CADTH Reimbursement Review

Faricimab (Vabysmo)

Sponsor: Hoffmann-La Roche Canada

Therapeutic area: Diabetic macular edema

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Introduction

Diabetic macular edema (DME) is vision-threatening complication of diabetic retinopathy (DR) that occurs when damaged capillaries in the eye leak fluid into the centre of the retina (the macula) causing it to thicken.¹ Generally, DME manifests as slowly progressive vision loss in people with either type 1 or type 2 diabetes mellitus. Untreated DME is a leading cause of visual loss, visual disability, and legal blindness in people with diabetes.^2-4 An estimated 60,000 adults with DME in Canada experience vision impairment that requires treatment.⁵

In Canada, the current first-line standard of care for patients with DME and central macular thickening are anti–vascular endothelial growth factor (anti-VEGF) drugs, which include ranibizumab (Lucentis), aflibercept (Eylea), and bevacizumab (Avastin) (off-label).⁶ Anti-VEGFs have been shown to be more effective than the previous standard of care (i.e., laser therapy) for centre-involved DME. These drugs can delay and, in some cases, reverse the progression of DME or retinopathy, as well as improve vision-related and general health-related quality of life (HRQoL). Anti-VEGFs are administered as intravitreal (IVT) injections on an ongoing basis; the interval between injections ranges from every 1 to 3 months after completion of loading doses. As adjunctive therapies, patients may receive focal laser therapy or vitrectomy (for eyes with vitreomacular traction). For patients who have had cataract extraction with lens implants (i.e., pseudophakic), IVT steroids may be used as a second-line adjunctive treatment.

Faricimab is a bispecific antibody that inhibits both VEGF-A and angiopoietin-2 (Ang-2), 2 disease pathways involved in the development of DME.⁷ It is indicated for the treatment of DME in patients 18 years and older.⁸ The recommended dose of faricimab for patients with DME is either 6 mg (0.05 mL) given intravitreally for 6 loading doses every 4 weeks, followed by injections every 8 weeks; or 6 mg (0.05 mL) given intravitreally every 4 weeks for at least the first 4 doses, followed by dosing using the treat-and-extend approach, with dosing intervals of up to every 16 weeks, depending on patient outcome.⁸ This is the second CADTH review for faricimab. Faricimab was initially submitted to CADTH for the treatment of neovascular age-related macular degeneration. Faricimab received a Notice of Compliance for that indication on May 27, 2022, after undergoing standard review.

The objective of this report was to perform a systematic review of the beneficial and harmful effects of faricimab 6 mg IVT injection for the treatment of DME in adults.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups that responded to CADTH’s call for input and from the clinical expert consulted by CADTH for the purpose of this review.

Patient Input

CADTH received patient input submitted jointly from the following patient groups: Fighting Blindness Canada, Canadian Council of the Blind, CNIB, Vision Loss Rehabilitation Canada, and Diabetes Canada. People living in Canada with DME indicated that the condition had a “substantial and life-altering” impact on their lives, as the condition causes vision loss that can affect daily activities, such as reading, using a phone, and driving. Patients also mentioned experiencing emotional, psychological, and social impacts from the condition related to worries about the condition worsening and the need for help to get to appointments. Further, patients also must cope with the common symptoms of diabetes, including extreme fatigue, weight changes, and frequent urination. Patients indicated a need for treatment that reduces the physical (e.g., pain from injection), psychological (e.g., anxiety or fear about the injection), and logistical (e.g., frequency of appointments) burden of current treatments. Patients expressed interest in a treatment that is less invasive or similarly invasive but administered less frequently, requiring less travel to appointments and less dependence on caregivers. Patients living outside of Canada’s urban centres and members of vulnerable populations may experience greater burdens (e.g., increased challenges attending appointments).

Clinician Input

Input From the Clinical Experts Consulted by CADTH

The clinical expert consulted by CADTH indicated that the treatment goals of DME are to delay and, in some cases, reverse the progression of DME or DR, as well as to improve vision-related and general quality of life. Because most patients are currently required to attend treatment visits once every 1 to 3 months, the clinical expert noted that there is an unmet need for effective treatments that can be administered at longer treatment intervals, reducing the burden on patients and caregivers associated with frequent treatment visits and increasing adherence with treatment regimens.

The clinical expert noted that faricimab is expected to have a place as a first-line or later-line treatment in patients with DME, similar to other anti-VEGF drugs. The clinical expert indicated that if faricimab is reimbursed, a shift in the treatment paradigm is likely, given that faricimab is the first anti-VEGF approved for an extended interval of up to 16 weeks, which could help address the burden of frequent treatment visits. The clinical expert noted that the dual mechanism of faricimab, which targets both the VEGF-A and Ang-2 pathways, is particularly relevant to DR.

The clinical expert noted that patients with DR associated with vision loss secondary to centre-involved DME are suitable candidates for faricimab. The clinical expert indicated that faricimab can be used in patients who are treatment-naive or who require a change in therapy due to inadequate responses to other anti-VEGF drugs. Patients who may not be suitable for treatment include those who present with major structural damage to the macular retina (e.g., macular atrophy or fibrosis), according to the expert.

The clinical expert noted that clinical evaluation and optical coherence tomography (OCT) should be performed at dosing visits to determine prognosis and follow-up. Key assessment outcomes include change in visual acuity, retinal thickness, and the presence of retinal fluid. According to the expert, an optimal response to anti-VEGFs is generally achieved 6 to 12 months after the initiation of therapy.

The clinical expert indicated that faricimab should be discontinued in patients with treatment futility and proof of irreversible anatomic or functional damage, such as those with macular atrophy (schema) and fibrosis.

Regarding prescribing conditions, the clinical expert recommended retina subspecialty care as the most appropriate setting for the prescription and administration of faricimab in urban areas; in rural settings, trained comprehensive ophthalmologists with experience and expertise in the management of DME would be sufficient.

Clinician Group Input

CADTH received input from 1 clinician group: the Canadian Retina Society.

The clinician group input was consistent with the clinical expert CADTH consulted with respect to the unmet need for a durable treatment with fewer injections that could reduce treatment burden while maintaining maximal vision gain. The clinical group also noted the importance of minimizing side effects, such as injection-related complications, including inflammation, infection, bleeding, retinal detachment, cataract, and glaucoma.

Clinician group input was consistent with the clinical expert input regarding the potential place in therapy for faricimab and the suitable patient population. The clinician group also noted that patients without centre-involved DME should not be treated with faricimab, and those without vision loss secondary to DME (pre-symptomatic patients) should be monitored as long as very close follow-up can be maintained.

Clinician group input generally aligned with the clinical expert input on the assessment of response to treatment and discontinuation of treatment. The clinician group noted that clinically meaningful outcomes include improvement in vision, reduction or resolution of macular edema, regression in Diabetic Retinopathy Severity Scale (DRSS) score, and reduction in the frequency of treatment (intervals of 4 months or longer between treatments).

The clinician group broadly identified the setting for treatment administration as ophthalmology offices in the community setting and/or hospital setting.

Drug Program Input

The drug programs noted an interest in understanding the following: the potential usefulness of the inclusion of active comparators, in addition to aflibercept, in pivotal trials of faricimab; the adequacy of indirect treatment comparisons (ITCs); potential initiation criteria; the frequency of bilateral treatment (in both eyes); faricimab’s potential place in therapy; and criteria for treatment discontinuation. The clinical expert consulted by CADTH did not identify any particular concerns with the sole use of aflibercept as a comparator in the trials. Apart from hemoglobin A1C, the clinical expert noted that it would be reasonable to align the criteria for therapy initiation with the inclusion criteria of pivotal trials, and stated that it is quite common for patients with DME to require treatment in both eyes. The expert thought it would be very likely that faricimab would be used as a first-line treatment and would not be restricted to patients who failed previous anti-VEGF treatment. According to the expert, treatment with faricimab would be discontinued in cases of extensive retinal atrophy (ischemia) and/or retinal fibrosis in the macula (making improvement of vision impossible), and in cases of traction retinal detachment.

Other considerations of interest to the drug programs included the expected proportions of patients receiving faricimab at the various treatment intervals, whether those receiving faricimab at shorter intervals (8 weeks or less) would likely be switched to another anti-VEGF, the appropriate setting for treatment with faricimab, and pricing. The clinical expert expected that the percentage of patients receiving faricimab at various intervals in practice would align with the results of the pivotal trials (around 70% of patients were on either 12- or 16-week intervals at 1 year). The clinical expert also noted that a switch to another drug could be considered for patients on 4-week intervals, but those on 8-week intervals would most likely continue on faricimab. According to the clinical expert, retina subspecialist offices and hospital clinics, where available, are the most appropriate setting for the administration of faricimab, but in nonurban settings, trained comprehensive ophthalmologists with experience and expertise in the management of DME may suffice.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

The YOSEMITE and RHINE studies met the inclusion criteria for the systematic review. They were identically designed phase III, multi-centre, randomized, double-blind, active-controlled, noninferiority trials that compared faricimab with aflibercept in patients with DME (YOSEMITE, n = 940; RHINE, n = 951) over 100 weeks. Patients were randomized in a 1:1:1 ratio to 1 of 3 arms: fixed-dose faricimab every 8 weeks; faricimab dosing on a personalized treatment interval (PTI); and fixed-dose aflibercept every 8 weeks. Patients in the 8-week faricimab arm received faricimab 6 mg intravitreally every 4 weeks for 6 loading doses, followed by maintenance doses every 8 weeks. Patients in the PTI faricimab arm received faricimab 6 mg intravitreally every 4 weeks for 4 loading doses, after which maintenance doses could be administered every 4, 8, 12, or 16 weeks, depending on patient outcome, determined by a predefined algorithm. Patients in the aflibercept arm received aflibercept 2 mg intravitreally every 4 weeks for 5 loading doses, followed by a fixed maintenance interval of every 8 weeks.

Both studies aimed to establish the noninferiority of faricimab to aflibercept for the primary outcome, which was change from baseline in best corrected visual acuity (BCVA) (measured using the Early Treatment Diabetic Retinopathy Study [ETDRS] chart) averaged over weeks 48, 52, and 56 in the intention-to-treat (ITT) population. The noninferiority margin was specified as 4 letters on the ETDRS chart. The proportion of patients with improvement from baseline of 2 or more steps on the ETDRS DRSS score at week 52 was a key secondary end point. The noninferiority margin for this outcome was specified as a difference of 10% between treatment arms. Other secondary outcomes included the frequency of administration for faricimab at a PTI, retinal thickness, presence of retinal fluids, and measures of HRQoL and vision-related function, all of which were analyzed without control for multiplicity. The primary analysis was conducted at week 56, and secondary analysis data were available up to week 100.

The baseline demographic and ocular characteristics of patients were, overall, balanced in the treatment arms in each study. The baseline characteristics were generally similar in the 2 studies, except median months since DME diagnosis was shorter for patients in the YOSEMITE trial than in the RHINE trial (3.1 months versus 6.6 months) and mean baseline central subfield thickness (CST) was slightly higher for patients in YOSEMITE than in RHINE (487.5 µm versus 471.6 µm). In both studies, the median age of patients at baseline was 62 to 64 years, and the majority were male (> 57%) and White (> 76%). At the start of the studies, most patients (around 70% to 75%) had DRSS scores of 35 to 47 (mild to moderately severe nonproliferative DR with an anti-VEGF drug.

Efficacy Results

A summary of the key efficacy results is provided in Table 2.

Change in Visual Acuity

The primary outcome of both studies was the change from baseline in BCVA (ETDRS letters) averaged over weeks 48, 52, and 56 in the ITT population. In the YOSEMITE trial, the mean difference in change between the 8-week faricimab group and the aflibercept group was –0.2 letters (97.5% confidence interval [CI], –2.0 to 1.6 letters), and between the PTI faricimab group and the aflibercept group was 0.7 letters (97.5% CI, –1.1 to 2.5 letters). In the RHINE trial, the mean difference in change between the 8-week faricimab group and the aflibercept group was 1.5 letters (97.5% CI, –0.1 to 3.2 letters), and between the PTI faricimab group and the aflibercept group was 0.5 letters (97.5% CI, –1.1 to 2.1 letters). The CIs for all these estimates did not cross the pre-established noninferiority margin of 4 letters. All the CIs in these comparisons crossed the line of no effect and, therefore, neither faricimab arm was superior to aflibercept for the change in BCVA. Results of the sensitivity analyses, the supplemental analyses, and the per-protocol population were congruent with the primary analysis.

The proportion of patients gaining 15 or more ETDRS letters in BCVA from baseline averaged over weeks 48, 52, and 56 (a secondary outcome) was comparable across treatment arms and studies: 29.2%, 35.5%, and 31.9% in the 8-week faricimab, PTI faricimab, and aflibercept groups, respectively, in YOSEMITE; and 33.6%, 28.3%, and 30.5%, respectively, in RHINE. Most patients (> 95% across treatment arms) avoided a loss of 15 or more ETDRS letters in BCVA from baseline during the studies. Comparable results were seen across all 3 treatment arms for patients gaining 10 or more, 5 or more, or 0 or more letters, and for patients avoiding a loss of 10 or more or 5 or more letters in BCVA from baseline in the 2 studies; these end points were other secondary outcomes in the trials.

