_REF] Yun | Angiopoietin 2 induces astrocyte apoptosis via αvβ5integrin signaling in diabetic retinopathy[END_REF] Faricimab was designed as a novel bispecific antibody for intraocular use that binds and neutralizes both Ang-2 and VEGF-A. [START_REF] Regula | Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases[END_REF] Data from proof of concept phase 2 and confirmatory phase 3 clinical trials across 3 J o u r n a l P r e -p r o o f retinal indications (DME, neovascular age-related macular degeneration, and retinal vein occlusion) supported the hypothesis that dual Ang-2/VEGF-A pathway inhibition with faricimab may promote vascular stability, extend treatment durability (yet to be confirmed for retinal vein occlusion), and optimize outcomes for these retinal diseases. [START_REF] Heier | Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials[END_REF][START_REF] Khanani | Efficacy of every four monthly and quarterly dosing of faricimab vs ranibizumab in neovascular age-related macular degeneration: the STAIRWAY phase 2 randomized clinical trial[END_REF][START_REF] Sahni | Safety and efficacy of different doses and regimens of faricimab vs ranibizumab in neovascular age-related macular degeneration: the AVENUE phase 2 randomized clinical trial[END_REF][START_REF] Sahni | Simultaneous inhibition of angiopoietin-2 and vascular endothelial growth factor-A with faricimab in diabetic macular edema: BOULEVARD phase 2 randomized trial[END_REF][START_REF] Tadayoni | Faricimab in RVO: results from the BALATON and COMINO phase 3 studies[END_REF][START_REF] Wykoff | 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[END_REF] The phase 3 YOSEMITE and RHINE randomized active-controlled trials evaluated faricimab treatment for DME (N=1891). Patients with DME received intravitreal faricimab every 8 weeks (Q8W), faricimab according to a personalized treat-and-extend-based regimen (T&E) with dosing extended up to every 16 weeks (Q16W), or aflibercept 2.0 mg Q8W over 2 years. [START_REF] Wykoff | 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[END_REF][START_REF] Eter | YOSEMITE and RHINE: phase 3 randomized clinical trials of faricimab for diabetic macular edema: study design and rationale[END_REF] At 1 year, YOSEMITE and RHINE each met their primary endpoint; adjusted mean best-corrected visual acuity (BCVA) changes from baseline with faricimab Q8W and T&E up to Q16W dosing ranged between 10.8 and 11.8 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and were noninferior to aflibercept Q8W. [START_REF] Wykoff | 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[END_REF] Secondary endpoints at year 1 also showed greater anatomical benefits with faricimab Q8W and faricimab T&E compared with aflibercept Q8W; central subfield thickness (CST) reductions were greater with faricimab versus aflibercept at 1 year, and more faricimab-treated patients achieved absence of protocol-defined DME (CST <325 µm) and absence of intraretinal fluid (IRF) compared with aflibercept over time. [START_REF] Wykoff | 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[END_REF] Importantly, in the faricimab T&E up to Q16W dosing arms, clinically significant visual acuity gains and anatomic improvements were achieved with extended dosing; >70% of patients were extended to every-12-week (Q12W) or longer dosing and >50% were extended to Q16W dosing at week 52. [START_REF] Wykoff | 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[END_REF] Faricimab was well tolerated through year 1 with a safety profile comparable to aflibercept, and no cases of retinal vasculitis or occlusive retinal vasculitis reported. [START_REF] Wykoff | 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[END_REF] The year 1 data from YOSEMITE and RHINE, the largest DME program ever conducted, suggest that dual Ang-2/VEGF-A pathway inhibition with faricimab in DME may confer anatomic and durability advantages over VEGF inhibition alone. [START_REF] Wykoff | 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[END_REF] To evaluate the longer-term efficacy, durability, and safety of faricimab in patients with DME, we herein report 2-year results from the phase 3 YOSEMITE and RHINE trials.

J o u r n a l P r e -p r o o f

Methods

YOSEMITE and RHINE

The study design, rationale, and primary 1-year results of YOSEMITE and RHINE are described in detail elsewhere. [START_REF] Wykoff | 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[END_REF][START_REF] Eter | YOSEMITE and RHINE: phase 3 randomized clinical trials of faricimab for diabetic macular edema: study design and rationale[END_REF] Patients eligible for inclusion were aged ≥18 years and had center-involving DME secondary to diabetes (Type 1 or 2), defined as CST ≥325 µm (measured as the average thickness between the internal limiting membrane and Bruch's membrane in the central 1-mm diameter of the ETDRS grid) and BCVA 25-73 ETDRS letters (approximate Snellen equivalent, 20/320-20/40). Full eligibility criteria for YOSEMITE and RHINE are reported in the primary trial publication. [START_REF] Wykoff | 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[END_REF] One eye per patient was designated the study eye; if both eyes were eligible, the eye with worse BCVA at screening was selected. Previously anti-VEGF-treated eyes (last treated ≥3 months before day 1) were eligible for inclusion but limited to 25% of total enrolment. Patients were randomized 1:1:1 to intravitreal faricimab 6.0 mg Q8W after 6 initial every-4-week (Q4W) doses, intravitreal faricimab 6.0 mg T&E with up to Q16W dosing intervals after ≥4 initial Q4W doses, or intravitreal aflibercept Q8W after 5 initial Q4W doses. Aflibercept Q8W dosing was selected to align with the approved aflibercept label, in the absence of a globally J o u r n a l P r e -p r o o f 2-Year Efficacy, Durability, and Safety of Faricimab in DME 10 accepted extended dosing regimen. [START_REF]Eylea 40mg/ml solution for injection in a vial. Summary of product characteristics[END_REF][34][35] The T&E regimen is a personalized treat-and-extendbased dosing regimen that allowed adjustable dosing (from Q4W up to Q16W) based on protocol prespecified CST and BCVA criteria at active dosing visits. [START_REF] Wykoff | 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[END_REF][START_REF] Eter | YOSEMITE and RHINE: phase 3 randomized clinical trials of faricimab for diabetic macular edema: study design and rationale[END_REF] The personalized T&E regimen is commonly used clinically, [START_REF] Rezaei | Global Trends in Retina Survey[END_REF] but in the registrational phase 3 trial setting was referred to as "personalized treatment interval", as the regimen used an automated treatment algorithm driven by an interactive voice or web-based response system to determine whether a patient's treatment interval should be reduced, maintained, or extended based on protocol pre-specified criteria. [START_REF] Eter | YOSEMITE and RHINE: phase 3 randomized clinical trials of faricimab for diabetic macular edema: study design and rationale[END_REF]

