Reimbursement Review

Faricimab (Vabysmo)

Sponsor: Hoffmann-La Roche Limited

Therapeutic area: Retinal vein occlusion

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance.

Sources: Product monograph for faricimab injection (Vabysmo).¹ Details included in the table are from the sponsor’s summary of clinical evidence.²

Introduction

Retinal vein occlusion (RVO) develops when a thrombus blocks the venous outflow of the retina, resulting in macular edema (fluid accumulation at the back of the eye).³ Macular edema can lead to significant retinal thickening, hemorrhage, and leakage.^4,5 Patients with RVO usually experience acute, painless visual symptoms, including vision loss or varying degrees of visual alteration due to the edema.^4-6 There are 3 subtypes of RVO that are classified according to the location of the occlusion: branch (involving a complete or partial obstruction at a branch or tributary of the central retinal vein), central (involving obstruction of the retinal vein at or posterior to the optic nerve head), and hemicentral (involving occlusion occurring at the disc that commonly involves half of the neurosensory retinal venous drainage, either the superior or inferior hemifield).^4,6

In Canada, the annual estimated incidence rate of visual impairment due to macular edema secondary to branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) was 0.056% and 0.021%, respectively (56 and 21 per 100,000, respectively).⁷ Based on pooled data from 11 population-based studies from the US, Europe, Asia, and Australia, the estimated prevalence rates of RVO, BRVO, and CRVO were 0.52%, 0.44%, and 0.08%, respectively (520, 440, and 80 people per 100,000, respectively).⁸

The Optimal Treatment of Retinal Vein Occlusion: Canadian Expert Consensus guidelines (published in 2015)⁷ advise the following:

• BRVO with OCT evidence of macular edema: If visual acuity is greater than 20/40, then observation and close follow-up are suggested. Alternatively, anti-VEGF therapy can be considered in patients with relatively good functional vision and optical coherence tomography (OCT) evidence of minimal subclinical macular edema (i.e., 1 to 2 small intraretinal cysts). If there is no foveal involvement, then focal laser therapy is also an option. If visual acuity is less than 20/40 with subfoveal involvement, then treatment with anti-VEGF monotherapy is advised. According to the Optimal Treatment of Retinal Vein Occlusion: Canadian Expert Consensus, most clinicians manage macular edema secondary to hemiretinal vein occlusion (HRVO) similarly to BRVO.⁷

• CRVO with OCT evidence of macular edema: If visual acuity is greater than 20/40, then observation and close follow-up are suggested. Otherwise, treatment with anti-VEGF monotherapy is advised.⁷

Patients with RVO have expressed the need for new treatments that prevent or slow down further vision loss and restore vision. The clinical expert identified the need for therapies to treat patients whose condition does not respond to available treatments or becomes refractory to current treatment options. They also noted the need for treatments that can reverse the course of disease (none currently exist) and address key outcomes, and for treatments that are better tolerated and improve adherence and convenience. Additionally, the clinical expert indicated that treatments that reduce treatment frequency and associated socioeconomic burden are needed. The clinician groups identified a need for efficacious, durable, and long-lasting treatments that can minimize treatment burden compared with existing options.

Faricimab was previously reviewed in 2022 for the following indications: the treatment of neovascular (wet) age-related macular degeneration (nAMD) and the treatment of diabetic macular edema (DME).

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of faricimab 6 mg/0.05 mL solution for intravitreal injection for the treatment of RVO.

Perspectives of Patients, Clinicians, and Drug Programs

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

Patient Input

Input from 1 joint patient advocacy group (comprising Fighting Blindness Canada, the Canadian Council of the Blind, and Vision Loss Rehabilitation Canada) has been summarized for this report. The patient input submission included a summary of the results of an online survey made available from March to April 2024 to people in Canada living with RVO, supplemented with qualitative interviews with 3 patients diagnosed with RVO conducted in March and April 2024. The joint survey gathered information about patient-lived experiences associated vision loss and current treatments for RVO. In total, 32 patients living in Canada (62.5% of respondents had CRVO and 21.9% had BRVO; 15.6% did not know what type of RVO they had been diagnosed with) responded to the survey. Most respondents worried about vision worsening (53%). Respondents to the survey revealed that RVO significantly impacted their day-to-day lives and psychological well-being. Some respondents expressed being anxious about their RVO diagnosis, while others expressed feelings of fear, isolation, anger, and/or a loss of confidence or self-worth. Due to the sudden nature of RVO and its severity, respondents expressed ongoing fear of progression or that the unaffected eye could one day be affected. Overall, 60.0% of respondents indicated they had received anti-VEGF injections for their condition.

When patients were asked how they felt about their current ongoing treatments, the main reasons for stress were anxiety about injections (83%), symptoms from the injections (50%), and travel to appointments (33%). Respondents primarily expressed that treatment improved their vision or made their vision stable. Survey respondents highlighted the need for new treatments that prevent or slow down further vision loss and restore vision. Patients also expressed that they would like treatments that lower out-of-pocket costs, lower side effects, require fewer injections, and are effective.

The joint patient group noted that RVO leads to visual complications that render certain daily activities — such as reading or driving — either problematic or impossible. The joint input noted that while the current anti-VEGF treatments on the market have shown high levels of effectiveness in slowing or halting vision loss, they also come with highly burdensome regular intravitreal injections, creating challenges for many patients, such as the painfulness of the injection, both during and after the procedure, and their difficulties managing their bidirectional commute for their appointments. Patients expressed that they preferred treatment options that could be administered less frequently and supported treatments that could be made available to patients regardless of their province.