Results were mostly congruent at year 2 and year 1 for these BCVA secondary outcomes, except a numerically lower adjusted proportion of patients in the PTI faricimab arm than in the aflibercept arm in RHINE gained 15 or more ETDRS letters in BCVA from baseline averaged over weeks 92, 96, and 100.

Change in CST

In both YOSEMITE and RHINE, reductions in CST from baseline to weeks 48, 52, and 56 were numerically greater in the faricimab arms (8-week and PTI) than in the aflibercept arm (a secondary outcome). In YOSEMITE, the difference in mean adjusted change between the 8-week faricimab arm and the aflibercept arm was –36.2 µm (95% CI, –47.8 µm to –24.7 µm) and the difference between the PTI faricimab arm and the aflibercept arm was –26.2 µm (95% CI, –37.7 µm to –14.7 µm); in RHINE, and differences were –25.7 µm (95% CI, –37.4 µm to –14.0 µm) and–17.6 µm (95% CI, –29.2 µm to –6.0 µm), respectively.

A numerically higher proportion of patients had an absence of DME (CST < 325 µm for Spectralis spectral-domain [SD]-OCT) averaged over weeks 48, 52, and 56 in the 8-week faricimab arm and in the PTI faricimab arm than in the aflibercept arm. In YOSEMITE, the difference in the adjusted proportion between the 8-week faricimab arm and the aflibercept arm was 16.0% (95% CI, 8.9% to 23.1%) and the difference between the PTI faricimab arm and the aflibercept arm was 12.7% (95% CI, 5.4% to 20.0%); in RHINE, the differences were 12.3% (95% CI, 5.7% to 18.9%) and 8.2% (95% CI, 1.5% to 14.9%), respectively.

The differences between the faricimab arm and the aflibercept arm for both CST-related outcomes (CST reduction and absence of DME) were less pronounced at year 2 than at year 1 in the 2 studies (Table 13).

Frequency of Faricimab Injections

The studies measured the proportion of patients in the PTI faricimab arm on 4-, 8-, 12-, and 16-week injection intervals as a secondary outcome. In YOSEMITE at week 52, the proportion of patients on 4-, 8-, 12-, and 16-week intervals was 10.8%, 15.4%, 21.0%, and 52.8%, respectively, and in RHINE at week 52, the proportions were 13.3%, 15.6%, 20.1%, and 51.0%, respectively. In YOSEMITE at week 96, the proportion of patients in the PTI faricimab arm on 4-, 8-, 12-, and 16-week intervals was 7.0%, 14.8%, 18.1%, and 60.0%, respectively, and in RHINE at week 96, the proportions were 10.1%, 11.8%, 13.6%, and 64.5%, respectively.

HRQoL and Vision-Related Function

Mean changes from baseline in National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) composite scores at week 24, week 52, and week 100 were comparable in patients treated with faricimab (8-week or PTI) and in those treated with aflibercept in the 2 studies (a secondary outcome). At week 52, the difference in the adjusted mean change from baseline in NEI VFQ-25 composite score between the 8-week faricimab arm and the aflibercept arm in YOSEMITE was –0.2 points (95% CI, –2.1 to 1.7 points) and between the PTI arm and the aflibercept arm was 0.5 points (95% CI, –1.5 to 2.4 points); in RHINE, the differences were–0.8 points (95% CI,–-2.7 to 1.1 points) and –1.0 points (95% CI, –2.9 to 0.8 points), respectively. At week 24, around half the patients (46.0% to 52.5%) in all treatment groups had an improvement from baseline in NEI VFQ-25 composite score (an exploratory outcome) of at least 4 points in the 2 studies (Table 15).

A comparable proportion of patients, around 2-thirds of patients (68.8% to 77.2%) in all treatment groups in the 2 studies, had a BCVA Snellen equivalent of 20/40 or better averaged over weeks 48, 52, and 56 (a secondary outcome and a common visual acuity standard used for driver licencing in the US), with consistent results at year 2 in the studies (Table 15).

The number of patients progressing to legal blindness (a secondary outcome, defined as a BCVA Snellen equivalent of 20/200 or worse) was small in all treatment arms in the 2 studies over the study periods (1.5% to 2.1% per arm).

Absence of Retinal Fluids

Over the course of both studies, a numerically higher proportion of patients in the 8-week faricimab arm than in the aflibercept arm had an absence of intraretinal fluid (IRF) at week 52 (a secondary outcome), with a difference in the adjusted proportion of 16.6% (95% CI, 8.7% to 24.5%) in YOSEMITE and 10.7% (95% CI, 2.8% to 18.6%) in RHINE. Differences in the adjusted proportion of patients with an absence of IRF between the PTI faricimab and aflibercept groups at week 52 were less pronounced, at 13.4% (95% CI, 5.4% to 21.3%) in YOSEMITE and 7.2% (95% CI, –0.5% to 14.9%) in RHINE. After week 48, the vast majority of patients (> 94% across treatment arms) in the 2 studies had an absence of subretinal fluid (SRF) (a secondary outcome).

Improvement From Baseline on the ETDRS DRSS

There were conflicting results between YOSEMITE and RHINE for the proportion of patients with a change on the ETDRS DRSS score from baseline of at least 2 steps at week 52, the key secondary end point in the studies (Table 17). In YOSEMITE, noninferiority for this end point was met, with the difference in the adjusted proportion between the 8-week faricimab arm and the aflibercept arm of 10.2% (97.5% CI, 0.3% to 20.0%) and between the PTI faricimab arm and the aflibercept arm of 6.1% (97.5% CI, –3.6% to 15.8%). However, in RHINE, noninferiority was not met for this outcome, as the lower bound of the 97.5% CI for the difference from baseline in the adjusted proportion was less than –10%; at week 52, the difference between the 8-week faricimab arm and the aflibercept arm was –2.6% (97.5% CI, –12.6% to 7.4%) and the difference between the PTI faricimab arm and the aflibercept arm was –3.5% (97.5% CI, –13.4% to 6.3%). At week 96, the proportion of patients who achieved an improvement on the ETDRS DRSS score of at least 2 steps from baseline was generally comparable in the 8-week faricimab arm, the PTI faricimab arm, and the aflibercept arm in the 2 studies.

The proportion of patients who achieved an improvement of at least 3 steps on the ETDRS DRSS score from baseline at week 52, a secondary outcome, was comparable across treatment arms (14.8% to 19.5%) in both studies. Few patients (< 3%) developed new proliferative diabetic retinopathy (PDR) in the study eye up to week 96 (a secondary outcome) in any treatment arm in the 2 studies. Similarly, few patients in any treatment arm in either study experienced a worsening of at least 2 steps or at least 3 steps at week 52, received vitrectomy, or received panretinal photocoagulation (PRP) (< 1.5% per arm for each of these exploratory outcomes; refer to Table 17).

Harms Results

A summary of the key harms results is provided in Table 2.

Over 100 weeks in the safety-evaluable population in the YOSEMITE trial, the proportion of patients reporting at least 1 ocular adverse event (AE) in the study eye was comparable across treatment arms (47.0% in the 8-week faricimab arm, 46.6% in the PTI faricimab arm, and 46.3% in the aflibercept arm). In the RHINE study, a higher proportion of patients in the 8-week faricimab and PTI faricimab arms reported an ocular AE than in the aflibercept arm (52.4%, 51.7%, and 44.6%, respectively). In the RHINE study, the ocular AEs that occurred at a higher incidence in the 2 faricimab arms than in the aflibercept arm include cataract, dry eye, and blepharitis, and the ocular AEs that were numerically more common in the 8-week faricimab arm than in the aflibercept arm include conjunctival hemorrhage, increased intraocular pressure, vitreous floaters, cataract subcapsular, posterior capsule opacification, eye pruritis, and conjunctivitis allergic. The most common ocular AEs in both studies were cataract (9.9% to 17.6% in each treatment arm) and conjunctival hemorrhage (5.6% to 9.8% in each arm).

Ocular serious adverse events (SAEs) were reported with low frequency in both trials; however, there was a slightly higher frequency of ocular SAEs in the PTI faricimab arm than in the aflibercept arm in both YOSEMITE and RHINE, and the 8-week and PTI faricimab arms were somewhat higher than the aflibercept arm in YOSEMITE (3.8%, 4.5%, and 2.3%, respectively) and in RHINE (4.4%, 6.3%, and 4.1%, respectively). The most common ocular SAE reported in both studies was cataract (0.6% to 2.2% across treatment arms). The frequency of nonocular SAEs in any arm of the studies ranged from 20.1% to 31.6%, with COVID-19 (1.3% to 3.2%) and pneumonia (1.3% to 2.6%) being the most frequently reported.

In both studies, a small proportion of patients in all arms discontinued treatment due to AEs (1.6% to 2.9% per arm). The most common AE (≥ 1% in any arm) related to treatment discontinuation was uveitis (3 patients in the PTI faricimab arm of YOSEMITE). The proportion of patients in all arms that discontinued the study due to AEs ranged from 4.4% to 8.6% across treatment arms. The most common reason for study discontinuation was death (9 patients in the faricimab arms and 1 patient in aflibercept arm) and COVID-19 (8 patients in the faricimab arms and 1 patient in aflibercept arm).

In the pooled YOSEMITE and RHINE population, 81 patients died (4.4%, 4.7%, 3.7% in the 8-week faricimab arm, PTI faricimab arm, and aflibercept arm, respectively). The most common primary causes of death included gunshot wounds, falls, natural causes, advanced hepatocellular carcinoma with metastases to the bone, head injury, and unexplained death (3 patients, 6 patients, and 1 patient in the 8-week faricimab arm, PTI faricimab arm, and aflibercept arm, respectively). Study investigators did not consider any of the deaths to be related to the study treatment.

Cataract was the most common notable harm, occurring in 9.9% to 17.6% of patients across all treatment arms in the 2 studies. Over the course of both studies, 6 patients in the faricimab arms and 1 patient in the aflibercept arm reported endophthalmitis. Uveitis and iritis were the most commonly reported intraocular inflammation events. Uveitis occurred in 7 patients in the faricimab arms and no patients in the aflibercept arm. The occurrence of iritis was comparable across treatment arms. Nonocular arterial thromboembolic events were reported in 6.9% to 10.9% of patients across both studies, with comparable frequencies in the treatment arms. Vitreous floaters were reported in 1.9% to 5.4% of patients, and these events were numerically higher in the 8-week faricimab arm than in the aflibercept arm of both studies. Retinal detachment, retinal tear, glaucoma, retinal vascular occlusive disease events, eye irritation, ocular discomfort, and blurred vision occurred infrequently (< 2% for each harm across all treatment arms in both studies). A small number of patients in the faricimab arms reported retinal detachments (6 in the 2 studies) and retinal tears (3 in the 2 studies); in the aflibercept arm, there were 2 retinal detachments and no retinal tears in either study. There were no reports of retinal hemorrhage in either study.

Critical Appraisal

Internal Validity

The overall study designs of YOSEMITE and RHINE were appropriate for the objectives of the studies. There were no major concerns with the methods of randomization, allocation concealment, or blinding. The noninferiority of faricimab to aflibercept was concluded from an ITT analysis of the primary outcome. For a conservative approach in the context of noninferiority studies, it is generally preferred that the claim of noninferiority be based on agreement between both the ITT population and the per-protocol population. Nonetheless, the results of a supplementary per-protocol analysis of the studies and several sensitivity analyses conducted by the sponsor and the FDA were consistent with those of the primary ITT analysis. Although there was a large proportion of patients with at least 1 major protocol deviation (around 50%) in both studies (most frequently missed visits), the sensitivity and supplemental analyses were consistent with the primary estimand. The noninferiority margin of 4 ETDRS letters was considered reasonable by the clinical expert. The studies were adequately powered for the assessment of the primary outcome. Intercurrent events (ICEs) were reported in approximately 9% to 10% of patients in both studies, and most were COVID-19–related. A key limitation of the statistical analysis was the lack of adjustment for multiplicity for secondary outcomes and subgroup analyses, and no sensitivity analyses were conducted to assess the impact of missing data on the secondary outcomes. As such, these findings were considered exploratory. Another limitation is the different dosing schedules used in the treatment arms. In the maintenance phase, the treatment interval could be modified after randomization in the PTI faricimab arm, using pre-specified criteria based on a patient’s BCVA and CST outcomes, to either every 4-, 8-, 12-, or 16-week intervals; intervals in the aflibercept arm, however, were fixed throughout the study period.