Outcome Measures

The primary efficacy endpoint of YOSEMITE and RHINE was change in BCVA from baseline at 1 year, averaged over weeks 48, 52, and 56. [START_REF] Wykoff | 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[END_REF] Two-year trial outcomes reported herein were consistent with prespecified endpoints in the primary analysis, [START_REF] Wykoff | 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[END_REF] and included change in BCVA J o u r n a l P r e -p r o o f from baseline at 2 years (defined as the average of weeks 92, 96, and 100) and over time; the proportion of patients in the faricimab T&E dosing arms on Q4W, Q8W, Q12W, or Q16W dosing intervals at week 96 and over time; change in CST from baseline at 2 years and over time; the proportion of patients with absence of DME (CST <325 μm based on protocol-defined DME at screening) over time; the proportion of patients with absence of IRF over time (measured in the central 1 mm ETDRS circle); and the incidence and severity of ocular and nonocular adverse events (AEs) through study end. Other 2-year efficacy endpoints included the proportion of patients that gained BCVA (≥15, ≥10, ≥5, or ≥0 ETDRS letters) or avoided BCVA loss (≥15, ≥10, or ≥5 ETDRS letters) at 2 years; patients that gained ≥15 ETDRS letters or achieved Snellen BCVA 20/20 or better (≥84 ETDRS letters) at 2 years; patients with Snellen BCVA 20/40 or better (≥69 ETDRS letters) at 2 years; and the proportion of patients with ≥2-step improvement on the ETDRS Diabetic Retinopathy Severity Scale (DRSS) at week 96.

Statistical Analysis

Two-year efficacy and safety analyses were performed as described in the primary 1-year trial publication. [START_REF] Wykoff | 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[END_REF] Efficacy analyses were based on the intent-to-treat (ITT) population, grouped by treatment arm at randomization. Adjusted means for continuous endpoints were assessed using a mixed model for repeated measures (MMRM), with the same analysis method and data handling rules as described previously for the primary endpoint. In brief, the MMRM included change from baseline as the response variable, and categorical covariates of treatment group, visit, visit-by-treatment group interaction, baseline value for the response variable (continuous), study (YOSEMITE vs. RHINE; for the pooled cohort data only), and randomization stratification factors as fixed effects. The model assumed an unstructured covariance structure; missing data were implicitly imputed assuming a missing at random mechanism. For binary secondary endpoints, weighted proportions were estimated using the Cochran-Mantel-Haenszel (CMH) method stratified by baseline BCVA score (<64 letters vs. ≥64 letters), prior intravitreal anti-J o u r n a l P r e -p r o o f 2-Year Efficacy, Durability, and Safety of Faricimab in DME 12 VEGF therapy (yes vs. no), region (US and Canada, Asia, and the rest of the world), and study (YOSEMITE vs. RHINE; for the pooled cohort data only). For all MMRM and CMH analyses, intercurrent events related to the COVID-19 pandemic were handled using a hypothetical strategy where all values were censored after the intercurrent event, and non-COVID-19related intercurrent events were handled using a treatment policy strategy where all observed values were used regardless of the intercurrent event. Adjusted means and weighted proportions are reported with 95.04% confidence intervals (CIs) for the individual trial data, to adjust for interim safety assessments conducted through to the completion of the primary analysis, and as 95% CIs for the pooled cohort data. [START_REF] Wykoff | 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[END_REF] Post hoc hypothesis tests were performed to detect differences between faricimab and aflibercept treatment arms, with Pvalues presented for reference. The YOSEMITE/RHINE safety analysis population included all patients who received ≥1 dose of faricimab or aflibercept, grouped by actual treatment regimen received. Safety and tolerability were assessed through descriptive summaries of ocular and nonocular AEs (coded using Medical Dictionary for Regulatory Activities thesaurus terms), deaths, and ocular assessments through study end.

Results

Patient Disposition

A total of 940 and 951 patients were enrolled in YOSEMITE (September 2018 to September 2019) and RHINE (October 2018 to September 2019), respectively. [START_REF] Wykoff | 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[END_REF]

J o u r n a l P r e -p r o o f

Overall, 84% of patients who received ≥1 dose of faricimab or aflibercept in YOSEMITE and 87% of those in RHINE completed study treatment through week 100. The proportion of patients who discontinued study treatment and the reasons for discontinuation were generally balanced across treatment arms and trials (Fig 2). Major protocol deviations through study end were reported for 563 (60%) patients in YOSEMITE and 602 (63%) patients in RHINE (Table S1, available at www.aaojournal.org). The number, proportion of patients, and type of major protocol deviations through study end were consistent across treatment arms and trials. The majority of the major protocol deviations were procedural, such as selected missed visits (YOSEMITE: 308 As reported in the primary trial publication, [START_REF] Wykoff | 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[END_REF] baseline patient characteristics in YOSEMITE and RHINE were generally well balanced across treatment arms and trials. available at www.aaojournal.org]). Sensitivity and supplemental analyses to test the robustness of these results were consistent across different methods for handling missing data and intercurrent events (Table S2, available at www.aaojournal.org). Additional 2-year BCVA endpoints were similarly consistent across treatment arms and reproducible across trials (Table S3, available at www.aaojournal.org).