Clinician Input

Input From the Clinical Expert Consulted

The clinical expert identified the need for therapies to treat patients whose condition does not respond to available treatments or becomes refractory to current treatment options. They also noted the need for treatments that can reverse the course of disease (none currently exist) and address key outcomes, and for treatments that are better tolerated and improve adherence and convenience. Additionally, the clinical expert indicated that treatments that reduce treatment frequency and associated socioeconomic burden (i.e., treatment burden for clinicians and associated costs for patients and their families, such as transportation costs and lost income due to missed workdays) are needed. The clinical expert indicated that the anticipated place in therapy for faricimab is as an alternative to other currently available anti-VEGF therapies (i.e., the clinical expert did not expect a shift in the current treatment paradigm for macular edema secondary to RVO). The clinical expert noted that clinical practice, treatment history (suboptimal response with other treatments), access, and drug costs can influence treatment decisions. The clinical expert indicated that the anticipated target population for faricimab includes all patients with RVO, regardless of subtype, severity, symptoms, and so forth. Additionally, the clinical expert indicated that patients currently being treated with an anti-VEGF therapy may also be considered candidates for treatment with faricimab.

Based on clinical expert input, the diagnosis of RVO and treatment with faricimab should ideally be performed by a retina specialist. In situations where a retina specialist is not available, such as in remote areas, the clinical expert advised that the diagnosis of RVO and treatment with faricimab should ideally be performed by a well-trained general ophthalmologist. The clinical expert further advised that an outpatient setting that is well equipped for ophthalmic examination and OCT imaging is an appropriate setting for treatment with faricimab.

The clinical expert acknowledged the goal of treatment is to improve visual acuity; however, in practice, the clinical expert indicated that an OCT quantitative measurement of macular edema (central subfield thickness [CST] measurement) is the most important outcome used to assess response to treatment. The clinical expert noted that some clinicians also use qualitative parameters to assess treatment response, such as the presence and size of cystoid spaces. For visual acuity, the clinical expert indicated that a difference of more than 1 line of acuity in a Snellen chart is typically considered clinically meaningful (in the context of a comparison with a similar treatment). However, depending on variability in the light conditions, technician factors, and patient concentration, the clinical expert indicated that a difference of at least 2 Snellen lines can be considered clinically meaningful. For macular edema measured by OCT, the clinical expert indicated that a difference of 10% is typically considered clinically meaningful. The clinical expert indicated that assessment of treatment response usually coincides with treatment schedule (i.e., initially, once per month). When the condition is stabilized and the patient enters into the treat-and-extend phase, the clinical expert indicated that both the treatment and the response assessment are extended accordingly.

The clinical expert suggested the following scenarios in which the discontinuation of faricimab could be considered: when the underlying pathology has resolved, when the presence or absence of macular edema shows no difference in acuity, and when the treat-and-extend protocol allows an extension to more than 4 to 6 months between injections.

Clinician Group Input

Inputs from 4 clinician groups were summarized for this review: Toronto Retina Institute, Southeastern Ontario Community Ophthalmologists, Southwestern Ontario Community Ophthalmologists, and Northeastern Ontario Community Ophthalmologists. In total, 19 ophthalmologists contributed to the clinician input submission. Treatment goals highlighted by the groups included extending the treatment intervals, reducing macular edema, preserving visual acuity, improving visual acuity, reducing VEGF levels, and preventing neovascularization and neovascular glaucoma in patients with RVO. According to the groups, an ideal treatment is one that has demonstrated efficacy in sustaining improvements in visual acuity over the long-term and is durable in reducing the treatment burden associated with repetitive intravitreal therapy (i.e., requiring fewer injections, reducing the frequency of patient visits, and lowering costs and the burden on the health care system). There is an unmet need for patients whose condition does not achieve durable responses to existing treatment options. Therefore, there is a need for efficacious, durable, and long-lasting treatments that can minimize treatment burden compared with existing ones and extend treatment intervals while maintaining efficacy. The clinician groups anticipate that faricimab will be used as a first-line option for patients newly diagnosed with RVO based on its bispecific action mechanism and likelihood of generating a greater response. According to the clinician groups, faricimab would be suited for any patient with RVO, particularly those whose condition has failed to respond to other treatment options, although caution would be exercised for patients who have inflammation from other pre-existing conditions. The clinician groups did not anticipate any misdiagnoses. Any improvement in swelling, determined with an OCT scan, was considered a clinically meaningful improvement. The groups noted the following outcomes to assess whether a patient’s condition has responded to treatment: stable or improved visual acuity (improved vision); reduced presence of fluid assessed by an OCT scan; improved clinical exam measures of retinal hemorrhages, ischemia, and neovascularization; and fewer injections required and/or an increased interval between injections. The clinician groups highlighted that the factors considered for treatment discontinuation would be similar to those for currently approved therapies. These included no response or the presence of irreversible macular damage. One group highlighted that if a patient responds well and the treatment extension has increased to 4 months or more, clinicians would assess whether to stop treatment and would ensure the patient undergoes reasonably close observation. Faricimab can be administered in any outpatient setting and should preferably be administered by trained retina specialists.

Drug Program Input

Input was obtained from the drug programs that participate in the Reimbursement Review process. The following items were identified as key factors that could potentially impact the implementation of a recommendation of faricimab:

• relevant comparators

• initiation of therapy

• continuation or renewal of therapy

• discontinuation of therapy

• prescribing of therapy

• system and economic issues.

The clinical expert consulted for this review provided advice on the potential implementation issues raised by the drug programs, which is presented in Table 5.