External Validity

In terms of generalizability, a strength of the trials is that they included patients who had previously received another anti-VEGF and patients who were treatment-naive. A limitation to note is that the studies excluded some patients who would typically receive treatment in clinical practice; patients with hemoglobin A1C greater than 10% were excluded, as were patients with high-risk PDR. The generalizability of trial results to these patient populations is unclear. In addition, aflibercept was given at a fixed dosing interval in the maintenance phase, which does not align with the treat-and-extend protocol commonly used in clinical practice, so the generalizability of the results is limited. There is also some uncertainty about the impact of the frequency of faricimab injections on outcomes, because the method of interval assignment for PTI faricimab in the maintenance phase may be more rigid than what would be used in clinical practice, although the expert noted that simplified thresholds for BCVA and OCT from the algorithm could be applied by clinicians in practice. In the trials, patients were monitored monthly, but in clinical practice, monitoring would typically only occur at treatment visits during the maintenance phase, according to the clinical expert. Furthermore, although the length of assessment in the primary analysis was adequate to determine the efficacy and safety of faricimab in the context of a noninferiority trial, according to the clinical expert, longer-term data are required to determine the durability and long-term safety of faricimab. In addition, there is no direct evidence comparing faricimab to ranibizumab (at Health Canada–approved dosages) or with bevacizumab, which is an important evidence gap in the evaluation of anti-VEGFs.

Indirect Comparisons

Description of Studies

One ITC was submitted by the sponsor and is included in this review. No additional ITCs were identified in the literature. The sponsor performed a Bayesian network meta-analysis (NMA) to estimate the efficacy of faricimab and of other anti-VEGFs in patients with DME.

Efficacy Results

For the outcome of BCVA at 1 year, 23 trials were analyzed using a random-effects model. In the ITC, no treatment ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

For the outcome of number of injections at 1 year, 11 trials were analyzed under a random-effects model. The ITC showed that that |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| these data are impacted by the administration of therapies with fixed intervals in clinical trials, according to protocols within the 1-year time frame of the randomized controlled trials (RCTs).

For the outcome of retinal thickness at 1 year, 23 RCTs were analyzed using a random-effects model. The results of |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. However, 95% credible intervals (CrIs) are wide and heterogeneity in the methods to assess retinal thickness across studies adds considerable uncertainty to the results for this analysis and limit conclusions about the relative effect of faricimab on central retinal thickness (CRT).

The outcome of the proportion of patients gaining or losing 10 or 15 ETDRS letters at 1 year was analyzed, but poor model fit precludes conclusions about the effect of faricimab, compared with comparators, for this outcome.

Harms Results

There were limited data available for the NMAs conducted for ocular adverse effects and for discontinuation; therefore, fixed-effects models were used for these end points and there was a high degree of uncertainty in these models. Limitations of the NMAs preclude conclusions about ocular adverse effects and overall treatment discontinuation.

Critical Appraisal

There may be important sources of bias related to different study or patient characteristics that could impact conclusions about this ITC. The limitations described may pose a considerable challenge when trying to come to conclusive decisions about the validity of the results that can inform clinical practice. There were many trials with missing information about study and baseline characteristics and there was considerable heterogeneity among these characteristics. Most notably, there was heterogeneity in the methods used to assess retinal thickness and in the availability of information related to the presence of significant diabetic macular ischemia or systemic comorbidities. Additionally, there was a weak connection between faricimab and the rest of the network through aflibercept.

Although PTI faricimab may be more favourable than ranibizumab pro re nata (PRN) (i.e., as needed), treat and extend, every 4 weeks, and bevacizumab PRN for the outcome of BCVA, CrIs were very close to the null value for this analysis. The results of the analysis related to the number of injections will have been affected by the administration of therapies with fixed intervals in clinical trials, according to study protocols. Limitations to the NMA preclude conclusions about the proportion of patients gaining or losing 10 or 15 ETDRS letters and about retinal thickness.

There were limited data available for the NMAs conducted for ocular adverse effects and for treatment discontinuation; therefore, fixed-effects models were used for these end points and there was a high degree of statistical uncertainty in these models. Therefore, there are limited data from which to draw any conclusions about the effect of faricimab, compared with comparators, on ocular adverse effects and treatment discontinuation.

Other Relevant Evidence

No other relevant evidence was identified for inclusion.

Conclusions

Faricimab, at 8-week intervals or PTI dosing, was shown to be noninferior, but not superior, to aflibercept for the mean change in BCVA from baseline after 1 year of treatment in adults with DME, based on evidence from 2 double-blind phase III RCTs. The results of other BCVA outcomes, anatomic outcomes, vision-related functions, and HRQoL did not contradict the findings of the primary analysis, but their interpretation is limited by the lack of a noninferiority margin and the lack of adjustment for multiple testing. There is no direct evidence on faricimab compared with other anti-VEGFs at dosages approved in Canada. The safety profile of faricimab was generally comparable to that of aflibercept in the trials. The long-term safety of faricimab is not known.

Evidence from 1 NMA suggests ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The NMA suggests |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| these data are impacted by the administration of therapies with fixed intervals in clinical trials, according to protocols within the 1-year time frame of the RCTs. However, the heterogeneity in study design and patient characteristics may limit conclusions that can be drawn from the NMA. No conclusions on ocular adverse effects could be drawn from the NMA because of limited data, and the long-term risk of harm with aflibercept relative to other treatments is not known.

Introduction

Disease Background

DME is a vision-threatening complication of diabetes mellitus (both type 1 and type 2). The persistent elevation of blood glucose in persons with diabetes causes damage to the smallest blood vessels (capillaries), such as those in the eye, resulting in DR.¹³ Some patients with DR, especially those with continued poorly managed blood glucose, can experience swelling in the retina, which is known as DME.³ Generally, DME manifests as a slowly progressive loss of vision. The degree of vision loss can vary considerably and depends on the severity, duration, and location of IRF, among other factors. Clinically significant macular edema can be defined by retinal thickening at or within 500 µm of the centre of the macula.^6,14,15 Signs of DME include blurred vision, retinal hemorrhage, retinal detachment, colours appearing washed out or faded, changes in contrast sensitivity, impaired colour vision, gaps in vision (scotomas), and potentially permanent vision loss. Untreated DME is considered to be the leading cause of visual loss, visual disability, and legal blindness in people with DR.^2-4

The Eye Diseases Prevalence Research Group reported in 2004 that the prevalence of DR in adults in the US was 40.3%, and that sight-threatening retinopathy occurred in 8.2% of such individuals.¹⁶ The prevalence of macular edema in patients with type 1 diabetes, patients with type 2 diabetes treated with insulin therapy, and patients treated with antihyperglycemic therapies have been estimated to be 11%, 15%, and 4%, respectively.¹⁷ A Canadian retrospective study using records from the Southwestern Ontario database estimated the prevalence of DME in adults with diabetes to be 15.70% and the prevalence of vision loss due to DME to be 2.56%.¹⁴ In this study, more than 50% of patients with DME experiencing vision loss were older than 60 years and more than 22% of patients with DME experiencing vision loss were members of First Nations communities.¹⁴ Indigenous populations in Canada are disproportionally affected by diabetes,⁶ and prevalence rates of DR are higher than in the general population,^18,19 although accurate data on vision loss in this population are limited.⁶ Based on the Ontario study’s estimates¹⁴ and a 2020 Statistics Canada estimate of 2.3 million adults in Canada with diabetes, there are approximately 60,000 adults with DME in Canada who experience vision impairment that requires treatment.⁵ The incidence and prevalence of diabetes in Canada are projected to increase in coming years in tandem with an aging population and rising rates of obesity, and this rise in diabetes cases is expected to lead to corresponding increases in DR and DME.⁶

Generally, vision loss is associated with significant morbidity, including increased falls, hip fracture, and mortality.²⁰ In addition, it has been suggested that amputation and visual loss due to DR are independent predictors of early death among patients with type 1 diabetes.²¹ Such progressive visual impairment typically results in significant decrements in daily functioning and quality of life, and indirect costs due to lost productivity are high if the condition is left untreated.^22-24 Therefore, early detection and treatment of DME is vital.^25,26

Standards of Therapy

Current therapies for DME in Canada include nonpharmacological interventions (laser therapy and vitrectomy) and pharmacological interventions (IVT anti-VEGF drugs and IVT steroids). Health Canada–approved anti-VEGF drugs for DME include ranibizumab and aflibercept, and approved IVT steroids include dexamethasone.

Macular laser photocoagulation (including focal, grid laser, and panretinal therapy) for DME was the standard of care for more than 25 years before the introduction of anti-VEGF drugs and is still widely used, either alone or in combination with anti-VEGF treatment.¹⁵ Laser therapy has been shown to slow and/or stabilize vision loss, but is minimally effective in restoring vision.²⁷ Laser therapy also has the disadvantage of causing permanent damage to retinal tissue during treatment.^28-30 Clinical studies have shown robust efficacy and safety for frequent (e.g., monthly or bimonthly) anti-VEGF injections for the treatment of DME.^31-34 The results from these trials demonstrate that treatment with anti-VEGF drugs substantially improves visual and anatomic outcomes, compared with laser photocoagulation, and eliminates the ocular side effects associated with laser treatment. Canadian evidence-based guidelines and clinical treatment algorithms recommend anti-VEGF injections as therapy (alone or in conjunction with focal laser therapy) for most patients with clinically significant DME that involves central macular thickening. For eyes without central macular thickening, focal laser is recommended, and for eyes with vitreomacular traction and macular edema, vitrectomy is recommended.⁶

The first of the anti-VEGF drugs to be approved in Canada for the treatment of DME was ranibizumab (a humanized recombinant monoclonal antibody fragment with anti-VEGF activity).³⁵ The recommended dose of ranibizumab is 0.5 mg injected intravitreally once a month and continued until maximum visual acuity is achieved, confirmed by stable visual acuity in 3 consecutive monthly assessments performed while the patient is on the treatment.³⁵ Other anti-VEGF therapies include aflibercept at the recommended dose of 2.0 mg administered by IVT injection monthly for the first 5 consecutive doses, followed by 1 injection every 2 months.³⁶ After the first year, injections of aflibercept may extended by up to 2-week increments, based on disease activity, although data on intervals longer than 4 months are limited.³⁶ Bevacizumab, another anti-VEGF drug approved for the treatment of cancers, such as colorectal and lung cancer,³⁷ has been used off-label as an IVT treatment for macular edema in some Canadian jurisdictions. Although not approved for use in patients with DME in Canada, a 2016 CADTH Therapeutic Review examined the evidence on age-related macular degeneration, DME, retinal vein occlusion, and choroidal neovascularization due to pathologic myopia. Subsequently, the CADTH Canadian Drug Expert Committee (CDEC) issued a recommendation suggesting bevacizumab as the preferred initial anti-VEGF therapy because its clinical effectiveness is similar to other anti-VEGF treatments and its cost is lower.³⁸

Although anti-VEGF therapies are widely accepted as the standard of care for patients with DME, they require frequent injections (8 to 12 per eye per year) to achieve desirable outcomes, creating a high treatment burden for patients and caregivers. Anti-VEGF therapies are also associated with an increased risk of cerebrovascular and cardiovascular events, such as thromboembolic events; therefore, they may not be appropriate for all patients with DME, especially those who have had a previous stroke or who have other cardiovascular comorbidities. Some patients have an inadequate response to anti-VEGF treatment, although the frequency of suboptimal response is unclear. According to the clinical expert consulted for this review, around 10% of patients may have an inadequate response, although some studies have reported a suboptimal response rate as high as 25%³⁹ to 40%⁴⁰ in patients on anti-VEGF therapy, depending on how suboptimal response is defined.⁴⁰ There is limited evidence of the benefit and risk of continuous anti-VEGF injections among patients who did not respond well to prior anti-VEGF therapy.⁴⁰

IVT steroids may be required as a second-line treatment especially for patients who have artificial lens implants (i.e., pseudophakia). In Canada, IVT dexamethasone implants are indicated for use in patients with DME who are pseudophakic. However, in October 2018, CDEC recommended that dexamethasone not be reimbursed for this indication, given its uncertain efficacy and safety compared with other available therapies.⁴¹ Triamcinolone acetonide monotherapy administered as an IVT steroid injection is considered for off-label use in Canada for the treatment of macular edema, according to the clinical expert consulted for this CDR review, as a second-line treatment in pseudophakic patients.

Drug

Faricimab is a humanized bispecific immunoglobulin G1 antibody that selectively binds to and neutralizes VEGF-A and Ang-2, which are key mediators in the pathogenesis of DME.⁸ VEGF-A promotes endothelial cell proliferation, leading to increased neovascularization and vascular permeability. Ang-2 promotes endothelial destabilization, pericyte loss, and pathological angiogenesis, and sensitizes blood vessels to the activity of VEGF-A. Through the inhibition of Ang-2 and VEGF-A, faricimab reduces vascular permeability and inflammation, inhibits pathological angiogenesis, and restores vascular stability.⁷ Faricimab received FDA approval in January 2022 for the treatment of DME and neovascular age-related macular degeneration.

This is the second CADTH review for faricimab. The drug was initially submitted to CADTH for the treatment of neovascular age-related macular degeneration. The faricimab dossiers were submitted to CADTH as a pre-Notice of Compliance submission. During the review process, on May 27, 2022, faricimab received a NOC from Health Canada. The approved indication related to the current review is for the treatment of DME in patients 18 years and older. Per the faricimab product monograph,⁸ 1 of these 2 dose regimens is recommended for DME:

• faricimab 6 mg (0.05 mL) administered by IVT injection every 4 weeks (approximately every 28 ± 7 days) for the first 6 doses, followed by 6 mg (0.05 mL) every 8 weeks

• faricimab 6 mg (0.05 mL) administered by IVT injection every 4 weeks (approximately every 28 ± 7 days) for at least 4 doses or until macular edema is resolved, based on the CST of the macula, measured by OCT. Thereafter, the dosing interval may be modified using a treat-and- extend approach based on anatomic and visual acuity outcomes at dosing visits. The dosing interval may be extended up to every 16 weeks (4 months) in up to 4-week increments. If anatomic and/or visual outcomes deteriorate, the treatment interval should be shortened accordingly.