Visual Acuity Outcomes

Durability Outcomes

The durability of faricimab reported in the 1-year primary analysis [START_REF] Wykoff | 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[END_REF]

Anatomic Outcomes

Overall, improved anatomic outcomes achieved with faricimab versus aflibercept at 1 year [START_REF] Wykoff | 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[END_REF] were maintained through year 2. In YOSEMITE, adjusted mean CST change from baseline at Consistent with the 1-year primary analysis, [START_REF] Wykoff | 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[END_REF] the proportion of patients who achieved absence of protocol-defined DME was higher for faricimab compared with aflibercept through year 2 (Fig 9). The proportion of patients in YOSEMITE who achieved absence of DME at weeks 92-100 was 87%-92% in the faricimab Q8W arm and 78%-86% in the faricimab T&E arm, compared with 77%-81% in the aflibercept Q8W arm. Corresponding proportions in RHINE were 88%-93% and 85%-88% versus 80%-84%, respectively (Fig 9). In the pooled YOSEMITE/RHINE cohort, the proportion of patients who achieved absence of DME at weeks J o u r n a l P r e -p r o o f 92-100 was 88%-92% in the faricimab Q8W arm, 81%-86% in the faricimab T&E arm, and 79%-83% in the aflibercept Q8W arm (Fig S10, available at www.aaojournal.org).

Absence of IRF was also achieved by more patients treated with faricimab when compared to those treated with aflibercept through year 2 (Fig 11). At weeks 92-100 of YOSEMITE, the proportion of patients who achieved absence of IRF was 59%-63% in the faricimab Q8W arm and 43%-48% in the faricimab T&E arm, compared with 33%-38% in the aflibercept Q8W arm.

Proportions were similar in RHINE (56%-62% and 45%-52% vs. 39%-45%, respectively).

Corresponding proportions for the pooled YOSEMITE/RHINE cohort were 57%-63% and 44%-48% in the faricimab Q8W and faricimab T&E arms, respectively, vs. 36%-41% in the aflibercept Q8W arm (Fig S12, available at www.aaojournal.org).

The proportion of patients that had ≥2-step ETDRS-DRSS improvement from baseline at week 96 was similar across treatment arms and trials (Fig 13). In YOSEMITE, 51.4% (95.04% CI, 44.8-57.9) of patients in the faricimab Q8W arm had ≥2-step ETDRS-DRSS improvement at week 96 compared with 42.2% (35.9-48.5) in the aflibercept Q8W arm (nominal P > 0.05). In RHINE, the corresponding estimate was 53.5% (46.9-60.1) in the faricimab Q8W dosing arm, which was greater than that in the aflibercept Q8W arm (43.8% [37.2-50.4]; nominal P = 0.0475). In the faricimab T&E arms, the proportion of patients that had ≥2-step ETDRS-DRSS improvement at week 96 was comparable with aflibercept Q8W in YOSEMITE (42.8% [36.

J o u r n a l P r e -p r o o f

Safety Outcomes

Consistent with the 1-year primary analysis, [START_REF] Wykoff | 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[END_REF] faricimab was well tolerated with a safety profile that remained comparable to aflibercept through study end (Table 4 andTables S5-S8 [available at www.aaojournal.org]). The incidence of ocular AEs in the study eye through study end was similar between the faricimab Q8W (YOSEMITE, 147 [47%] patients; RHINE, 166 patients), and aflibercept Q8W (5 [2%] patients; 2 [1%] patients). All IOI events were considered by the investigator to be mild or moderate in severity with the exception of 4 events in YOSEMITE. There was 1 case of severe vitritis reported in the faricimab Q8W arm, which led to treatment withdrawal; this event was treated and not associated with BCVA loss and had recovered/resolved by end of study. Three cases of severe uveitis were reported in the faricimab T&E arm and led to treatment withdrawal: 1 patient with moderate chorioretinitis and severe uveitis associated with BCVA loss of 11 ETDRS letters (treated with topical steroids), 1 patient with severe uveitis associated with BCVA loss of 31 ETDRS letters (treated with topical steroids), and one patient with mild keratic precipitates and severe uveitis associated with BCVA loss of 37 ETDRS letters (treated with topical antibiotics and non-steroidal anti-inflammatory J o u r n a l P r e -p r o o f drugs). There were no severe IOI events in the aflibercept Q8W arms of YOSEMITE or RHINE.

All IOI events except 1 in YOSEMITE (mild iritis in the faricimab up to Q16W dosing arm) had recovered/resolved or were recovering/resolving by end of study. No IOI events were associated with retinal occlusive events, and there were no cases of retinal vasculitis or occlusive retinal vasculitis reported through study end.