Clinical Evidence

Systematic Review

Description of Studies

BALATON and COMINO were phase III, multicentre, randomized, double-masked, active comparator–controlled, parallel-group, 2-part studies. Part 1 evaluated the efficacy, safety, and pharmacokinetics of intravitreal faricimab 6 mg every 4 weeks compared with intravitreal aflibercept 2 mg every 4 weeks in patients with macular edema secondary to BRVO (in the BALATON trial) or CRVO or HRVO (in the COMINO trial) from day 1 through week 24 (24 weeks of treatment). Part 2 evaluated the efficacy, durability, safety, and pharmacokinetics of faricimab administered at masked treatment intervals of every 4, 8, 12, or 16 weeks based on personalized treatment interval dosing criteria, without an active control from week 24 through week 72 (48 weeks of treatment). Of note, there was no comparator in part 2 of the studies because all patients from part 1 received faricimab intravitreal injections according to a personalized treatment interval dosing regimen plus sham procedures to maintain masking of the treatment intervals.

The studies included patients with foveal centre–involved macular edema in the study eye due to BRVO (BALATON study), or CRVO or HRVO (COMINO study), diagnosed no longer than 4 months before screening and confirmed by the central reading centre based on spectral-domain optical coherence tomography (SD-OCT) (or swept-source OCT) images. The studies excluded patients with a history of previous episodes of macular edema due to RVO or persistent macular edema due to RVO diagnosed greater than 4 months before screening, as well as any prior or current treatment for macular edema due to RVO, including anti-VEGF intravitreal injections, in the study eye.

In BALATON, the mean age of patients was 64.3 years (standard deviation [SD] = 10.7 years; range, 35 to 93 years) in the faricimab group and 63.8 years (SD = 10.6 years; range, 28 to 88 years) in the aflibercept group. The mean best-corrected visual acuity (BCVA) in the study eye was 57.50 letters (SD = 13.04 letters; range, 19.0 to 76.0 letters) in the faricimab group and 57.64 letters (SD = 12.15 letters; range, 21.0 to 73.0 letters) in the aflibercept group. The mean CST in the study eye was 558.32 µm (SD = 177.03 µm; range, 281.0 µm to 1,154.0 µm) in the faricimab group and 558.12 µm (SD = 180.26 µm; range, 290.0 µm to 1,208.0 µm) in the aflibercept group. A total of 2.9% of patients (8 of 276 patients) in the faricimab group and 5.8% of patients (16 of 277 patients) in the aflibercept group had experience with at least 1 prior targeted ocular therapy or treatment in the study eye. A total of 17.4% of patients (48 of 276 patients) in the faricimab group and 16.6% of patients (46 of 277 patients) in the aflibercept group had at least 1 prior ocular surgery or procedure in the study eye, with the most common being cataract surgery.

In the COMINO trial, the mean age of patients was 65.6 years (SD = 13.1 years; range, 22 to 100 years) in the faricimab group and 64.7 years (SD = 13.3 years; range, 27 to 95 years) in the aflibercept group. A total of 83.0% of patients (303 of 366 patients) randomized to receive faricimab and 81.9% of patients (294 of 363 patients) randomized to receive aflibercept were reported with CRVO. A total of 17.0% of patients (62 patients) randomized to receive faricimab and 18.1% of patients (65 patients) randomized to receive aflibercept were reported with HRVO. The mean BCVA in the study eye was 50.25 letters (SD = 16.25 letters; range, 19.0 to 87.0 letters) in the faricimab group and 50.71 letters (SD = 16.34 letters; range, 19.0 to 73.0 letters) in the aflibercept group. The mean CST in the study eye was 702.21 µm (SD = 244.00 µm; range, 266.0 µm to 1,500.0 µm) in the faricimab group and 721.07 µm (SD = 242.86 µm; range, 281.0 µm to 1,419.0 µm) in the aflibercept group. A total of 5.7% of patients (21 patients) in the faricimab group and 5.0% of patients (18 patients) in the aflibercept group had experience with at least 1 prior targeted ocular therapy or treatment in the study eye. A total of 17.5% of patients (64 patients) in the faricimab group and 15.2% of patients (55 patients) in the aflibercept group had at least 1 prior ocular surgery or procedure in the study eye, with the most common being cataract surgery.

The BALATON and COMINO studies were ongoing at the time of the primary analysis; that analysis report reflected a data cut-off date of July 6, 2022, and August 9, 2022, respectively, when all patients from the global enrolment phase had either completed the study through week 24 or had discontinued from the study before week 24. This report also presented data from the final analysis through week 72, corresponding to the last patient last visit date of June 12, 2023, in the BALATON trial and July 12, 2023, in the COMINO trial (global enrolment phase only).

Note that efficacy and safety data from the BALATON and COMINO studies were available up to week 68; however, these data were not summarized in this report because the results at week 24 (with the exception of the treatment interval) were considered to be the most relevant for the purpose of this review to inform expert committee deliberations.

Efficacy Results

Visual Acuity Outcomes

The assessments of visual acuity that were determined to be the most relevant for this review were change in BCVA and the proportion of patients with an improvement in BCVA. These outcomes provide information on the degree of improvement in visual acuity and the proportion of patients with an improvement in visual acuity, respectively. Scores are based on the number of letters read correctly on an Early Treatment Diabetic Retinopathy Study (ETDRS) chart, with higher letter scores indicating better visual acuity (the maximum score is 100).

The primary end point in both studies was change from baseline in BCVA at week 24. If statistical significance was achieved on the noninferiority test, then the test for superiority could proceed; the noninferiority margin was 4 letters.

BALATON trial: The treatment difference in the mean change from baseline in BCVA in the study eye at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −0.6 letters (95% confidence interval [CI], −2.2 to 1.1 letters; P value for superiority test = 0.4978). A sensitivity analysis was performed for this outcome using multiple imputation to handle missing data differently. Two supplementary analyses were also performed: an analysis of the per-protocol (PP) population and an analysis using a hypothetical strategy for all intercurrent events. The results of the sensitivity and supplementary analyses were generally supportive of the primary analysis results.