Patients should be assessed regularly. Monitoring between the dosing visits should be scheduled based on the patient's status and at the physician's discretion.⁸

The sponsor is seeking reimbursement of faricimab, per the Health Canada–approved indication, for the treatment of DME.⁷

The key characteristics of commonly used anti-VEGF treatments for DME are presented in Table 3.

Table 3: Key Characteristics of Faricimab, Aflibercept, Ranibizumab, and Bevacizumab

Ang-2 = angiopoietin-2; ATE = arterial thromboembolic events (includes nonfatal stroke, nonfatal myocardial infarction, and vascular death); DME: diabetic macular edema; IOP = intraocular pressure; IVT = intravitreal; mAb = monoclonal antibody; PIGF = placental growth factor; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; q.16.w. = every 16 weeks; VA = visual acuity; VEGF = vascular endothelial growth factor.

^aBevacizumab is used off-label in the treatment of DME.

^bHealth Canada–approved indication.

^cBased on expert opinion.

Sources: Vabysmo product monograph,⁸ Eylea product monograph,³⁶ Lucentis product monograph,³⁵ Avastin product monograph.³⁷

Stakeholder Perspectives

Patient Group Input

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from clinical expert(s) consulted by CADTH for the purpose of this review.

Patient Input

Five patient groups contributed jointly to the patient group input: Fighting Blindness Canada (with input from an independent consultant and a research and consulting firm), the Canadian Council of the Blind, CNIB, Vision Loss Rehabilitation Canada, and Diabetes Canada. Fighting Blindness Canada is involved in vision research for treatments and cures for blinding eye diseases. The Canadian Council of the Blind engages in social, recreational, and community activities to enhance quality of life for and increase awareness of people with seeing disabilities. CNIB delivers programs and advocacy to empower people affected by blindness. Vision Loss Rehabilitation Canada is a rehabilitation and health services organization that provides blind and partially sighted people with training, on a referral basis, in homes and communities. And Diabetes Canada provides education, services, and advocacy, and supports research for people living with diabetes. The submitted input, which was collected during the first months of 2020, was part of a larger research project (Valuation and Interpretation of Experiences with Diabetic Retinopathy/Diabetic Macular Edema). A total of 67 people in Canada living with DR and DME responded to the survey. Additionally, the Canadian Council of the Blind conducted a separate survey in April 2020 to focus exclusively on the pandemic and its effects on people with age-related macular edema and DR. This additional survey result is not summarized.

According to more than 50% of respondents (n = 55 to 59) to the Valuation and Interpretation of Experiences with Diabetic Retinopathy/Diabetic Macular Edema survey, DR and DME have a “substantial and life-altering” impact on patients’ activities of daily life, such as reading, using a phone, and driving. Also, DR and DME create an emotional, psychological, and social burden. For example, 80.3% of 61 respondents reported worries about their condition worsening, 45.9% reported needing help for activities such as getting to appointments, and 36.1% reported that explaining their condition to family and friends was a burden. A majority of the 61 patients (> 60%) reported feeling lonely or isolated in the previous month. In addition, patients still have to cope with common symptoms of diabetes, including extreme fatigue, weight changes, and frequent urination. Patients want treatment that reduces the physical (pain from injection), psychological (anxiety or fear about the injection), and logistical strain, and expressed an interest in treatment that is less invasive or similarly invasive but administered less frequently, requiring less travel for appointments and less dependence on caregivers. Patients living outside of Canada’s urban centres and members of vulnerable populations experience greater burdens. Moreover, the number of people living with diabetes continues to increase. Therefore, more patients in rural communities will need options that are less complex but effective for the treatment of DR and DME.

Clinician Input

Input From the Clinical Expert Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of DME.

Unmet Needs

The clinical expert consulted by CADTH indicated that the treatment goals of current therapies are to delay DME and, in some cases, to reverse the progression of DME and/or retinopathy, as well as to improve vision-related and general quality of life. Although current anti-VEGF treatments for DME have been useful for the treatment of DME over the past 10 to 15 years, they need to be given intravitreally by trained clinicians once every 1 to 3 months on an ongoing basis, often for years. This frequent administration poses a significant burden to patients and caregivers, especially in Canada where travel distances can be long and challenging in the winter. The clinical expert noted that longer-acting treatments would fill a significant unmet medical need by improving convenience of the treatment regimen and reducing the burden on patients and caregivers. As well, they could improve outcomes, in part, by increasing adherence with treatment regimens. Additionally, the expert noted that not all patients respond to available treatments and, in some cases, patients may become refractory to current treatment options.

Place in Therapy

As faricimab is the first anti-VEGF to target the Ang-2 pathway in addition to the VEGF pathway, the expert noted that its mechanism of action is a rational approach, given the underlying disease process. The expert noted that the Ang-2 pathway of angiogenesis is relevant in DR. According to the clinical expert, faricimab is expected to have a place in therapy, along with other anti-VEGFs, as a first-line or later-line treatment in patients with DME. The clinical expert indicated that if faricimab is reimbursed, a shift in the treatment paradigm is likely, given that faricimab is the first anti-VEGF approved for an extended interval of up to 16 weeks, which could potentially address the unmet need related to frequent treatment visits.

In the clinical expert’s opinion, there are no clinical reasons to make patients try other treatments before faricimab is initiated. Faricimab is expected to be prescribed as a first-line (or later-line) treatment for DME and, as with any of the existing treatments, early initiation is important for the best clinical outcomes.

Patient Population

Patients with DR associated with vision loss secondary to centre-involved macular edema are the best candidates for faricimab, according to the clinical expert. The clinical expert indicated that faricimab can be used in patients who are treatment-naive or who require a change in therapy due to inadequate responses to other anti-VEGF drugs. Patients with better baseline visual acuity, centre-involved edema of recent onset, and better control of diabetes and comorbid conditions may be more likely to benefit from treatment. Patients who present with major structural damage to the macular retina (e.g., macular atrophy or fibrosis) may not be suitable for treatment. Suitability for treatment would be assessed using a clinical exam, IV fluorescein angiography and OCT, potentially with the addition of OCT angiography. In current clinical practice, OCT is unlikely to lead to misdiagnosis. OCT is used not only for diagnosis, but also for prognosis and follow-up.

Assessing Response to Treatment

The clinical expert noted that clinical evaluation and OCT should be performed at almost every dosing visit to assess treatment response, with a treat-and-extend approach to achieve the longest sustainable interval without recurrence, and that monitoring between dosing visits would not be required. Key assessment outcomes include change in visual acuity, retinal thickness, injection frequency, and the presence of retinal fluid.

The clinical expert reported that the optimal response to anti-VEGFs is generally achieved at least 6 to 12 months after initiation of therapy. In the experience of the expert, the majority of patients can achieve stabilized vision and improved quality of life, and about 50% to 65% of patients can achieve visual acuity improvement.

The clinical expert noted that when assessing the magnitude of change in visual acuity, it is crucial to keep in mind that patients with better vision at baseline generally have less room for improvement than those with poor vision at baseline. As such, the clinical expert reported that there is not an agreed-upon threshold that is indicative of a clinically meaningful change in visual acuity in patients with DME.

The clinical expert indicated that the presence of SRF or IRF is an indicator of active disease, which should prompt modification of the treatment plan (often a reduction in injection interval).

Discontinuing Treatment

The clinical expert indicated that faricimab should be discontinued in patients with treatment futility with proof of irreversible anatomic or functional damage, such as macular atrophy (ischemia) or fibrosis.

Prescribing Conditions

The clinical expert recommended retina subspecialty care as the most appropriate treatment setting for the prescription and administration of faricimab, especially in urban areas. In rural settings, trained comprehensive ophthalmologists with experience and expertise in the management of DME may be able to provide care.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

Five clinicians associated with the Canadian Retina Society, which represents ophthalmologists who specialize in the surgical and/or medical treatment of vitreoretinal disease, jointly submitted their clinical group input, based on phase III randomized controlled clinical trials, systematic reviews, meta-analyses, and presentations.

Unmet Needs

Even though the current standard of therapy (i.e., anti-VEGF) is more effective than the previous standard of care (i.e., laser) for centre-involved DME, the clinician group stated that durability and a robust safety profile that improves long-term outcomes are unmet needs. Durability reduces treatment burden (with less frequent dosing) and maintains maximal vision gain (with improved compliance and monitoring). Durability will be translated into improved quality of life and independence, and will reduce the risk of falls, depression, and surgical intervention (vitrectomy). The minimization of side effects, such as injection-related complications like inflammation, infection, bleeding, retinal detachment, cataract, and glaucoma, is also important because side effects can compromise visual outcomes and result in blindness. The clinician group stated that all patients with DME have these unmet needs.

Place in Therapy

The clinician group said that faricimab can be considered a first-line treatment and/or a rescue treatment for patients who do not respond to the current therapies available for DME. The clinician group said that there is currently no standard of care in cases of treatment failure. Moreover, the clinician group noted that the vision of treatment-naive patients and of patients previously treated with other anti-VEGF drugs can benefit from a switch to faricimab. According to the clinician group, it is not necessary for patients to try other therapies before faricimab is initiated.

Patient Population

According to the clinician group, all patients with centre-involved DME will be suitable for treatment with faricimab. The clinician group stated that eligible patients can be identified with clinical exams and diagnostic tests (OCT, OCT angiography, IV fluorescein angiography) in the routine clinical practice setting. The clinician group said that patients without centre-involved DME should not be treated with faricimab and that those without vision loss secondary to DME (pre-symptomatic patients) should be monitored, as long as very close follow-up can be maintained. The clinician group also noted that patients with good baseline vision are likely to maintain good vision in the long term, although patients with all levels of vision would benefit from faricimab.

Assessing Response to Treatment

The clinician group said that response to treatment can be measured with visual acuity testing (subjective outcome), fluid can be measured with OCT testing (objective outcome), and macular thickening can be assessed with a clinical exam. According to the clinician group, improvement in vision, a reduction or resolution of macular edema, a regression in DRSS score, and a reduction in the frequency of treatment (4 months or longer between treatments) are considered clinically meaningful responses. Last, the clinician group said that response to treatment should be assessed at every clinical visit, which is determined by treatment need.

Discontinuing Treatment

The clinician group said that in the case of end-stage disease with significant atrophy, fibrosis, and/or no improvement despite regular treatments, discontinuation of faricimab should be considered.

Prescribing Conditions

The clinician group stated that ophthalmology offices in the community and/or hospital setting are appropriate for the administration of faricimab. The group added that an ophthalmologist is required to accurately diagnose, treat, and monitor patients being treated with faricimab.

Drug Program Input

Drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical expert consulted by CADTH are summarized in Table 4.

Clinical Evidence

The clinical evidence included in the review of faricimab is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review.

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of faricimab 6 mg/0.05 mL solution for IVT injection for the treatment of DME in adults.

Methods

Studies selected for inclusion in the systematic review will include pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Of note, the systematic review protocol was established before the granting of a Notice of Compliance from Health Canada.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; CRT = central retinal thickness; DME = diabetic macular edema; DR = diabetic retinopathy; DRS = diabetic retinopathy severity; DRSS = Diabetic Retinopathy Severity Scale; ETDRS = Early Treatment Diabetic Retinopathy Study; HRQoL = health-related quality of life; IRF = subretinal fluid. IVT = intravitreal; NEI VFQ-25 = National Eye Institute Visual Functioning Questionnaire-25; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; q.16.w. = every 16 weeks; RCT = randomized controlled trial; SAE = serious adverse event; SRF = subretinal fluid; VEGF = vascular endothelial growth factor; WDAE = withdrawal due to adverse event.

^aOff-label treatment. No Health Canada–approved indication for the treatment of DME.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy, according to the PRESS Peer Review of Electronic Search Strategies checklist.⁴²

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was faricimab. The following clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on April 20, 2022. Regular alerts updated the search until the meeting of the CADTH CDEC on August 24, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature resource.⁴³ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

A total of 7 reports^9-12,44-46 presenting data from 2 unique studies (YOSEMITE and RHINE) were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

Two studies were included in the systematic review: YOSEMITE and RHINE.⁴⁶ They were identically designed phase III, multi-centre, randomized, double-blind, active-controlled, noninferiority trials that aimed to evaluate the efficacy, safety, durability, and pharmacokinetics of faricimab compared with aflibercept in patients with DME (both treatment-naive and previously treated with an anti-VEGF). There were 2 treatment arms for faricimab with different administration schedules. Both studies were funded by Hoffmann-La Roche.