Discussion

Building on the year 1 primary outcome analysis, [START_REF] Wykoff | 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[END_REF] we report the 2-year data from the phase 3 YOSEMITE and RHINE trials. We demonstrated consistency of results across 2 years; comparable clinically meaningful BCVA gains and greater anatomic improvements with faricimab versus aflibercept were maintained through study end at year 2. In the faricimab T&E arms, the year 1 durability findings were further improved and extended in year 2. These findings further support the role of Ang/Tie signalling in vascular stability and the potential for dual Ang-2/VEGF-A inhibition to promote vascular stability and extend treatment durability beyond targeting VEGF inhibition alone for DME.

The current standard of care for DME using available anti-VEGF agents is limited by the considerable burden of frequent visits, which can lead to undertreatment and, as a result, realworld clinical practice outcomes often appear to not match those achieved in trial participants. [START_REF] Ciulla | Real-world outcomes of anti-vascular endothelial growth factor therapy in diabetic macular edema in the United States[END_REF][START_REF] Ciulla | Visual acuity outcomes and anti-VEGF therapy intensity in diabetic macular oedema: a real-world analysis of 28 658 patient eyes[END_REF][START_REF] Massin | Real-world outcomes after 36-month treatment with ranibizumab 0.5 mg in patients with visual impairment due to diabetic macular edema (BOREAL-DME)[END_REF][START_REF] Shimura | Real-world management of treatment-naive diabetic macular oedema in Japan: two-year visual outcomes with and without anti-VEGF therapy in the STREAT-DME study[END_REF][START_REF] Sugimoto | Intravitreal aflibercept for diabetic macular edema in real-world clinical practice in Japan: 24-month outcomes[END_REF][START_REF] Van Aken | Real-world outcomes in patients with diabetic macular edema treated long term with ranibizumab (VISION study)[END_REF] In YOSEMITE and RHINE, patients randomized to faricimab T&E received fewer injections per year (a median of 8 and 3 injections during year 1 and 2, respectively) compared with patients in the faricimab Q8W arm (a median of 10 and 5 injections, respectively). Furthermore, the median number of faricimab T&E injections received during the 2-year YOSEMITE and RHINE trials was less than those reported in previous clinical trials of anti-VEGF treatments administered using as-needed (pro re nata) dosing regimens. In the Diabetic Retinopathy Clinical Research Network (DRCR.Net) Protocol T study, where patients with DME received intravitreal aflibercept J o u r n a l P r e -p r o o f 2-Year Efficacy, Durability, and Safety of Faricimab in DME 20 2.0 mg, bevacizumab 1.25 mg, or ranibizumab 0.3 mg as needed based on protocol-specified BCVA and CST retreatment criteria, a median of 9-10 anti-VEGF injections were given across treatment arms in year 1, and 5-6 injections during year 2. [START_REF] Wells | Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema[END_REF][START_REF] Wells | Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial[END_REF] As patients in the active comparator arms of YOSEMITE and RHINE received aflibercept Q8W, it was not possible to assess whether the median number of aflibercept injections received during the 2-year trials differed to that reported in the DRCR.Net Protocol T study, where as-needed dosing regimens were used. Overall, these findings highlight the potential for T&E dosing with faricimab to extend treatment durability and reduce the burden of frequent visits and injections for patients with DME over 2 years. Year 2 data from YOSEMITE and RHINE showed that initial 1-year visual acuity gains achieved with faricimab Q8W and faricimab T&E were maintained through year 2 and remained comparable with aflibercept Q8W. In the year 1 primary analysis, faricimab Q8W and faricimab T&E demonstrated greater anatomic improvements over aflibercept Q8W through year 1 [START_REF] Wykoff | 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[END_REF] ; this faricimab-associated benefit was maintained through year 2. The adjusted mean CST change from baseline at 2 years was greater with faricimab Q8W and faricimab T&E dosing versus aflibercept Q8W, and greater proportions of patients achieved absence of DME and absence of IRF with faricimab Q8W and faricimab T&E versus aflibercept Q8W at most time points across both trials. Together, these data suggest that dual Ang-2/VEGF-A inhibition with faricimab may improve resolution of retinal fluid compared with VEGF inhibition alone and that fewer faricimab injections may be needed to reach this outcome. In clinical practice, retinal drying is important to assess treatment effectiveness and to guide treatment decisions; however, the clinical implications of the observed difference remain to be determined as visual acuity was similar between the faricimab and aflibercept arms through the trial. Guidance from future studies is needed to definitively answer remaining questions about whether there are differences in BCVA efficacy between these treatments over the course of more long-term follow up. Similar to the anatomical findings of YOSEMITE/RHINE, the phase 2 RUBY (NCT02712008) study of J o u r n a l P r e -p r o o f nesvacumab (anti-Ang-2 antibody) and aflibercept combination treatment for DME showed greater anatomical improvements with aflibercept plus high-dose nesvacumab compared with aflibercept alone at week 12 of the trial, including greater CST changes from baseline and increased proportions of eyes with complete resolution of fluid at the foveal center and normalization of macular thickness. [START_REF] Brown | Intravitreal nesvacumab (antiangiopoietin 2) plus aflibercept in diabetic macular edema: phase 2 RUBY randomized trial[END_REF] Although direct comparisons are limited by differences between the trials, including different treatment regimens and patient populations, overall, the results of RUBY further support the potential for improved anatomical outcomes when both Ang-2 and VEGF are inhibited in patients with DME.