The treatment difference in the estimated proportion of patients with a gain in BCVA of 15 letters or greater in the study eye from baseline at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −4.3% (95% CI, −12.3% to 3.8%; P = 0.3023). The supplementary analysis result was generally supportive of the primary analysis result.

COMINO trial: The treatment difference in the mean change from baseline in BCVA in the study eye at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −0.4 letters (95% CI, −2.5 to 1.6 letters; P value for superiority test = 0.6715). The sensitivity and supplementary analysis results were generally supportive of the primary analysis results.

A subgroup analysis based on baseline RVO status (CRVO and HRVO) was performed for the change from baseline in BCVA in the study eye at week 24. In the subgroup of patients with CRVO, the treatment difference in the mean change from baseline in BCVA in the study eye at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was 0.2 letters (95% CI, −2.1 to 2.6 letters). In the subgroup of patients with HRVO, the treatment difference in the mean change from baseline in BCVA in the study eye at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −3.8 letters (95% CI, −7.3 to −0.4 letters).

The treatment difference in the estimated proportion of patients with a gain in BCVA of 15 letters or greater in the study eye from baseline at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −1.5% (95% CI, −8.4% to 5.3%; P = 0.6661). The supplementary analysis result was generally supportive of the primary analysis result.

Anatomic Outcomes

The assessments of the anatomy of the study eye that were determined to be the most relevant to this review were change in CST and the proportion of patients with an absence of macular edema and fluid. According to the clinical expert, these outcomes provide information on the extent of improvement in tissue swelling or edema, the physiological environment (i.e., re-establishment of the blood–retina barrier), and the presence or absence of cystoid spaces, respectively.

In both studies, CST was defined as the distance measured between the internal limiting membrane and Bruch membrane, standardized to Spectralis SD-OCT; the absence of macular edema was defined as a CST of less than 325 µm, and the absence of both intraretinal fluid and subretinal fluid was measured in the central subfield (within the 1 mm diameter centre of the macula).

BALATON trial: The treatment difference in the mean change from baseline in CST in the study eye at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −7.0 µm (95% CI, −14.1 to 0.0 µm; P value for superiority test = 0.0495).

The treatment difference in the estimated proportion of patients with an absence of macular edema at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was 1.4% (95% CI, −2.3% to 5.0%; P value for superiority test = 0.4742).

The treatment difference in the estimated proportion of patients with an absence of both intraretinal fluid and subretinal fluid at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was 5.3% (95% CI, −2.7% to 13.3%; P value for superiority test = 0.1967).

COMINO trial: The treatment difference in the mean change from baseline in CST in the study eye at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −12.8 µm (95% CI, −26.7 to 1.0 µm; P value for superiority test = 0.0684).

The treatment difference in the estimated proportion of patients with an absence of macular edema at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was 1.7% (95% CI, −2.0% to 5.4%; P value for superiority test = 0.3589).

The treatment difference in the estimated proportion of patients with an absence of both intraretinal fluid and subretinal fluid at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was 6.5% (95% CI, 0.1% to 13.0%; P value for superiority test = 0.0489).

Vision-Related Functioning and Health-Related Quality of Life Outcome

The assessment of vision-related functioning and health-related quality of life (HRQoL) that was determined to be the most relevant to this review was change in the National Eye Institute Visual Functioning Questionnaire–25 (NEI-VFQ-25) composite score. This outcome provides information on the degree of improvement in vision-related functioning and HRQoL from the patient’s perspective. Specifically, subscales include general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, colour vision, and peripheral vision. The composite score ranges from 0 to 100, with higher scores indicating better vision-related functioning and HRQoL.

BALATON trial: The treatment difference in the mean change from baseline in the NEI-VFQ-25 composite score at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −0.4 (95% CI, −1.9 to 1.1; P value for superiority test = 0.6370).

COMINO trial: The treatment difference in the mean change from baseline in the NEI-VFQ-25 composite score at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −1.2 (95% CI, −2.7 to 0.3; P value for superiority test = 0.1088).

Treatment Interval Outcomes

Treatment interval was identified as a relevant outcome for this review because the clinician groups indicated that an ideal treatment demonstrates a durable effect (i.e., demonstrates efficacy in sustaining improvement in visual acuity over the long-term) measured by a reduction in the treatment burden associated with repetitive intravitreal injections.

The treatment interval for a patient at week 68 was defined as the treatment interval decision made at week 68. The algorithm for the interactive web-based response system that determined the personalized treatment interval dosing regimen for faricimab in part 2 of the BALATON and COMINO studies is presented in Table 7.

BALATON trial: The proportions of patients on an extended treatment interval at week 68 were as follows (patients randomized to receive faricimab every 4 weeks in part 1 versus patients randomized to receive aflibercept every 4 weeks in part 1):

• Faricimab every 8 weeks: 13.3% (95% CI, 9.1% to 17.5%) versus 18.0% (95% CI, 13.2% to 22.9%), respectively.

• Faricimab every 12 weeks: 11.7% (95% CI, 7.7% to 15.7%) versus 9.4% (95% CI, 5.8% to 13.1%), respectively.

• Faricimab every 16 weeks: 52.4% (95% CI, 46.2% to 58.6%) versus 47.5% (95% CI, 41.3% to 53.8%), respectively.

COMINO trial: The proportions of patients on an extended treatment interval at week 68 were as follows (patients randomized to receive faricimab every 4 weeks in part 1 versus patients randomized to receive aflibercept every 4 weeks in part 1):

• Faricimab every 8 weeks: 20.0% (95% CI, 15.7% to 24.3%) versus 17.5% (95% CI, 13.3% to 21.7%), respectively.