YOSEMITE (N = 940) was conducted at 179 sites in 16 countries (Canada not included) and RHINE (N = 951) was conducted at 174 sites in 24 countries (and included 10 Canadian sites). Both trials consisted of screening period of up to 28 days (days –28 to –1), followed by a 100-week double-blind phase. During the screening phase, patients were assessed for study eligibility based on pre-specified inclusion and exclusion criteria. Patients who failed an initial screening could be eligible for re-screening up to 2 additional times during the study’s enrolment period. On day 1 of the double-blind phase, eligible patients were assigned a randomization identification number by an Interactive Voice/Web Response System, then randomized on a 1:1:1 basis to 1 of 3 treatment arms: 6 mg IVT faricimab injections every 4 weeks to week 20, followed by 6 mg IVT faricimab injections every 8 weeks; 6 mg IVT faricimab injections every 4 weeks to at least week 12, followed by PTI dosing; 2 mg IVT aflibercept injections every 4 weeks to week 16, followed by 2 mg IVT aflibercept injections every 8 weeks. Randomization was stratified by 3 baseline factors: baseline BCVA ETDRS letter score (64 letters or better versus 63 letters or worse); prior IVT anti-VEGF therapy (yes or no); and region (US and Canada, Asia, and the rest of the world). Patients in all arms received the assigned treatment up to and including week 96 and returned for a final visit at week 100 in the double-masked period. Study visits occurred every 4 weeks until the end of the study period in both studies. Patients in all arms received a sham procedure at study visits when they were not receiving treatment with either faricimab or aflibercept. The study design of both studies is illustrated in Figure 2. The data cut-off for the primary end point analysis at year 1 was October 20, 2020, for YOSEMITE and October 19, 2020, for RHINE. For the 2-year results, the last patient visit was September 3, 2021, for YOSEMITE and August 27, 2021, for RHINE.

Figure 2: Study Design Schematic for YOSEMITE and RHINE

IVT = intravitreal; q.8.w. = every 8 weeks; PTI = personalized treatment interval (every 4 weeks to up to every 16 weeks); q.8.w. = every 8 weeks; RO687461 = faricimab; W = week.

^aThe definition of 1 year used for the primary efficacy end point (the change from baseline in BCVA, as measured on the ETDRS chart at a starting distance of 4 m at 1 year) is the average of week 48, 52, and 56 visits.

Sources: YOSEMITE Clinical Study Report,⁹ RHINE Clinical Study Report.¹¹

Populations

Inclusion and Exclusion Criteria

The key inclusion criteria for both studies included macular thickening secondary to DME involving the centre of the fovea (CST ≥ 325 µm on Spectralis SD-OCT or ≥ 315 µm on Cirrus SD-OCT or Topcon SD-OCT) in patients 18 years and older; current use of oral or injectable antidiabetic medication for the treatment of type 1 or type 2 diabetes, with a hemoglobin A1C level of 10% or less; and BCVA scores of 73 to 25 letters using the ETDRS protocol (20/40 to 20/320 Snellen equivalent). Patients could have been previously treated with an anti-VEGF in the study eye or could be treatment-naive. Enrolment of participants with anti-VEGF experience was capped at a maximum 25%. Key exclusion criteria were untreated diabetes, uncontrolled blood pressure, stroke or myocardial infarction in the previous 6 months, high-risk PDR in the study eye, use of medicated intraocular implants in the previous 6 months, any previous use of Iluvien implants, PRP, or macular laser treatment in the previous 3 months, and concurrent ocular conditions that could affect vision in the study eye. The key inclusion and exclusion criteria for the 2 trials are shown Table 6. Only 1 eye was assigned as the study eye in the studies. If both eyes were eligible, the eye with the worst BCVA at baseline was selected (unless the other eye was deemed by investigators to be more suitable for treatment).

Baseline Characteristics

A summary of baseline characteristics of the ITT population in both studies is shown in Table 7. The baseline demographic and ocular characteristics of patients were, overall, balanced in the treatment arms within each study. The baseline characteristics were generally similar across the studies, except months since DME diagnosis was shorter in YOSEMITE than in RHINE (median [minimum to maximum] months = 3.1 [0 to 304] months and 6.6 [0 to 380] months, respectively) and baseline CST was slightly higher in YOSEMITE than in RHINE (mean [standard deviation] = 487.5 [132.5] µm and 471.6 [125.3] µm, respectively). In both studies, patients had a median age of 62 to 64 years and the majority were male (> 57%) and White (> 76%). Macular ischemia (nonperfusion) was present at baseline in more than 1-third of patients (37% to 43%), and most patients had macular leakage (> 93%). At the start of the studies, most patients (approximately 70% to 75%) had a diabetic retinopathy severity (DRS) level of 35 to 47 (mild to moderately severe nonproliferative DR), with mean baseline BCVA scores of around 62 letters. Slightly more than 1 in 5 patients had been previously treated with an anti-VEGF (20.4% in RHINE; 22.9% in YOSEMITE).

Table 7: Summary of Baseline Characteristics in the YOSEMITE and RHINE Trials (ITT Population)

BCVA = best corrected visual acuity; CST = central subfield thickness; DME = diabetic macular edema; DR = diabetic retinopathy; DRS = diabetic retinopathy severity; ILM-BM = distance between internal limiting membrane and Bruch's membrane; ITT = intent-to-treat; NPDR = nonproliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy; PRP = panretinal photocoagulation; PTI = personalized treatment interval (from every 4 weeks up to every 16 weeks); q.8.w. = every 8 weeks; SD = standard deviation; VEGF = vascular endothelial growth factor.

Note: Baseline is the last available value taken on or before randomization.

Sources: YOSEMITE Clinical Study Report,⁹ RHINE Clinical Study Report.¹¹

Interventions

In the YOSEMITE and RHINE studies, eligible patients were randomized in a 1:1:1 ratio to 1 of 3 treatment arms — faricimab 6 mg every 8 weeks, faricimab 6 mg PTI, or aflibercept 2 mg every 8 weeks — for a duration of 100 weeks.

In the 8-week faricimab arm, patients received faricimab 6 mg intravitreally every 4 weeks for 6 loading doses (day 1, week 4, week 8, week 12, week 16, week 20), followed by 9 maintenance injections of faricimab 6 mg IVT every 8 weeks to week 96, with a final study visit at week 100.

In the PTI faricimab arm, patients received faricimab 6 mg intravitreally every 4 weeks for 4 loading doses (day 1, week 4, week 8, and week 12) or until CST met the predefined reference threshold (CST < 325 µm for Spectralis SD-OCT or < 315 µm for Cirrus SD-OCT or Topcon SD-OCT), after which a PTI was used until week 96, with a final visit at week 100. Once a patient’s initial reference CST was established, their study drug dosing interval was increased by 4 weeks, to an initial 8-week dosing interval. From that point forward, the study drug dosing interval was extended, reduced, or maintained based on assessments made at study drug dosing visits. Adjustments to the study drug dosing interval were made in 4-week increments to a maximum of 16 weeks and a minimum of 4 weeks. These decisions on the treatment interval were made through an Interactive Voice/Web Response System, which automatically calculated dosing intervals according to a pre-established algorithm (refer to Figure 3). The algorithm’s criteria were based on relative change in CST and BCVA, compared with reference CST and reference BCVA, as follows:

Interval extended by 4 weeks:

• if the CST value increased or decreased by no more than 10% without an associated BCVA decrease 10 letters or more

Interval maintained:

• if the CST value decreased by more than 10%, or

• if the CST value increased or decreased by 10% or less with an associated BCVA decrease of 10 letters or more, or

• if the CST value increased by more than 10% to 20% or less without an associated BCVA decrease of 5 letters or more

Interval reduced by 4 weeks:

• if the CST value increased by more than 10% to 20% or less with an associated BCVA decrease of 5 letters or more to fewer than 10 letters, or

• if the CST value increased by more than 20% without an associated BCVA decrease of 10 letters or more

Interval reduced by 8 weeks:

• if the CST value increased by more than 10% with an associated BCVA decrease of 10 letters or more

In the aflibercept arm, patients received aflibercept 2 mg intravitreally every 4 weeks for 5 loading doses (day 1, week 4, week 8, week 12, week 16), followed by 10 maintenance injections of 2 mg at a fixed interval of every 8 weeks until week 96, with a final visit at week 100.

Patients in all 3 treatment arms completed scheduled study visits every 4 weeks for the duration of the study. A sham procedure, which involved a needle-less syringe being pressed against the anesthetized eye to mimic an IVT injection, was performed on patients in all treatment arms at study visits when no treatment was scheduled to preserve masking.

Treatment assignments were masked to all patients, assessors, and investigators, but not to treatment administrators.

Patients were permitted to continue using maintenance therapies (e.g., treatments for glaucoma, ocular hypertension, cataracts, or PRP for the treatment of DR). Treatment of the nonstudy eye with an anti-VEGF therapy licensed for ocular use was also permitted. The following therapies were prohibited during both studies: systemic anti-VEGF therapy; systemic drugs known to cause macular edema (fingolimod, tamoxifen); IVT anti-VEGF drugs in the study eye (other than the assigned study intervention); IVT, periocular (subtenon), steroid implants (i.e., Ozurdex, Iluvien) and chronic topical (ocular) corticosteroids in the study eye; treatment with verteporfin (Visudyne) in the study eye; administration of micropulse and focal or grid laser in the study eye; and other experimental therapies (except vitamins and minerals).

Figure 3: Algorithm for IxRS-Determined PTI Study Drug Dosing

BCVA = best corrected visual acuity; CST = central subfield thickness; IxRS = Interactive Voice/Web Response System; PTI = personalized treatment interval (every 4 weeks up to every 16 weeks).

* Reference CST is the CST value when the initial CST threshold criteria are met. Reference CST was adjusted if CST decreased by > 10% from the previous reference CST at 2 consecutive study drug dosing visits and the values obtained were within 30 µm. The CST value obtained at the latter visit served as the new reference CST, starting immediately at that visit.

** Reference BCVA is the mean of the 3 best BCVA scores obtained at any prior study drug dosing visit.

Sources: YOSEMITE Clinical Study Report,⁹ RHINE Clinical Study Report.¹¹

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 8. These end points are further summarized in the text that follows the table. A detailed discussion and critical appraisal of the outcome measures are provided in Appendix 4.

Table 8: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

AE = adverse event; BCVA = best corrected visual acuity; CRT = central retinal thickness; CST = central subfield thickness; DME = diabetic macular edema; DRS = diabetic retinopathy severity; DRSS = Diabetic Retinopathy Severity Scale; ETDRS = Early Treatment Diabetic Retinopathy Study; HRQoL = health-related quality of life; IRF = subretinal fluid; NEI VFQ-25 = National Eye Institute Visual Functioning Questionnaire-25; PDR = proliferative diabetic retinopathy; PRP = panretinal photocoagulation; PTI = personalized treatment interval (from every 4 weeks up to every 16 weeks); q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; q.12.w. = every 12 weeks; q.16.w. = every 16 weeks; SAE = serious adverse events; SD-OCT = spectral-domain optical coherence tomography; SRF = subretinal fluid; WDAE = withdrawal due to adverse event.

Note: Only outcomes pre-specified in the protocol are included in this table.

Sources: YOSEMITE Clinical Study Report,⁹ RHINE Clinical Study Report.¹¹

Efficacy Outcomes

Change From Baseline in Visual Acuity

The change from baseline in BCVA (ETDRS letters) averaged over weeks 48, 52, and 56 was the primary end point in both studies. Secondary end points of visual acuity change included the proportion of patients gaining greater than or equal to 15, 10, 5, or 0 ETDRS letters in BCVA from baseline; the proportion of patients avoiding a loss of greater than or equal to 15, 10, or 5 ETDRS letters in BCVA from baseline averaged over weeks 48, 52, and 56. These outcomes were also assessed over time (i.e., at all assessment time points through week 100). The proportion of patients gaining greater or equal to 15 letters or achieving BCVA of greater or equal 84 letters over time and the proportion of patients with a BCVA Snellen equivalent of 20/40 or better were assessed at similar time points.

The BCVA score was measured with the ETDRS visual acuity chart at a starting distance of 4 m. The ETDRS charts consist of 70 letters distributed across 14 rows. Each row contains a series of 5 letters of equal difficulty, with standardized spacing between letters and rows. The level of difficulty increases with successive rows as the size of the characters decreases. The BCVA score corresponds to the number of letters a person can read from the ETDRS chart. The maximum score is 100. Reading more lines (i.e., more letters) indicates better visual acuity.⁴⁷ Generally, 2 to 3 lines (10 to 15 letters) is considered a clinically important difference.^48,49 The FDA has recommended a mean change of 15 letters or more on an ETDRS chart or a statistically significant difference in the proportion of patients with a change in visual acuity of at least 15 letters as clinically relevant outcome measures in trials of interventions for macular edema.^50,51 For more information regarding the ETDRS, refer to Appendix 4.