In the faricimab T&E arms, it was possible to extend the dosing intervals by the end of year 2 compared with the end of year 1, 31 while maintaining durable visual acuity gains and anatomic improvements through year 2. Overall, the proportion of patients on Q16W dosing increased from 52% to 62% between week 52 and week 96, and the proportion of patients on Q12W dosing or longer increased from 72% to 78% over the same period. Furthermore, for the majority of patients on Q12W or Q16W dosing at 1 year, it was possible to maintain the extended dosing regimen without an interval reduction through year 2. Only approximately 4% of patients required continued Q4W dosing throughout the entire period of both studies, and these patients never qualified for interval extension because the CST did not drop below 325 µm. These results demonstrate the potential for faricimab to extend treatment durability for patients with DME when given in a real-world treatment scenario.

The T&E regimen in YOSEMITE and RHINE was designed specifically to test the durability of faricimab using a T&E-based regimen commonly used in clinical practice to reduce the burden of frequent clinic visits. [START_REF] Eter | YOSEMITE and RHINE: phase 3 randomized clinical trials of faricimab for diabetic macular edema: study design and rationale[END_REF] In the setting of the registrational clinical trials, we used the term "personalized treatment interval" as patients were required to undergo monthly visits to maintain masking and to enable collection of monthly efficacy and safety data. Of note, dosing interval decisions in the T&E arms were dependent on BCVA and CST values from active dosing visits only, and as such, the criteria for treatment interval reductions, maintenance, or J o u r n a l P r e -p r o o f extensions were based on standard routine criteria in clinical practice. In YOSEMITE and RHINE, the faricimab T&E arms were designed with treatment intervals that could be extended by 4-week increments following the 4 initial monthly loading doses (and when CST of <325 µm was met). Although physicians across global real-world clinical practices may follow variable patterns, including T&E extensions and reductions of ~2-week increments (dependent on the individual patient's situation and scheduling availability), [START_REF] Rezaei | Global Trends in Retina Survey[END_REF] the objective in a clinical trial setting is to ensure a feasible schedule with minimal variability to minimize potential bias. Our results of visual acuity stability and anatomical improvements achieved over 2 years with faricimab dosed up to Q16W support extension of faricimab dosing intervals by up to 4-week increments in the real world, and the potential to decrease both the number of injections and frequency of clinic visits for patients with DME.

Consistent with the year 1 primary analysis, [START_REF] Wykoff | 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[END_REF] faricimab remained well tolerated through study end and no new safety signals were identified. Ocular AEs in the study eye were mostly mild or moderate in severity, and the incidence of these events was similar across faricimab and aflibercept treatment arms. The incidence of IOI events through study end was low (1.6% and 1.1% for faricimab-and aflibercept-treated patients, respectively); most IOI events were mild or moderate in severity, and none were associated with retinal vasculitis or retinal occlusive events.

Our study has some limitations that warrant discussion. First, the fixed dosing faricimab Q8W arms of YOSEMITE and RHINE were designed to evaluate the maximal efficacy of faricimab, whereas the faricimab T&E arms were designed to test optimal durability. However, following the 5 initial Q4W does, the active comparator arms received aflibercept Q8W per the globally aligned aflibercept label, 35 which precluded a head-to-head comparison of durability between faricimab and aflibercept. The number of injections across treatment arms was not compared statistically as only patients in the faricimab T&E arms could receive a variable number of injections. The globally aligned and accepted aflibercept posology was selected due J o u r n a l P r e -p r o o f to the registrational nature of the YOSEMITE and RHINE trials, and because no extended dosing regimen exists for aflibercept that is globally approved or uniformly practiced. [START_REF]Eylea 40mg/ml solution for injection in a vial. Summary of product characteristics[END_REF][34][35] Second, the YOSEMITE and RHINE trials were conducted throughout the COVID-19 pandemic, which affected patient participation at some sites and had an impact on the rate of major protocol deviations; however, sensitivity and supplemental analyses showed that the pandemic had limited impact on data integrity and study outcomes. Third, and as discussed in more detail above, although the faricimab T&E arms were designed with treatment intervals that could be extended by 4-week increments and may differ from variable patterns followed by physicians in real-world clinical practice, [START_REF] Eter | YOSEMITE and RHINE: phase 3 randomized clinical trials of faricimab for diabetic macular edema: study design and rationale[END_REF][START_REF] Rezaei | Global Trends in Retina Survey[END_REF] we believe the criteria used in our T&E regimen for treatment interval extension, maintenance, or reduction can be readily applied in clinical settings.

The substantial potential of dual Ang-2/VEGF-A inhibition for DME should be confirmed with further studies. The YOSEMITE and RHINE trials enrolled a large cohort of 1891 patients across 353 study sites worldwide, which to our knowledge, is the largest study in patients with DME. Patients who completed YOSEMITE and RHINE were eligible to enter the RHONE-X long-term extension study (NCT04432831), which will continue to provide data on the safety and tolerability of faricimab, administered open label and T&E, for a further 2 years, and will provide data on the effects of switching from bimonthly aflibercept to faricimab T&E. The majority of patients in YOSEMITE and RHINE were of white race or ethnicity; the treatment response to faricimab in underrepresented patients with DME will be evaluated in the phase 4 ELEVATUM trial (NCT05224102). Additionally, VOYAGER (NCT05476926), an observational, prospective, multinational, multicenter study, will offer real-world insights for both faricimab and the Port Delivery System with ranibizumab among patients with DME and neovascular agerelated macular degeneration in routine clinical practice globally. Furthermore, the phase 2b ALTIMETER (NCT04597918) biomarker hypothesis-generating study will explore the associations between clinical endpoints, multimodal imaging assessments, and aqueous humor biomarker patterns in patients with DME treated with faricimab. Previous studies have explored J o u r n a l P r e -p r o o f associations between specific characteristics on OCT with outcomes of patients with DME in an effort to identify OCT imaging biomarkers predictive of treatment response to anti-VEGF therapy. [START_REF] Hui | Optical coherence tomography classification systems for diabetic macular edema and their associations with visual outcome and treatment responses -an updated review[END_REF]41 In ALTIMETER, exploratory endpoints will evaluate changes from baseline over time in multimodal imaging, including CST and absence of IRF and subretinal fluid, and aqueous humor protein/metabolite composition to identify potential biomarkers of the Ang-2 effect of faricimab.