• Faricimab every 12 weeks: 8.5% (95% CI, 5.5% to 11.5%) versus 11.1% (95% CI, 7.6% to 14.6%), respectively.

• Faricimab every 16 weeks: 37.0% (95% CI, 31.8% to 42.2%) versus 39.0% (95% CI, 33.7% to 44.4%), respectively.

Harms Results

At the primary analysis, safety was assessed through a descriptive summary based on data through week 24. At the final analysis, safety was also assessed through a descriptive summary based on data through week 72 for to the various predefined groups (due to the crossover) (refer to Table 26).

Adverse Events Through Week 24

BALATON trial: Of the patients who received at least 1 injection of the active study drug in the study eye, 16.3% of those (45 of 276 patients) randomized to receive faricimab and 20.4% of those (56 of 274 patients) randomized to receive aflibercept were reported with at least 1 ocular adverse event (AE) in the study eye. Each type of ocular AE in the study eye was reported in less than 4.0% of patients in each group.

An independent clinical events coding committee adjudicated the thromboembolic events reported during the study. Antiplatelet Trialists’ Collaboration (APTC) events were defined as nonfatal strokes or nonfatal myocardial infarctions, or vascular deaths (including deaths of unknown cause). Of the patients who received at least 1 injection of the active study drug in the study eye, 1.1% of those (3 patients) randomized to receive faricimab and 1.5% of those (4 patients) randomized to receive aflibercept were reported with at least 1 adjudicated APTC-defined AE. Each type of adjudicated APTC-defined AE was reported in less than 1.0% of patients in each group.

COMINO trial: Of the patients who received at least 1 injection of the active study drug in the study eye, 23.0% of those (84 of 365 patients) randomized to receive faricimab and 27.7% of those (100 of 361 patients) randomized to receive aflibercept were reported with at least 1 ocular AE in the study eye. Each type of ocular AE in the study eye was reported in less than 4.0% of patients in each group.

Of the patients who received at least 1 injection of the active study drug in the study eye, 1.1% of those (4 patients) randomized to receive faricimab and 1.4% of those (5 patients) randomized to receive aflibercept were reported with at least 1 adjudicated APTC-defined AE. Each type of adjudicated APTC-defined AE was reported in less than 1.0% of patients in each group.

Serious Adverse Events Through Week 24

BALATON trial: Of the patients who received at least 1 injection of the active study drug in the study eye, 1.1% of those (3 patients) randomized to receive faricimab and 0.7% of those (2 patients) randomized to receive aflibercept were reported with at least 1 serious ocular AE in the study eye. Each type of serious ocular AE in the study eye was reported in less than 1.0% of patients in each group.

COMINO trial: Of the patients who received at least 1 injection of the active study drug in the study eye, 2.5% of those (9 patients) randomized to receive faricimab and 3.3% of those (12 patients) randomized to receive aflibercept were reported with at least 1 serious ocular AE in the study eye. Each type of serious ocular AE in the study eye was reported in less than 1.0% of patients in each group.

Withdrawals Due to Adverse Events Through Week 24

BALATON trial: Of the patients who received at least 1 injection of the active study drug in the study eye, no patients stopped study treatment due to ocular AEs.

COMINO trial: Of the patients who received at least 1 injection of the active study drug in the study eye, 0.8% of patients (3 patients) randomized to receive faricimab and 0.6% of patients (2 patients) randomized to receive aflibercept stopped study treatment due to ocular AEs. Each ocular AE that led to a patient stopping their study treatment was reported in less than 1.0% of patients in each group.

Mortality Through Week 24

BALATON trial: Of the patients who received at least 1 injection of the active study drug in the study eye, 0.4% of patients (1 patient due to cerebrovascular accident) randomized to receive faricimab and no patients randomized to receive aflibercept died during the study through week 24.

COMINO trial: Of the patients who received at least 1 injection of the active study drug in the study eye, 0.3% (1 patient due to pneumonia) of patients randomized to receive faricimab and 0.6% of patients (2 patients due to myocardial infarction) randomized to receive aflibercept died during the study through week 24.

Notable Harms Through Week 24

BALATON trial: Of the patients who received at least 1 injection of the active study drug in the study eye, no patients were reported with endophthalmitis in the study eye.

COMINO trial: Of the patients who received at least 1 injection of the active study drug in the study eye, no patients randomized to receive faricimab and 0.3% of patients (1 patient) randomized to receive aflibercept were reported with endophthalmitis in the study eye.

Critical Appraisal

Internal Validity

Part 1 of the BALATON and COMINO studies was appropriately designed and powered to evaluate the efficacy of faricimab relative to aflibercept. The methods for randomization and allocation concealment were appropriate, and the review team judged that the risk of bias arising from the randomization process is unlikely. Part 2 of the studies did not have a relevant comparison group; therefore, conclusions about the number of injections relative to aflibercept or any other active comparator could not be drawn.

There is a lack of evidence in the literature to inform the measurement properties of BCVA as measured by ETDRS charts, CST as measured by OCT, and vision-related functioning and HRQoL as measured by NEI-VFQ-25 in patients with RVO. However, there was also no evidence in the literature to suggest there are concerns with these tools. Because the studies were masked, the risk of bias in the measurement of the outcomes is likely low.

As noted in guidance by the FDA,⁹ there was no impact on the type I error rate for the superiority test following the noninferiority test.¹⁰ The review team judged that the methods for deciding the 4-letter noninferiority margin were appropriate. Further, the clinical expert agreed that a difference of 5 letters or 1 Snellen line can be considered clinically meaningful in the context of comparisons with a similar treatment. Because no formal superiority tests were performed for the secondary end points and the subgroup analysis of the primary end point, these results are considered supportive evidence only. For statistically significant results, there is an increased risk that the null hypothesis was rejected erroneously.