ETDRS results can be converted to Snellen fractions, another common measure of visual acuity, in which the numerator indicates the distance at which the chart was read and the denominator indicates the distance at which a person can discern letters of a particular size. A larger denominator indicates worse vision. For example, a person with 20/100 vision can read letters at 20 feet that a person with 20/20 vision can read at 100 feet.⁵²

Change in CRT

Retinal thickness was measured using OCT of the study eye. The change from baseline in CST averaged over weeks 48, 52, and 56 was a secondary outcome in both studies. CST was measured as the distance between the internal limiting membrane and Bruch’s membrane (ILM-BM). The change from baseline in CST (ILM-BM) over time and the proportion of patients with an absence of DME (CST < 325 µm for Spectralis SD-OCT or < 315 µm for Cirrus SD-OCT or Topcon SD-OCT) averaged over weeks 48, 52, and 56 and over time were also reported as secondary outcomes. A reduction in CST is considered a favourable outcome in the treatment of DME; however, a minimal important difference (MID) has not been established. For more information on the use of OCT to measure changes in retinal thickness, refer to Appendix 4.

Frequency of Injection

The proportion of patients in the PTI faricimab arm at 4-, 8-, 12-, and 16-week treatment intervals at 1 year and 2 years, as well as the treatment intervals in this arm over time, were secondary outcomes of the studies.

HRQoL and Vision-Related Function

NEI VFQ-25

Both studies measured the change from baseline in NEI VFQ-25 composite score at week 52 (and over time) as a secondary end point. Additionally, change from baseline in the NEI VFQ-25 Near Activities, Distance Activities, and Driving subscales at year 1 (averaged over weeks 48, 52, and 56), as well as the proportion of patients with a greater or equal to 4-point improvement from baseline in the NEI VFQ-25 composite score at 1 year (averaged over weeks 48, 52, and 56), were assessed as exploratory end points. NEI VFQ-25 was administered masked site staff on day 1, week 24, week 52, and week 100 visits. NEI VFQ-25 is a questionnaire developed to measure vision-targeted quality of life. The questionnaire consists of 25 items relevant to 11 vision-related constructs and a single-item, general health component. The overall composite score ranges from 0 to 100, with 0 representing the worst vision-related function and 100 representing the best vision-related function. In addition, there are 12 subscale scores (e.g., near vision, distance vision, driving). The questionnaire has a reported MID of 3.3 to 6.13 points for the overall composite score. A psychometric validation study of the NEI VFQ-25 specifically in patients with DME showed that the MID for each NEI VFQ-25 domain ranged from 8.80 (general vision) to 14.40 (role difficulties) and produced a composite score MID of 6.13 points.⁵³ For more information on the properties of the NEI VFQ-25, refer to Appendix 4.

Minimum Vision Required for Driving

The visual acuity eligibility standard for obtaining a noncommercial driving licence in Canada is defined by the Canadian Council of Motor Transport Administrators as BCVA not less than 20/50 (6/15) with both eyes open and examined together.⁵⁴ The proportion of patients meeting or not meeting this visual acuity standard needed for driving was not assessed in the included studies as an outcome. However, a corresponding minimal BCVA required for driver licencing used in most regions of the US (i.e., visual acuity not less than 20/40)⁵⁵ was assessed. The proportion of patients with a BCVA Snellen equivalent of 20/40 or worse over time was measured in both studies as a secondary outcome.

Blindness (Legal)

Legal blindness is defined as a BCVA of 20/200 or less in both eyes measured with a Snellen chart and/or a visual field of 20 degrees or narrower.⁵⁶ The proportion of patients with a BCVA Snellen equivalent of 20/200 or worse averaged over weeks 48, 52, and 56 (and over time) was measured in both studies as a secondary outcome.

Presence of IRF and/or SRF

The proportion of patients with an absence of IRF and/or with an absence of SRF at week 52 and over time were measured as secondary end points. SRF and IRF specifically in the central subfield (within the 1 mm diameter centre of the macula) were of interest.

Change From Baseline in DRS

The proportion of patients with an improvement in DRS of 2 steps or more from baseline on the ETDRS DRSS at week 52 was the key secondary end point in both studies. Other end points included an improvement of 2 steps or more or at least 3 steps (secondary) or worsening (exploratory) from baseline over time on the ETDRS DRSS. The ETDRS DRSS is a scale that consists of 13 levels of graded photographic characteristics defined to categorize the severity of DR for individual eyes, ranging from no retinopathy to severe vitreous hemorrhage. Higher scores on the scale indicate worsening of DR. Each of the 13 levels on the scale is defined by a set of criteria based on presence and/or severity of abnormalities, rated from 10 to 85 in order of increasing severity. Step progression refers to an increase in photographic level that can be used to describe change (improvement or worsening) in DR over time.^57,58 In the ETDRS, the proportion of eyes with progression of 2 or more levels at follow-up was relatively similar among all severity categories at the 1-year follow-up time point, establishing 2-step progression as a reasonable outcome measure for all baseline retinopathy levels.⁵⁷ An improvement of 3 or more steps is associated with a clinically meaningful improvement of 15 ETDRS letters in visual acuity and has been accepted by the FDA as an efficacy end point for the assessment of improvement in DR.⁵⁹ For more information regarding the DRSS, refer to Appendix 4.

Other outcomes related to DRS included the proportion of patients who develop new PDR at week 52 and over time (secondary outcome), defined as the achievement of an ETDRS DRSS score of 61 or greater in the assessment of 7-field colour fundus photography images using only people without PDR at baseline (DRSS score of 53 or better), and the proportion of patients who received vitrectomy or PRP over time during the study (exploratory outcomes).

Harms Outcomes

The safety analysis included the incidence and severity of ocular and nonocular AEs that occurring during the study period. The occurrence of AEs was assessed at all assessment time points.

Statistical Analysis

Noninferiority Margin

In the YOSEMITE and RHINE studies, a noninferiority margin of 4 ETDRS letters was used in the primary outcome analysis, where noninferiority would be demonstrated if the lower limit of the 97.5% CI of the difference in change in adjusted mean BCVA from baseline between the faricimab arms (8-week and PTI) and the active comparator (aflibercept) was greater than –4 ETDRS letters. The noninferiority margin of 4 ETDRS letters was selected based on data from the VISTA and VIVID trials, which compared aflibercept with laser control in patients with DME. A margin of 4 ETDRS letters represents approximately 50% of the least estimated benefit of aflibercept over laser control at week 52 in the VISTA study (10.7 letters for aflibercept versus 0.2 for control) and the VIVID study (10.7 letters for aflibercept versus 1.2 for control). The investigators also considered that a loss of 5 letters (1 ETDRS line) between treatments is generally clinically relevant, and therefore inferred that the noninferiority margin of 4 ETDRS letters, being smaller than a loss of 5 letters, would be small enough to allow the conclusion that the new treatment is not inferior to active control to an unacceptable extent. If the noninferiority of faricimab (8-week or PTI) to aflibercept for the primary end point was met in the ITT population, tests for superiority would be conducted, first in the treatment-naive population and then in the overall ITT population. Further details on the order of testing are provided in Figure 4.

In the key secondary efficacy analysis, a noninferiority margin of 10% was used, in which noninferiority would be demonstrated if the lower limit of the 97.5% CI for the difference in weighted proportions of patients with an improvement in DRS of at least 2 steps from baseline on the ETDRS DRSS between the treatment group (8-week or PTI faricimab) and the active comparator group (aflibercept) at week 52 was greater than –10%. No justification was provided for this noninferiority margin. In the case that noninferiority of faricimab (8-week or PTI) to aflibercept for the key secondary end point was met in the ITT population, tests for superiority would be conducted, first in the treatment-naive population, then in the overall ITT population.

Type I Error Control

The noninferiority and superiority hypotheses for the primary end point were tested at an overall significance level of alpha of 0.0496, using a graph-based testing procedure to control for the overall type I error rate. Pairwise comparisons between each dose of faricimab and aflibercept were conducted according to the testing procedure order illustrated in Figure 4. If the tests for 1 treatment sequence were all positive at the alpha/2 ( = 0.0248) level, then alpha/2 was propagated to the beginning of the other treatment sequence, which was tested at a significance level of alpha of 0.0496.

Sample Size Calculation

A sample size calculation determined that approximately 300 patients per treatment arm were required to demonstrate noninferiority between faricimab and aflibercept in the ITT population (using pairwise comparisons between the active comparator and each of the faricimab arms) with respect to the change in BCVA from baseline averaged over weeks 48, 52, and 56 at a 1-sided type I error rate of 1.25% with a power of 90% using a 2-sample t-test, assuming a noninferiority margin of 4 ETDRS letters, a standard deviation of ETDRS 11 letters, and a 10% dropout rate.

Figure 4: Graph-Based Testing Procedure for the Primary End Point

Sources: YOSEMITE Clinical Study Report,⁹ RHINE Clinical Study Report.¹¹

Statistical Analysis for Efficacy Outcomes

The primary outcome was change from baseline in BCVA averaged over weeks 48, 52, and 56. The primary analysis was based on the ITT population (and the treatment-naive population for the initial superiority test) and was performed using a mixed model for repeated measures (MMRM), which included the change from baseline at weeks 4 to 56 as the response variable and was adjusted for treatment group, visit, visit-by-treatment-group interaction, baseline BCVA (continuous), as well as randomization stratification factors as fixed effects (day 1 BCVA ETDRS letter score [64 letters or better versus 63 letters or worse], prior IVT anti-VEGF therapy [yes or no], and region [US and Canada, Asia, and the rest of the world]), assuming an unstructured covariance structure. In the primary estimand, ICEs not due to COVID-19 (study treatment discontinuation due to AEs or lack of efficacy, use of prohibited systemic treatment or therapy in the study eye) were handled using a treatment policy strategy where all observed values were used regardless of the occurrence of the ICE, whereas ICEs due to COVID-19 (study drug discontinuation, use of prohibited therapy, missed doses with a potentially major impact on efficacy, or death due to COVID-19) were handled with a hypothetical strategy in which all values were censored after the ICE. Missing data for continuous outcomes were implicitly imputed with the MMRM model, based on the assumption that data were missing at random (MAR). Nonstandard BCVA data (e.g., assessed by ETDRS BCVA testing with prior visit refraction, test performed by unmasked certified ETDRS BCVA assessor or by uncertified experienced ETDRS BCVA assessor) were excluded from the analyses.

Pre-specified subgroup analyses were conducted with respect to the primary end point and key secondary end point. Baseline BCVA subgroup (≥ 64 letters and ≤ 63 letters), prior IVT anti-VEGF therapy (yes and no), baseline DRS (< 47, 47 to 53 and > 53 ETDRS DRSS), and baseline hemoglobin A1C (≤ 8% and > 8%) were relevant to this review. Other subgroups identified as relevant to the systematic review in the protocol were not assessed in the studies, including history of ischemic (cerebrovascular or cardiovascular) disease, hypertension, dyslipidemia, and proliferative and nonproliferative DR.

A pre-specified sensitivity analysis was performed using the same estimand and analysis method as the primary analysis, except that a last observation carried forward imputation approach was used to account for missing BCVA data, as well as for BCVA assessments that were censored after COVID-19-related ICEs. Six supplementary analyses using the per-protocol population, a multiple imputation method, and different analysis methods (analysis of covariance, trimmed mean) and strategies for handling ICEs (treatment policy strategy only, hypothetical strategy only) were performed to further evaluate the robustness of the evidence from the primary analysis.

A summary of the statistical analyses of efficacy end points in both studies is shown in Table 9. The analysis for secondary outcomes assessed data in the ITT population (and the treatment-native population for the superiority test of the key secondary end point). Continuous secondary end points that were of interest in this review were analyzed using the same approach as the primary analysis, except that no sensitivity analysis was performed. Binary secondary end points that assessed the proportion of patients in each treatment group and the difference in proportion between treatment groups were calculated by applying Cochran-Mantel-Haenszel (CMH) weights and stratified by the following randomization stratification factors: day 1 BCVA ETDRS letter score (64 letters or better versus 63 letters or worse), prior IVT anti-VEGF therapy (yes versus no), and region (US and Canada, Asia, and the rest of the world). CIs for the proportion of patients in each treatment arm and the overall difference in proportions between treatment arms will be calculated using the normal approximation to the weighted proportions. Missing data were not imputed for secondary outcomes. Exploratory outcomes were analyzed using descriptive statistics (mean, standard deviation, median, and range for continuous end points, and counts and percentages for categorical end points).

Statistical Analysis for Harms Outcomes

The safety analysis was based on AEs recorded through week 100 and were summarized using descriptive statistics.

Table 9: Statistical Analysis of Efficacy End Points in the YOSEMITE and RHINE Trials

anti-VEGF = anti–vascular endothelial growth factor; BCVA = best corrected visual acuity; CMH = Cochran-Mantel-Haenszel; CST = central subfield thickness; DME = diabetic macular edema; DRS = diabetic retinopathy severity; DRSS = Diabetic Retinopathy Severity Scale; ETDRS = Early Treatment Diabetic Retinopathy Study; IRF = subretinal fluid; ITT = intention-to-treat; LOCF = last observation carried forward; MMRM = mixed-effect model repeated measure; NA = not applicable; NEI VFQ-25 = National Eye Institute Visual Function Questionnaire-25 ; PDR = proliferative diabetic retinopathy; PRP = panretinal photocoagulation; PTI = personalized treatment interval (from every 4 weeks up to every 16 weeks); q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; q.12.w. = every 12 weeks; q.16.w. = every 16 weeks; SD = standard deviation; SD-OCT = spectral-domain optical coherence tomography; SRF = subretinal fluid.