In conclusion, the 2-year results from the phase 3 YOSEMITE and RHINE trials demonstrate and confirm the durability, efficacy, and safety of faricimab in patients with DME. Clinically significant 1-year visual acuity gains with faricimab Q8W and T&E were maintained through year 2 and remained comparable to aflibercept Q8W, while anatomic improvements remained greater with faricimab over aflibercept Q8W. The impact of the anatomical improvements with faricimab on long-term visual acuity outcomes will be further evaluated in the RHONE-X extension study. The durability of faricimab was further extended in year 2, with more patients in the faricimab T&E arms achieving and maintaining dosing intervals of up to Q16W. During year 2, the median number of faricimab T&E injections was 3 (vs. 5-6 for the DRCR.Net Protocol T study) [START_REF] Wells | Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial[END_REF] , which may translate into fewer clinic visits and might reduce treatment burden with real-world faricimab use. These data reinforce the potential of dual inhibition of Ang-2 and VEGF-A with faricimab as a novel, multitargeted strategy that may extend DME treatment durability and improve outcomes beyond VEGF inhibition alone.

Roche Data Sharing Statement

For eligible studies, qualified researchers may request access to individual patient level clinical data through a data request platform. At the time of writing, this request platform is Vivli J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f

  photography [CFP], and fundus fluorescein angiography [FFA]) that were independently

  One eye per patient was designated as the study eye. The ITT population of YOSEMITE included 315 patients randomized to faricimab Q8W, 313 patients randomized to faricimab T&E, and 312 patients randomized to aflibercept Q8W (Fig 2A). The ITT population of RHINE included 317 patients randomized to faricimab Q8W, 319 patients randomized to faricimab T&E, and 315 patients randomized to aflibercept Q8W (Fig 2B).

[ 33 .

 33 0%] patients; RHINE: 328 [35.0%] patients) and issues with images of the study eye (YOSEMITE: 94 [10.0%] patients; RHINE: 139 [15.0%] patients). Among patients with major protocol deviations, 191 (20%) in YOSEMITE and 279 (29%) in RHINE reported ≥1 major protocol deviation related to COVID-19, most of whom missed ≥1 study visit around the primary endpoint and/or final study visits (167 [18%] and 210 [22%] patients, respectively). Of these, only 63 (6.7%) patients in YOSEMITE and 76 (8.0%) in RHINE missed ≥1 dose of study treatment around the primary endpoint visits, and 15 (1.6%) and 48 (5.0%) patients, respectively, missed ≥1 dose of study treatment around the final study visits.

  YOSEMITE and RHINE reproducibly demonstrated visual gains with faricimab Q8W and T&E that were maintained over time through year 2 and were comparable with aflibercept Q8W, despite fewer treatment doses administered in the faricimab T&E arm (Fig 3). In YOSEMITE, adjusted mean BCVA change from baseline at 2 years (averaged over weeks 92, 96, and 100) was +10.7 ETDRS letters (95.04% CI, +9.4 to +12.1) in the faricimab Q8W arm and +10.7 ETDRS letters (+9.4 to +12.1) in the faricimab T&E arm versus +11.4 ETDRS letters (+10.0 to J o u r n a l P r e -p r o o f 2-Year Efficacy, Durability, and Safety of Faricimab in DME 14 +12.7) in the aflibercept Q8W arm (mean difference vs. aflibercept Q8W, -0.7 ETDRS letters [-2.6 to +1.2] and -0.7 ETDRS letters [-2.5 to +1.2], respectively; nominal P > 0.05 for both). Corresponding 2-year BCVA gains in RHINE were +10.9 ETDRS letters (+9.5 to +12.3) and +10.1 ETDRS letters (+8.7 to +11.5) versus +9.4 ETDRS letters (+7.9 to +10.8), respectively (mean difference vs. aflibercept Q8W, +1.5 ETDRS letters [-0.5 to +3.6] and +0.7 ETDRS letters [-1.3 to +2.7]; nominal P > 0.05 for both). In the pooled YOSEMITE/RHINE cohort, 2year BCVA gains were +10.8 ETDRS letters (+9.8 to +11.8) and +10.4 ETDRS letters (+9.4 to +11.4) in the faricimab Q8W and faricimab PTI arms, respectively, versus +10.3 ETDRS letters (+9.3 to +11.3) in the aflibercept Q8W arm (mean difference vs. aflibercept Q8W, +0.5 ETDRS letters [-0.9 to +1.8] and +0.1 ETDRS letters [-1.3 to +1.5]; nominal P > 0.05 for both [Fig S4,