The number of patients with HRVO available for the subgroup analysis was relatively low (< 20%) and, as such, the small sample size introduced uncertainty in the results (i.e., whether they would be replicated in a larger sample). There was no formal statistical approach for testing subgroup differences by RVO type. Although the estimated effect was statistically significant in the HRVO subgroup (and not in the CRVO subgroup), this contrast is not sufficient for inferring effect modification.¹¹

Although major protocol deviation rates through week 24 were approximately 30% for each group from each study, the rates were generally balanced between groups. The most frequent type of major protocol deviation in both studies was procedural-related; however, each procedural-related protocol deviation was reported in less than 10% of patients in each group from both studies. As such, it was concluded that the risk of bias due to deviations from the intended intervention in part 1 of the studies is low. However, more than 50% of patients in each group from both studies were reported with at least 1 major protocol deviation through week 72, with more than 40% related to procedures. As such, it was concluded that the risk of bias (of unknown direction and magnitude) due to deviations from the intended interventions in part 2 of the studies is high.

Missing data were implicitly imputed by the mixed model for repeated measures (MMRM) model, assuming missing at random for both the primary end point of change from baseline in BCVA and the secondary end point of change from baseline in CST at week 24. A sensitivity analysis (in which missing data were assumed to be missing not at random and were assumed to have worse outcomes compared with the rest of the study population) was performed for the primary end point only. Because the results were consistent with the main analysis, the review team judged that the risk of bias due to missing outcomes data for this end point was low.

The assumptions for missing outcomes data (missing at random for change from baseline in CST at week 24 and last observation carried forward [LOCF] for categorical secondary outcomes at week 24) are likely not plausible and, for change from baseline in the NEI-VFQ-25 composite score at week 24 and treatment intervals at week 68, missing data were not imputed. Nonetheless, the amounts of missing outcomes data were generally low and balanced between groups in both studies, so the risk of bias due to missing outcomes data was considered low. The exception was for the proportion of patients with an absence of both intraretinal fluid and subretinal fluid in the BALATON trial, where the amount of missing outcome data was relatively high (13% to 16%). The clinical expert stated that the assumption that fluid status would stay constant over time is likely not plausible, so there is a potential for risk of bias due to missing outcomes data for this end point.

External Validity

The inclusion criteria in the BALATON and COMINO studies included the population of interest identified in the indication for faricimab, which is for the treatment of macular edema secondary to RVO. Notably, less than 20% of patients in the COMINO trial had HRVO; therefore, the generalizability of the study results to patients with HRVO is less certain.

The clinical expert indicated that the inclusion criteria adequately captured all patients who would be considered candidates for faricimab in practice. Further, the clinical expert indicated that the study population was generally representative of the patients typically seen in practice who would be candidates for treatment with faricimab. Of note, the clinical expert noted that patients with RVO generally present with uncontrolled blood pressure; cardiovascular disease, including stroke and myocardial infarction; diabetic retinopathy; and complications of cataract surgery. The clinical expert advised that these patients would be considered candidates for treatment with faricimab in practice.

In general, the Optimal Treatment of Retinal Vein Occlusion: Canadian Expert Consensus (published in 2015)⁷ advises on the use of anti-VEGF therapy in patients with RVO with OCT evidence of macular edema. This is aligned with input from the clinician groups and the clinical expert consulted for this review regarding the current treatment options that are available in practice. Therefore, the comparator in the studies (aflibercept) is relevant for the purpose of the present review; however, direct evidence for the effect of faricimab versus other anti-VEGF treatments (e.g., ranibizumab and bevacizumab) in the treatment of patients with macular edema secondary to RVO is lacking.

In consultation with the clinical expert, it was concluded that the outcome measures are generally reflective of assessments of treatment response in practice. Because the goal of treatment is to improve visual acuity, the clinical expert advised that if treatment response is demonstrated on imaging (CST measurement) but there is no change in visual acuity, then the clinician will consider discontinuing treatment. However, if treatment response is demonstrated in visual acuity with change in macular edema status, then the clinician will likely use the imaging results (CST as assessed by OCT) as an objective approach to determine whether to extend, maintain, or reduce the treatment interval in practice.

The clinical expert indicated that the common practice in Canada is to treat and extend, but it can also be a fixed treatment interval if extending is not possible. However, the clinical expert noted that the criteria used to determine a personalized treatment interval dosing regimen are not used uniformly by clinicians in practice.

In consultation with the clinical expert, it was concluded that the assessment time point at week 24 is considered appropriate for evaluating treatment effect in the therapeutic area of macular edema secondary to RVO. The exception is the outcome measure of treatment interval (proportion of patients on extended treatment intervals), for which the clinical expert suggested an assessment time point at month 24 (versus at week 68 in the studies).

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and randomized controlled trials (RCTs) identified in the sponsor’s systematic review, Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^12,13

• For RCTs: Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

• For single-arm trials: Although GRADE guidance is not available for noncomparative studies, the review team assessed pivotal single-arm trials for study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias to present these important considerations. Because the lack of a comparator arm does not allow for a conclusion to be drawn on the effect of the intervention versus any comparator, the certainty of evidence for single-arm trials started at very low certainty with no opportunity for rating up. In the current review, 68-week data from both trials were appraised as single-arm data, given the lack of a relevant comparator at this time point.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty-of-evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty-of-evidence assessment was the presence or absence of an important effect based on thresholds informed by the clinical expert consulted for this review. For the primary outcome of change from baseline in BCVA at week 24, the noninferiority margin used in the trials was the threshold.