Sources: YOSEMITE Clinical Study Report,⁹ RHINE Clinical Study Report.¹¹

Analysis Populations

Results are reported for the ITT, treatment-naive, per-protocol, and safety-evaluable populations in YOSEMITE⁹ and RHINE.¹¹

ITT population: All patients who were randomized in the study were included. Patients were assessed according to the treatment assigned at randomization. This analysis population served as the primary analysis set for all efficacy analyses.

Treatment-naive population: All patients who were randomized in the study who had not received any IVT anti-VEGF drugs in the study eye before day 1 were included. For analyses based on this population, patients were grouped according to the treatment assigned at randomization. This population was used in the initial test of superiority of faricimab over aflibercept.

Per-protocol population: All patients randomized in the study who received at least 1 dose of study treatment and who did not have a major protocol violation that affected the efficacy evaluation or treatment interval determination were included. Patients were assessed according to the actual treatment received. If a patient received a combination of different active treatments (faricimab and aflibercept) in the study eye, the patient’s treatment group was assessed as randomized. This population was used for supplementary analysis of the primary efficacy end point.

Safety-evaluable population: All patients who received at least 1 injection of either faricimab or aflibercept in the study eye were included. Patients were assessed according to the actual treatment received. If a patient received a combination of different active treatments (faricimab and aflibercept) in the study eye, the patient’s treatment group was as randomized. This population was used for safety analyses.

For this review, noninferiority will be assessed using the results from both the ITT and per-protocol analyses.

Results

Patient Disposition

A summary of patient disposition is shown in Table 10.

Of the 1,532 patients screened in the YOSEMITE trial, 940 were randomized (315 patients in the 8-week faricimab arm, 313 patients in the PTI faricimab arm, and 312 patients in the aflibercept arm). Of the 1,715 patients screened in the RHINE trial, 951 were randomized (317 patients in the 8-week faricimab arm, 319 patients in the PTI faricimab arm, and 315 patients in the aflibercept arm). Both trials had a large percentage of patients who failed screening and were not randomized; 38.6% of patients failed to meet the eligibility criteria in YOSEMITE and 44.5% failed to meet the eligibility criteria in RHINE. In both trials, the main reasons for screening failure were not having a BCVA in the 73 to 25 letter, inclusive (20/40 to 20/320), range; having a concurrent exclusionary ocular diagnosis, such as tractional retinal detachment, pre-retinal fibrosis, or epiretinal membrane involving the fovea or disrupting the macular architecture in the study eye; and failing to meet the criterion for macular thickening secondary to DME involving the centre of the fovea.

In YOSEMITE, the proportion of patients who discontinued the study treatment before week 56 was comparable in the treatment arms (range = 8.4% to 9.9%), whereas in RHINE, the proportion was lower in the PTI faricimab arm (3.4%) than in both the 8-week faricimab arm (7.6%) and the aflibercept arm (6.1%). The proportion of patients who discontinued study treatment any time during the study had similar patterns. Withdrawal by the patient was the most frequently reported reason for discontinuation from study treatment in both studies (2.3% in YOSEMITE; 1.7% in RHINE).

Exposure to Study Treatments

The mean duration of exposure to the study treatment was similar among treatment arms in the 2 studies, and ranged from 52.9 weeks to 54.5 weeks at week 56, and from 87.6 weeks to 91.6 weeks at week 100. The number of injections administered through week 56 (reported in the safety-evaluable population) was somewhat lower, numerically, in the PTI faricimab arms than in the other treatment arms in both studies, with a median of 8 injections in the PTI faricimab arm and of 10 injections in the 8-week faricimab and aflibercept arms in both studies. During the 100-week study period, patients in the PTI faricimab arm had a median of 10 injections in YOSEMITE and 11 injections in RHINE, whereas patients in the 8-week faricimab and aflibercept arms had a median of 15 injections and 14 injections, respectively (Table 11).

The proportion of faricimab-treated patients on an injection interval of 4-, 8-, 12-, and 16-weeks at week 56 and week 96 was a secondary efficacy outcome of the studies. Refer to the efficacy section – frequency of injection and Table 12 for details.

Table 10: Patient Disposition

AE = adverse event; ITT = intention-to-treat; PTI = personalized treatment interval (from every 4 weeks up to every 16 weeks); q.8.w. = every 8 weeks.

^aAs randomized.

^bAs treated.

Sources: YOSEMITE Primary and Final Clinical Study Reports,^9,10 RHINE Primary and Updated Clinical Study Reports.^11,12

Table 11: Summary of Study Treatment Exposure in the Study Eye (Safety-Evaluable Population)

PTI = personalized treatment interval (from every 4 weeks up to every 16 weeks); q.8.w. = every 8 weeks; SD = standard deviation.

Sources: YOSEMITE Primary and Final Clinical Study Reports,^9,10 RHINE Primary and Updated Clinical Study Reports.^11,12

Table 12: BCVA Outcomes

BCVA = best corrected visual acuity; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; ETDRS = Early Treatment Diabetic Retinopathy Study; ITT = intention-to-treat; MMRM = mixed model repeated measures; PTI = personalized treatment interval (from every 4 weeks up to every 16 weeks); q.8.w. = every 8 weeks; SE = standard error.

^aAdjusted mean. The primary end point was analyzed using MMRM, with the change from baseline in BCVA as the dependent variable. The model was adjusted for categorical covariates of treatment group, visit, visit-by-treatment-group interaction, baseline BCVA (continuous), as well as randomization stratification factors as fixed effects (day 1 BCVA ETDRS letter score [64 letters or better vs. 63 letters or worse], prior IVT anti-VEGF therapy [yes vs. no], and region [US and Canada, Asia, and the rest of the world]).

^bP value estimate was not adjusted for multiple testing. It does not account for the failure to meet superiority in previous testing in the treatment-naive population.

^cCMH weighted estimate. The observed proportions and the differences in observed proportions were obtained by applying CMH weight, stratified by randomization stratification factors: day 1 BCVA ETDRS letter score (64 letters or better vs. 63 letters or worse), prior IVT anti-VEGF therapy (yes vs. no), and region (US and Canada, Asia, and the rest of the world).

Sources: YOSEMITE Primary and Final Clinical Study Reports,^9,10 RHINE Primary and Updated Clinical Study Reports.^11,12

Efficacy

Only efficacy outcomes and analyses of subgroups identified in the review protocol are reported here. Refer to Appendix 3 for further details on efficacy data.

Change From Baseline in Visual Acuity

Change From Baseline in BCVA (Primary End Point)

For the change from baseline in BCVA averaged over weeks 48, 52, and 56, the mean difference in ETDRS letters between the 8-week faricimab arm and the aflibercept arm was –0.2 (97.5% CI, –2.0 to 1.6) letters and between the PTI faricimab arm and the aflibercept arm was 0.7 (97.5% CI, –1.1 to 2.5) letters in YOSEMITE, and in RHINE was 1.5 (97.5% CI, –0.1 to 3.2) letters and 0.5 (97.5% CI, –1.1 to 2.1) letters, respectively (Table 12), both of which met the primary end point of noninferiority (ITT population). Superiority for the primary end point was not met in either study; the mean change from baseline in BCVA averaged over weeks 48, 52, and 56 in the 8-week faricimab arm was not superior to that in the aflibercept arm, nor was the mean change in the PTI faricimab arm.

Similar results were found in the analysis of the treatment-naive population (Table 12). Results of a supplementary analysis of the per-protocol population aligned with the ITT analysis (Table 12). Results of the sensitivity analysis and other supplementary analyses were also consistent with the primary analysis (Table 31 in Appendix 3).

Pre-specified subgroup analyses for baseline BCVA (≥ 64 ETDRS letters and ≤ 63 ETDRS letters), baseline hemoglobin A1C (≤ 8% and > 8%), prior anti-VEGF use (yes or no), and baseline DRS (< 47, 47 to 53, and > 53 ETDRS DRSS) were mostly consistent with overall study population results for the change from baseline BCVA averaged over weeks 48, 52, and 56 between the faricimab arms (8-week and PTI) and the aflibercept arm, as outlined in Table 32, Table 33, Table 34, and Table 35 in Appendix 3. However, in the subgroup of patients with hemoglobin A1C levels above 8% for the mean difference in ETDRS letters between the 8-week faricimab arm and the aflibercept arm, the lower bound of the 95% CI extended beyond the noninferiority threshold in the YOSEMITE study (–1.7 [95% CI, –5.0 to 1.5] letters) (Table 33).

Changes from baseline in BCVA were comparable in the 2 faricimab arms (8-week and PTI) and the aflibercept arm through week 100 in both studies, as shown in Figure 11 and Figure 12 in Appendix 3. For the change from baseline BCVA averaged over weeks 92, 96, and 100, the mean difference in ETDRS letters between the 8-week faricimab arm and the aflibercept arm was –0.7 (95% CI, –2.6 to 1.2) letters and between the PTI faricimab arm and the aflibercept arm was –0.7 (95% CI, –2.5 to 1.2) letters in YOSEMITE; in RHINE, the mean differences were 1.5 (95% CI, –0.5 to 3.6) letters and 0.7 (95% CI, –1.3 to 2.7) letters, respectively (Table 12).

Proportion of Patients Gaining or Avoiding Loss of 15, 10, 5, or 0 ETDRS Letters or more in BCVA From Baseline

The between-group differences in the adjusted proportion of patients who gained 15 or more ETDRS letters in BCVA from baseline over weeks 48, 52, and 56 between the 8-week faricimab arm and the aflibercept arm was –2.6% (95% CI, –0.0% to 4.9%) and between the PTI faricimab arm and the aflibercept arm was 3.5% (95% CI, –4.0% to 11.1%) in YOSEMITE; in RHINE, the differences were 3.5% (95% CI, –4.0% to 11.1%) and –2.0% (95% CI, –9.1% to 5.2%), respectively (Table 12).

Most patients (> 95%) across treatment arms avoided a loss of 15 or more ETDRS letters in BCVA from baseline during the studies. The between-group differences in the adjusted proportion of patients who avoided a loss of 15 or more ETDRS letters in BCVA from baseline over weeks 48, 52, and 56 between the 8-week faricimab arm and the aflibercept arm was –0.8% (95% CI, –2.8% to 1.3%) and between the PTI faricimab arm and the aflibercept arm was –0.3% (95% CI, –2.2% to 1.5%) in YOSEMITE; in RHINE, the differences were 0.3% (95% CI, –1.6% to 2.1%) and 0.0% (95% CI, –1.8% to 1.9%), respectively (Table 12).

Comparable results were seen in all 3 treatment arms for patients gaining 10 or more, 5 or more, or more than 0 letters in BCVA from baseline, and for patients avoiding a loss of 10 or more or 5 or more letters in both studies (Table 12).

Proportion of Patients Gaining 15 or More ETDRS Letters in BCVA or Achieving a BCVA Snellen Equivalent of 20/20 or Better From Baseline

Results for the proportion of patients either gaining 15 or more letters or achieving a BCVA Snellen equivalent of 20/20 or better (BCVA ≥ 84 letters) were also comparable across treatment arms in both studies (Table 12).

Results at year 2 were mostly consistent with those at year 1 for the BCVA outcomes (Table 12 and, in Appendix 3, Table 36, Figure 11, and Figure 12), except in RHINE, the adjusted proportion of patients who gained at least 15 ETDRS letters in BCVA from baseline was numerically lower in the PTI faricimab arm than in the aflibercept arm (–8.0%; 95% CI, –15.7% to –0.3%), and the proportion of patients who gained at least 15 ETDRS letters in BCVA or achieved a BCVA Snellen equivalent of 20/20 or better from baseline averaged over weeks 92, 96, and 100 was numerically lower in the faricimab PTI arm than in the aflibercept arm (–9.0%; 95% CI, –16.8% to –1.1%) (Table 36 in Appendix 3).

Change in CRT

Change in CST From Baseline

In both YOSEMITE and RHINE, reductions in CST (ILM-BM) from baseline to weeks 48, 52, and 56 were numerically greater in the faricimab arms (8-week and PTI) than in the aflibercept arm. The difference in the adjusted mean change from baseline in CST averaged over weeks 48, 52, and 56 between the 8-week faricimab arm and the aflibercept arm was –36.2 µm (95% CI, –47.8 µm to –24.7 µm) and between the PTI faricimab arm and the aflibercept arm was –26.2 µm (95% CI, –37.7 µm to –14.7 µm) in YOSEMITE; in RHINE, the differences were –25.7 µm (95% CI, –37.4 µm to –14.0 µm) and –17.6 µm (95% CI, –29.2 µm to –6.0 µm), respectively (Table 13). These differences between each faricimab treatment arm and the aflibercept arm were smaller at year 2 (Table 13).

Absence of DME (CST < 325 µm)

The proportion of patients with an absence of DME (CST < 325 µm for Spectralis SD-OCT) averaged over weeks 48, 52, and 56 was numerically higher in the 8-week faricimab arm than in the aflibercept arm, with a difference in the adjusted proportion of 16.0% (95% CI, 8.9% to 23.1%), and in the PTI faricimab arm than in the aflibercept arm, with a difference in the adjusted proportion of 12.7% (95% CI, 5.4% to 20.0%) in YOSEMITE; in RHINE, the differences were 12.3% (95% CI, 5.7% to 18.9%) and 8.2% (95% CI, 1.5% to 14.9%), respectively. These differences in the proportion of patients with an absence of DME between the faricimab treatment arms and the aflibercept arm were smaller at year 2 (Table 13).