  In the safety analysis population, the median (mean [standard deviation (SD)]) number of study drug injections in each of the YOSEMITE and RHINE faricimab T&E arms was 8 injections (YOSEMITE 8.4 [2.45], RHINE 8.7 [2.50]) in year 1 (baseline to week 56), compared with 10 injections in each of the faricimab Q8W (YOSEMITE 9.5 [1.41], RHINE 9.3 [1.52]) and aflibercept Q8W (YOSEMITE 9.2 [1.47], RHINE 9.3 [1.36]) arms. During year 2 (week 60 to week 96), the faricimab T&E arms received a median (mean [SD]) of 3 study drug injections (YOSEMITE 3.5 [1.76], RHINE 3.6 [1.98]), versus 5 injections in each of the faricimab Q8W (YOSEMITE 4.7 [0.74], RHINE 4.7 [0.82]) and aflibercept Q8W (YOSEMITE 4.5 [0.92], RHINE 4.5 [0.99]) arms. From baseline during the entire study, the median (mean [SD]) number of study drug injections in the T&E arms was 10 (11.5 [3.98]) in YOSEMITE and 11 (12.1 [4.12]) in J o u r n a l P r e -p r o o f

year 2 (

 2 averaged over weeks 92, 96, and 100) was -216.0 µm (95.04% CI, -224.0 to -208.0) in the faricimab Q8W arm, which was greater than that in the aflibercept Q8W arm (-196.3 µm [-204.3 to -188.2]; nominal P = 0.0007) (Fig 7). In RHINE, mean 2-year CST reductions were also greater with faricimab Q8W versus aflibercept Q8W (-202.6 µm [-211.1 to -194.2] vs. -185.6 µm [-194.1 to -177.1]; nominal P = 0.0052) (Fig 7). In the faricimab T&E arms, adjusted mean CST change at 2 years was comparable with aflibercept Q8W in YOSEMITE (-204.5 µm [-212.4 to -196.5]; nominal P > 0.05) and RHINE (-197.1 µm [-205.3 to -188.9]; nominal P > 0.05), but was achieved with most patients on Q16W dosing (Fig 7). In the pooled YOSEMITE/RHINE cohort, mean 2-year CST reductions were greater in both the faricimab Q8W arm (-209.4 µm [-215.2 to -203.6]) and the faricimab T&E arm (-201.0 µm [-206.7 to -195.3]) compared with the aflibercept Q8W arm (-190.9 µm [-196.7 to -185.0]; nominal P < 0.0001 and P = 0.0150 vs aflibercept Q8W, respectively [Fig S8]).

  6-49.0]; nominal P > 0.05) and RHINE (44.3% [37.9-50.7]; nominal P > 0.05) (Fig 13). Corresponding proportions in the YOSEMITE/RHINE pooled cohort were 52.4% (47.8-57.0) in the faricimab Q8W arm and 43.5% (39.1-48.0) in the faricimab T&E arms versus 43.0% (38.4-47.5) in the aflibercept Q8W arm (nominal P = 0.0058 and P > 0.05 vs. aflibercept Q8W, respectively [Fig S14, available at www.aaojournal.org]). These findings were achieved in the T&E arms with 60% (3 injections) of the median number of injections received in the faricimab Q8W and aflibercept Q8W arms (5 injections) in year 2.

[

  52%] patients), faricimab T&E (146 [47%] patients; 165 [52%] patients), and aflibercept Q8W arms (144 [46%] patients; 140 [45%] patients). Most ocular AEs were mild or moderate in severity, and common ocular AEs reported were generally balanced across faricimab and aflibercept treatment arms. The incidence of serious ocular AEs through study end was low and comparable between patients receiving faricimab Q8W (YOSEMITE, 12 [4%] patients; RHINE, 14 [4%] patients), faricimab T&E (14 [4%] patients; 20 [6%] patients), and aflibercept Q8W (7 [2%] patients; 13 [4%] patients). Nonocular AEs and Anti-Platelet Trialists' Collaboration events were also similar across treatment arms and trials. The incidence of intraocular inflammation (IOI) events through study end was low and similar among patients receiving faricimab Q8W (YOSEMITE, 6 [2%] patients; RHINE, 3 [1%] patients), faricimab T&E (7 [2%] patients; 4 [1%]

(

  https://vivli.org/ourmember/roche/). For up-to-date details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://go.roche.com/data_sharing). Anonymized records for individual patients across more than one data source external to Roche cannot, and should not, be linked due to a potential increase in risk of patient re-identification J o u r n a l P r e -p r o o f 41. Szeto SK, Hui VWK, Tang FY, et al. OCT-based biomarkers for predicting treatment response in eyes with centre-involved diabetic macular oedema treated with anti-VEGF injections: a real-life retina clinic-based study. Br J Ophthalmol 2023;107(4):525-33.

Figure 1 .

 1 Figure 1. Faricimab T&E algorithm in YOSEMITE/RHINE. Reference CST was defined as the CST value when the initial CST threshold criteria were met (CST <325 μm at or after the

Figure 2 .

 2 Figure 2. CONSORT flow diagram for YOSEMITE (A) and RHINE (B). Q8W = every 8

Figure 3 .Figure 5 .

 35 Figure 3. Adjusted mean change in BCVA from baseline through week 100. a Adjusted mean

Figure 7 .

 7 Figure 7. Adjusted mean change in CST from baseline through week 100. *Nominal P <

Figure 9 .

 9 Figure 9. Proportion of patients with absence of DME through week 100. *Nominal P < 0.05

Figure 11 .

 11 Figure 11. Proportion of patients with absence of IRF through week 100. *Nominal P < 0.05

Figure 13 .

 13 Figure 13. Proportion of patients with ≥2-step ETDRS-DRSS improvement from baseline at

  In brief, YOSEMITE (Clinicaltrials.gov identifier NCT03622580) and RHINE (NCT03622593) were identically designed, randomized, double-masked, active comparator-controlled, phase 3 trials conducted across 353 study sites in 31 participating countries. YOSEMITE and RHINE adhered to the International Council for Harmonization E6 Guideline for Good Clinical Practice, tenets of the Declaration of Helsinki, US Food and Drug Administration regulations, European Union Clinical Trials Directive (2001/20/EC), and applicable local, state, and federal laws. Institutional Review Board (IRB)/Ethics Committee approval was obtained for study protocols as appropriate, and all patients provided written informed consent to participate.