The selection of outcomes for the GRADE assessment was based on the sponsor’s summary of clinical evidence, consultation with the clinical expert, and the input received from the patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• visual acuity (BCVA)

• anatomic outcomes (CST, absence of macular edema, absence of both intraretinal and subretinal fluid)

• vision-related functioning and HRQoL (NEI-VFQ-25)

• extended treatment interval (every 8 to 16 weeks)

• notable harms (endophthalmitis).

For the GRADE assessments, the BALATON and COMINO studies were assessed individually because the BALATON study had a patient population with macular edema secondary to BRVO and the COMINO study had a patient population with macular edema secondary to CRVO or HRVO.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for faricimab versus aflibercept in patients with macular edema secondary to BRVO.

Table 3 presents the GRADE summary of findings for faricimab versus aflibercept in patients with macular edema secondary to CRVO or HRVO.

Table 2: Summary of Findings for Faricimab vs. Aflibercept for Patients With Macular Edema Secondary to Branch Retinal Vein Occlusion

AE = adverse event; BCVA = best-corrected visual acuity; CI = confidence interval; CST = central subfield thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; HRQoL = health-related quality of life; NA = not applicable; NEI-VFQ-25 = National Eye Institute Visual Functioning Questionnaire–25; NR = not reported; PTI = personalized treatment interval; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; q.12.w. = every 12 weeks; q.16.w. = every 16 weeks; RCT = randomized controlled trial; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

The primary end point was change from baseline in BCVA at week 24; if statistical significance was achieved on the noninferiority test, then the test for superiority could proceed. No formal superiority tests were performed for the secondary end points; therefore, these results were considered to be supportive evidence only.

^aThe noninferiority margin of 4 letters was used as the threshold of importance for assessing imprecision.

^bRated down 1 level for serious imprecision. There was no known threshold for a clinically important effect, and the clinical expert consulted for this review could not estimate the threshold of a clinically important difference. The review team considered the 95% CI to include the potential for both little to no difference and clinically relevant comparative harm.

^cThere was no known threshold for a clinically important effect, and the clinical expert consulted for this review could not estimate the threshold of a clinically important difference. The review team considered the 95% CI to include the potential for little to no difference only.

^dRated down 1 level for serious study limitations. Missing outcome data were relatively high (13% to 16%), and it is unclear whether the reasons for missingness are balanced between groups. In consultation with the clinical expert, it was concluded that the assumption that fluid status would stay constant over time is likely not plausible. Therefore, it was concluded that there are some concerns for risk of bias due to missing outcome data. Rated down 1 level for serious imprecision. There was no known threshold for a clinically important effect, and the clinical expert consulted for this review could not estimate the threshold of a clinically important difference. The review team considered the 95% CI to include the potential for both little to no difference and clinically relevant comparative benefit.

^eIn the absence of a relevant comparison group, conclusions about the number of injections relative to aflibercept or any other active comparator could not be drawn and the certainty of evidence started at very low. Rated down 1 level for serious study limitations. A relatively large proportion of patients (> 50%) were reported with at least 1 major protocol deviation through week 72, with the majority of the major protocol deviations (> 40%) related to procedures. Therefore, it was concluded that the risk of bias (of unknown direction and magnitude) due to deviations from the intended intervention in part 2 of the studies is high. Rated down 1 level for serious indirectness. Per the clinical expert consulted for this review, the criteria for extending the treatment interval in the trials were not reflective of clinical practice in Canada.

^fRated down 2 levels for very serious imprecision. No events were observed; therefore, there was an inadequate number of events to inform a higher-certainty judgment.

Sources: Primary¹⁴ and final¹⁵ Clinical Study Reports for GR41984 (BALATON). Details included in the table are from the sponsor’s summary of clinical evidence.

Table 3: Summary of Findings for Faricimab vs. Aflibercept for Patients With Macular Edema Secondary to Hemiretinal and Central Retinal Vein Occlusion

AE = adverse event; BCVA = best-corrected visual acuity; CI = confidence interval; CST = central subfield thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; HRQoL = health-related quality of life; NA = not applicable; NEI-VFQ-25 = National Eye Institute Visual Functioning Questionnaire–25; NR = not reported; PTI = personalized treatment interval; q.4.w. = every 4 weeks; q.12.w. = every 12 weeks; q.16.w. = every 16 weeks; RCT = randomized controlled trial; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

The primary end point was change from baseline in BCVA at week 24; if statistical significance was achieved on the noninferiority test, then the test for superiority could proceed. No formal superiority tests were performed for the secondary end points; therefore, these results were considered to be supportive evidence only.

^aThe noninferiority margin of 4 letters was used as the threshold of importance for assessing imprecision.

^bThere was no known threshold for a clinically important effect, and the clinical expert consulted for this review could not estimate the threshold of a clinically important difference. The review team considered the 95% CI to include the potential for little to no difference only.

^cRated down 1 level for serious imprecision. There was no known threshold for a clinically important effect, and the clinical expert consulted for this review could not estimate the threshold of a clinically important difference. The review team considered the 95% CI to include the potential for both little to no difference and clinically relevant comparative benefit.

^dIn the absence of a relevant comparison group, conclusions about the number of injections relative to aflibercept or any other active comparator could not be drawn and the certainty of evidence started at very low. Rated down 1 level for serious study limitations. A relatively large proportion of patients (> 50%) were reported with at least 1 major protocol deviation through week 72, with the majority of the major protocol deviations (> 40%) related to procedures. Therefore, it was concluded that the risk of bias (of unknown direction and magnitude) due to deviations from the intended intervention in part 2 of the studies is high. Rated down 1 level for serious indirectness. Per the clinical expert consulted for this review, the criteria for extending the treatment interval in the trials were not reflective of clinical practice in Canada.

^eRated down 2 levels for very serious imprecision. Few to no events were observed; therefore, there was an inadequate number of events to inform a higher-certainty judgment.