Frequency of Injection

In YOSEMITE, the proportion of patients in the faricimab PTI arm on a 4-, 8-, 12-, and 16-week treatment interval at week 52, a secondary outcome, was 10.8%, 15.4%, 21.0%, and 52.8%, respectively; in RHINE, the proportions were 13.3%, 15.6%, 20.1%, and 51.0%, respectively (Table 14). An analysis of the number of patients in the PTI faricimab arm on 4-, 8-, 12-, and 16-week dosing at each monthly visit through week 52, prepared by FDA statistical reviewers, is presented in Figure 13 in Appendix 3.

Table 13: Change From Baseline in CST (ILM-BM) at 1 and 2 Years (ITT Population)

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; CST = central subfield thickness; DME = diabetic macular edema; ILM-BM = distance between internal limiting membrane and Bruch's membrane; ITT = intention-to-treat; MMRM = mixed model repeated measures; PTI = personalized treatment interval (from every 4 weeks up to every 16 weeks); q.8.w. = every 8 weeks; SE = standard error.

Note: Bolded numbers indicate that the 95% CI excludes the null value.

^aAdjusted mean. The primary end point was analyzed using MMRM, with the change from baseline in BCVA as the dependent variable. The model was adjusted for categorical covariates of treatment group, visit, visit-by-treatment-group interaction, baseline BCVA (continuous), as well as randomization stratification factors as fixed effects (day 1 BCVA ETDRS letter score [64 letters or better vs. 63 letters or worse], prior IVT anti-VEGF therapy [yes vs. no], and region [US and Canada, Asia, and the rest of the world]).

^bCMH weighted estimate. The observed proportions and the differences in observed proportions were obtained by applying CMH weight, stratified by randomization stratification factors: day 1 BCVA ETDRS letter score (64 letters or better vs. 63 letters or worse), prior IVT anti-VEGF therapy (yes vs. no), and region (US and Canada, Asia, and the rest of the world).

Sources: YOSEMITE Primary and Final Clinical Study Reports,^9,10 RHINE Primary and Updated Clinical Study Reports.^11,12

Table 14: Frequency of Injection Outcomes (ITT Population)

CI = confidence interval; ITT = intention-to-treat; PTI = personalized treatment interval (from every 4 weeks up to every 16 weeks); q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; q.12.w. = every 12 weeks; q.16.w. = every 16 weeks.

Sources: YOSEMITE Primary and Final Clinical Study Reports,^9,10 RHINE Primary and Updated Clinical Study Reports.^11,12

At week 96, the proportion of patients in the PTI faricimab arm on a 4-, 8-, 12-, and 16-week treatment interval was 7.0%, 14.8%, 18.1%, and 60.0%, respectively, in YOSEMITE; in RHINE, the proportions were 10.1%, 11.8%, 13.6%, and 64.5%, respectively (Table 14).

Results are descriptive and between-group analyses were not reported in either study.

HRQoL and Vision-Related Function

Change From Baseline in NEI VFQ-25 Composite Score

Mean changes from baseline in the NEI VFQ-25 composite score at week 24, week 52, and week 100 were comparable in all treatment arms in both studies (Table 15). At week 52, the difference in the adjusted mean change from baseline in NEI VFQ-25 composite score between the 8-week faricimab arm and the aflibercept arm was –0.2 (95% CI, –2.1 to 1.7) points and between the PTI faricimab arm and the aflibercept arm was 0.5 (95% CI, –1.5 to 2.4) points in YOSEMITE; in RHINE, the differences were –0.8 (95% CI, –2.7 to 1.1) points and –1.0 (95% CI, –2.9 to 0.8) points, respectively (Table 15).

Proportion of Patients With a 4-Point or More Improvement From Baseline in NEI VFQ-25 Composite Score

The proportion of patients with an improvement of 4 points or more from baseline in NEI VFQ-25 composite score was an exploratory outcome and only descriptive results were reported. As summarized in Table 15 at week 24, around half of the patients (from 46.0% to 52.5% per arm) in all treatment groups had an improvement of 4 points or more from baseline in NEI VFQ-25 composite score in both studies.

Change From Baseline in the NEI VFQ-25 Near Activities, Distance Activities, and Driving Subscales Over Time

Change from baseline in the NEI VFQ-25 Near Activities, Distance Activities, and Driving Subscales over time was an exploratory outcome and results were only analyzed descriptively. Generally, the descriptive results for the subscales were consistent with findings for the NEI VFQ-25 composite score and are not presented in this report.

Proportion of Patients With a BCVA Snellen Equivalent of 20/40 or Better (Vision Standard for Driving in Most US States)

In both studies, a comparable proportion of patients had a BCVA Snellen equivalent of 20/40 or better (BCVA ≥ 69 letters) averaged at week 48, 52, and 56, with a difference in the adjusted proportion between the 8-week faricimab arm and the aflibercept arm of –3.2% (95% CI, –10.2% to 3.8%) and a difference between the PTI faricimab arm and the aflibercept arm of 2.4% (95% CI, –4.3% to 9.2%) in YOSEMITE; in RHINE, the differences were 4.7% (95% CI, –2.4% to 11.8%) and 2.8% (95% CI, –4.1% to 9.8%), respectively (Table 15). Results at weeks 92, 96, and 100 were consistent with year 1 results (Table 15).

Proportion of Patients With a BCVA Snellen Equivalent of 20/200 or Worse (Legal Blindness)

The number of patients progressing to legal blindness (BCVA Snellen equivalent of 20/200 or worse [BCVA ETDRS ≤ 38 letters]) was small in all treatment arms in both studies (between 0 and 6 patients per arm), and the difference in the proportion of patients who progressed to legal blindness or worse was small (< 1%) between each faricimab arm and the aflibercept arm in both studies at 1 and 2 years (Table 15).

Table 15: NEI VFQ-25 and Other Vision Function Outcomes (ITT Population)

BCVA = best corrected visual acuity; CI = confidence interval; ETDRS = Early Treatment Diabetic Retinopathy Study; ITT = intention-to-treat; NEI VFQ-25 = National Eye Institute Visual Functioning Questionnaire-25; PTI = personalized treatment interval (from every 4 weeks up to every 16 weeks); q.8.w. = every 8 weeks; SE = standard error.

^aAdjusted mean. The primary end point was analyzed using MMRM, with the change from baseline in BCVA as the dependent variable. The model was adjusted for categorical covariates of treatment group, visit, visit-by-treatment-group interaction, baseline BCVA (continuous), as well as randomization stratification factors as fixed effects (day 1 BCVA ETDRS letter score [64 letters or better vs. 63 letters or worse], prior IVT anti-VEGF therapy [yes vs. no], and region [US and Canada, Asia, and the rest of the world]).

^bCMH weighted estimate. The differences in observed proportions were obtained by applying CMH weight, stratified by randomization stratification factors: day 1 BCVA ETDRS letter score (64 letters or better vs. 63 letters or worse), prior IVT anti-VEGF therapy (yes vs. no), and region (US and Canada, Asia, and the rest of the world).

Sources: YOSEMITE Primary and Final Clinical Study Reports,^9,10 RHINE Primary and Updated Clinical Study Reports.^11,12

Intraretinal Fluid and/or Subretinal Fluid

Absence of IRF

Over the course of both studies, the proportion of patients with an absence of IRF in the ETDRS central subfield was numerically higher in the 8-week faricimab arm than in the aflibercept arm, with a difference in the adjusted proportion of 16.6% (95% CI, 8.7% to 24.5%) at week 52 and of 23.8% (95% CI, 15.1% to 32.4%) at week 100 in YOSEMITE; in RHINE, the differences were 10.7% (95% CI, 2.8% to 18.6%) at week 52 and 11.6% (95% CI, 2.7% to 20.4%) at week 100. The differences in the adjusted proportion of patients with an absence of IRF between the PTI faricimab arm and aflibercept arm were less pronounced, at 13.4% (95% CI, 5.4% to 21.3%) at week 52 and 6.9% (95% CI, –1.7% to 15.5%) at week 100 in YOSEMITE; in RHINE, the differences were 7.2% (95% CI, –0.5% to 14.9%) at week 52 and 7.0% (95% CI, –1.7% to 15.8%) at week 100 (Table 16).

Absence of SRF

In both studies, the proportion of patients with an absence of SRF in the ETDRS central subfield from baseline through week 100 was comparable in the 8-week faricimab arm, the PTI faricimab arm, and the aflibercept arm. At week 52, the difference in the adjusted proportion in patients without SRF between the 8-week faricimab arm and the aflibercept arm was –2.2% (95% CI, –5.2% to 0.8%) and between the PTI faricimab arm and the aflibercept arm was –2.5% (95% CI, –5.6% to 0.5%) in YOSEMITE; in RHINE, the differences were –3.1% (95% CI, –6.3% to 0.1%) and –2.0% (95% CI, –4.9% to 0.9%), respectively (Table 16).

Given the inconsistency between the results for absence of IRF and the results for absence of SRF individually, the proportion of patients with an absence of both IRF and SRF is not presented here.

Table 16: Proportion of Patients With an Absence of IRF or SRF Over Time (ITT Population, CMH Method)

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; IRF = intraretinal fluid; ITT = intention-to-treat; PTI = personalized treatment interval (from every 4 weeks up to every 16 weeks); q.8.w. = every 8 weeks; SRF = subretinal fluid.

^aCMH weighted estimate. The differences in observed proportions were obtained by applying CMH weight, stratified by randomization stratification factors: day 1 BCVA ETDRS letter score (64 letters or better vs. 63 letters or worse), prior IVT anti-VEGF therapy (yes vs. no), and region (US and Canada, Asia, and the rest of the world). Note: Bolded numbers indicate that the 95% CI excludes the null value.

Sources: YOSEMITE Final Clinical Study Reports,¹⁰ RHINE Updated Clinical Study Reports.¹²

Change From Baseline in DRS

Proportion of Patients With a DRS Improvement of 2 Steps or More From Baseline on the ETDRS DRSS

There were conflicting results between YOSEMITE and RHINE in the proportion of patients with a change of 2 steps or more on the ETDRS DRSS from baseline at week 52, the key secondary end point in the studies. In YOSEMITE, noninferiority for this end point was met, with the difference in the adjusted proportion between the 8-week faricimab arm and the aflibercept arm at week 52 of 10.2% (97.5% CI, 0.3% to 20.0%) and between the PTI faricimab arm and the aflibercept arm of 6.1% (97.5% CI, –3.6% to 15.8%). However, in RHINE, noninferiority was not met for this outcome, as the lower bound of the 97.5% CI for the difference in the adjusted proportion between the faricimab and aflibercept arms was less than –10% for both the 8-week faricimab arm and the PTI faricimab arm at week 52, at –2.6% (97.5% CI, –12.6% to 7.4%) and –3.5% (97.5% CI, –13.4% to 6.3%), respectively. Similar results were found in each study for the per-protocol and treatment-naive populations, with noninferiority not being met in the RHINE study for these populations for the difference in the adjusted proportion between either the 8-week faricimab arm or the PTI faricimab arm and the aflibercept arm (Table 17).

At week 96, there was a generally comparable proportion of patients in the 8-week faricimab arm, the PTI faricimab arm, and the aflibercept arm in both studies who achieved an improvement of 2 steps or more on the ETDRS DRSS from baseline (Table 17).

Proportion of Patients With a DRS Improvement of 3 Steps or More From Baseline on the ETDRS DRSS

At 52 weeks, a comparable proportion of patients in the 3 treatment arms achieved an improvement of 3 steps or more on the ETDRS DRSS from baseline, with a difference in adjusted proportions between the 8-week faricimab arm and the aflibercept arm of 2.8% (95% CI, –3.5% to 9.1%) and between the PTI faricimab arm and the aflibercept arm of 0.8% (95%, –5.4% to 7.0%) in YOSEMITE; in RHINE, the differences were –3.0% (95% CI, –9.6% to 3.7%) and –0.4% (95% CI, –7.3% to 6.4%), respectively. Results were mostly consistent at week 96 in both studies (Table 17).

Proportion of Patients With a DRS Worsening of 2 or 3 Steps or More From Baseline on ETDRS DRSS Over Time

Very few patients in any treatment arm across both studies had a worsening of 2 steps or more on the ETDRS DRSS (< 1.5% at week 52 and < 2.5% at week 96 per treatment arm) or a worsening of 3 steps or more on the ETDRS DRSS (< 1% at week 52 and < 1.5% at week 96 per treatment arm). This outcome was exploratory and only descriptive results were provided.

Proportion of Patients Who Develop New PDR Over Time

Few patients who did not have PDR at baseline developed new PDR in the study eye over time (up to week 96) in the 2 studies (< 3% in any treatment arm). A comparable proportion of patients in the 8-week faricimab arm, the PTI faricimab arm, and the aflibercept arm had developed new PDR in YOSEMITE and RHINE at week 52 and week 96 (Table 17).