2 -

 2 Year Efficacy, Durability, and Safety of Faricimab in DME 15 RHINE, compared with 15 (YOSEMITE 13.6 [2.87], RHINE 13.5 [2.87]) in the faricimab Q8W arms and 14 (YOSEMITE 13.3 [2.75], RHINE 13.4 [2.66]) in the aflibercept Q8W arms.

  was further improved during year 2 of YOSEMITE and RHINE, with greater proportions of patients in the T&E arm extending their dosing while maintaining comparable visual acuity gains and greater anatomical benefits versus aflibercept (Fig 5). At week 96, 211 (78%) patients in the faricimab T&E arm of Fig S6A, available at www.aaojournal.org]). Patient ability to achieve and/or maintain extended faricimab dosing intervals up to Q16W through week 96 is shown in the dosing interval schematic, which shows that in most patients who achieved Q12W or Q16W dosing at 1 year, it was possible to maintain and/or extend their dosing interval through year 2 (Fig 5B; Fig S6B for the pooled YOSEMITE/RHINE cohort, available at www.aaojournal.org). of patients it was not possible to extend the dosing interval beyond Q4W from baseline through week 96 (YOSEMITE, 7 [3%] patients; RHINE, 15 [5%] patients).

	YOSEMITE and 224 (78%) patients in RHINE achieved ≥Q12W dosing intervals (557 patients [78%] in the pooled YOSEMITE/RHINE cohort), which included 162 (60%) and 185 (64%) patients, respectively, who achieved Q16W dosing (Fig 5A; pooled YOSEMITE/RHINE cohort, 347 patients [62%] [Approximately 79% of patients who achieved ≥Q12W dosing at week 52 maintained ≥Q12W J o u r n a l P r e -p r o o f
	dosing without an interval reduction below Q12W through week 96 (YOSEMITE, 150 [75%]
	patients; RHINE, 172 [83%] patients). Similarly, 76% of patients that achieved Q16W dosing at
	week 52 maintained Q16W dosing without an interval reduction through week 96 (YOSEMITE,
	100 [70%] patients; RHINE, 121 [82%] patients). Approximately 18% of patients rapidly
	achieved Q16W dosing at week 32 (i.e., the earliest time point that Q16W dosing was possible
	due to the study design) and subsequently maintained Q16W dosing through week 96
	(YOSEMITE, 44 [16%] patients; RHINE, 58 [20%] patients). Conversely, <5% of patients
	extended to Q8W dosing at or after week 12, and then remained on Q8W or Q4W dosing
	through week 96 (YOSEMITE, 10 [4%] patients; RHINE, 16 [6%] patients). In approximately 4%

Table 4 .

 4 Summary of Key Adverse Events Through Study End (Safety Analysis Population) 1 Total number of AEs and SAEs includes nonocular events and ocular events in the study or fellow eye. † Ocular AEs in the study eye only are presented. ‡ Ocular AEs of special interest were defined as events associated with severe IOI, events requiring surgical or medical intervention to prevent permanent loss of sight, or events associated with BCVA loss of ≥30 ETDRS letters for >1 hour. A full list of ocular AEs of special interest is provided in Table S6 (available at www.aaojournal.org). § Includes serious and nonserious IOI events; excludes endophthalmitis events. ¶ A full list of ocular SAEs is provided in Table S5 (available at www.aaojournal.org). ||APTC events were externally adjudicated; all other events were investigator reported. Includes AEs with onset from the first dose of study drug through study end; percentages are based on n values in the column headings. Multiple occurrences of the same AE in 1 individual are counted only once, except for the "Total number of events" rows, in which multiple occurrences of the same AE are counted separately. AE = adverse event; APTC = Anti-Platelet Trialists' Collaboration; BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; IOI = intraocular inflammation; Q8W = every 8 weeks; SAE = serious adverse event; T&E = treat-and-

		YOSEMITE (N = 937)			RHINE (N = 950)
	Faricimab Q8W	Faricimab T&E	Aflibercept Q8W	Faricimab Q8W	Faricimab T&E	Aflibercept Q8W
	(n = 313)	(n = 313)	(n = 311)	(n = 317)	(n = 319)	(n = 314)

*

Acknowledgments

The authors acknowledge Christopher Brittain, Aachal Kotecha, and Jeffrey R. Willis for their contributions to the faricimab phase 3 trial program. Funding was provided by F. Hoffmann-La Roche Ltd. (Basel, Switzerland) for the study and third-party writing assistance, which was provided by Ellen M. Ross, PhD, and Karina D. Hamilton-Peel, PhD, CMPP, of Envision Pharma Group.

J o u r n a l P r e -p r o o f

Financial support was provided by F. Hoffmann-La Roche Ltd. (Basel, Switzerland). The sponsor participated in the design of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript. Third-party writing assistance, provided by Karina D. Hamilton-Peel, PhD, CMPP, and Ellen M. Ross, PhD, of Envision Pharma Group, was funded by F. Hoffmann-La Roche Ltd.

Précis

Over 2 years, faricimab offered comparable visual acuity gains and improved anatomic outcomes compared with aflibercept. In the faricimab treat-and-extend arms, durable visual acuity gains, and anatomic improvements were maintained with up to every-16-week dosing.

J o u r n a l P r e -p r o o f