Sources: Primary¹⁶ and updated¹⁷ Clinical Study Reports for GR41986 (COMINO). Details included in the table are from the sponsor’s summary of clinical evidence.

Long-Term Extension Studies

The sponsor did not submit any long-term extension studies.

Indirect Comparisons

Description of Studies

One sponsor-conducted indirect treatment comparison (ITC) compared faricimab (6 mg every 4 weeks) with other anti-VEGF treatments, dexamethasone, and laser therapy for the treatment of RVO. The main comparators of interest identified in the systematic literature review (SLR) were anti-VEGF treatments (aflibercept 2 mg, ranibizumab, and bevacizumab), specifically those given in flexible regimens such as pro re nata (PRN) (as needed), which are typically used in clinical practice. A Bayesian approach under the random-effects model as the principal analysis and fixed-effects model for sensitivity was implemented. The outcomes assessed included the mean change from baseline in BCVA, proportion of patients gaining 15 or more letters, CST, and mean number of injections. The difference in the proportion of patients with any serious adverse events (SAEs) as well as all-cause discontinuations were also assessed. Treat-and-extend regimens could not be investigated due to a lack of connected studies.

Efficacy Results

Mean Change From Baseline in BCVA

Compared with other anti-VEGFs, the point estimates for the difference in mean change from baseline BCVA at 6 months mostly suggested little to no difference compared with faricimab 6 mg every 4 weeks. The point estimate for the comparison with bevacizumab 1.25 mg PRN favoured faricimab 6 mg every 4 weeks. In most comparisons, the 95% credible intervals (CrIs) were wide and included the possibility of clinically important effects favouring either treatment being compared. The mean changes and 95% CrIs for faricimab against anti-VEGFs administered PRN were as follows: aflibercept 2 mg PRN, 1.87 (95% CrI, −7.43 to 11.16); ranibizumab PRN, 3.59 (95% CrI, −2.94 to 10.17); and bevacizumab PRN, 5.22 (95% CrI, −3.35 to 13.80). The median between-study heterogeneity estimate (tau) was 2.85 (95% Crl, 1.397 to 3.911), indicating a low level of heterogeneity.

Mean Change From Baseline in CST

For change from baseline in CST at 6 months, faricimab 6 mg every 4 weeks was favoured over bevacizumab 1.25 mg PRN; however, the 95% CrI for the between-group difference included the possibility of little to no difference between the 2 treatments. In the comparisons with all other anti-VEGFs, the point estimates for between-group differences favoured faricimab 6 mg every 4 weeks; however, the 95% CrI included the possibility that either treatment could be favoured. The mean changes and 95% CrIs for faricimab against anti-VEGFs administered PRN were as follows: aflibercept 2 mg PRN, −37.3 (95% CrI, −107.99 to 35.72); ranibizumab PRN, −20.08 (95% CrI, −70.53 to 32.35); and bevacizumab PRN, −68.95 (95% CrI, −133.02 to −1.48). The between-study heterogeneity estimate (tau) had a median of 9.518 (95% Crl, 0.334 to 23.977), indicating a low level of heterogeneity.

Proportion of Patients Gaining at Least 15 ETDRS Letters

Results specific to the proportion of patients gaining at least 15 ETDRS were not reported in the sponsor-submitted ITC.

Mean Number of Injections

The network of studies for faricimab and anti-VEGF treatments allowing for a flexible (PRN) treatment regimen was connected with sham injections only; therefore, no treatment effect with regard to flexible regimens could be estimated.

Harms Results

Ocular Adverse Events

For ocular AEs, for comparisons with all anti-VEGFs, the 95% CrIs for the odds ratios were too wide to inform on which treatment might be favoured. The between-study heterogeneity estimate (tau) reported a median of 0.351 (95% Crl, 0.025 to 1.350). The odds ratio for faricimab against the anti-VEGF ranibizumab administered PRN was 0.64 (95% CrI, 0.14 to 2.80).

Serious Ocular AEs

For serious ocular AEs, for comparisons with all anti-VEGFs, the 95% CrIs for the odds ratios were too wide to inform on which treatment might be favoured. The odds ratio for faricimab against the anti-VEGF ranibizumab administered PRN was 0.53 (95% CrI, 0.03 to 10.5).

All-Cause Discontinuation

For comparisons with all other anti-VEGFs, the 95% CrIs for the odds ratios were too wide to inform about which treatment may be favoured. The between-study heterogeneity estimate (tau) had a median of 0.632 (95% Crl, 0.160 to 1.377). The odds ratios and 95% CrIs for faricimab against anti-VEGFs were as follows: aflibercept 2 mg every 4 weeks, 1.28 (95% CrI, 0.39 to 5.14); ranibizumab PRN, 1.00 (95% CrI, 0.16 to 6.53); and bevacizumab every 4 weeks, 0.79 (95% CrI, 0.11 to 6.20).

Critical Appraisal

There was variability in baseline characteristics (age, baseline BCVA, retinal thickness measurements, treatment patterns, number of injections administered, prior therapy, concomitant or background medications, intraocular pressure) across the studies included in the network meta-analysis (NMA) feasibility assessment. There was also a lack of reporting on several key study characteristics of interest for RVO (e.g., blood pressure, diabetes, concurrent diabetic retinopathy, coagulability, blood viscosity, and anemia) that could be potential effect modifiers. As such, there is uncertainty as to whether the assumptions related to homogeneity were met for the NMA. There was also a lack of clarity on the number of studies included in the network that enrolled treatment-experienced or treatment-naive patients with RVO. Prior treatment for macula edema with anti-VEGFs potentially negatively impacts treatment response. This adds uncertainty to the results and limits conclusions on the relative effect of faricimab against the anti-VEGFs commonly used as PRN regimens in practice. In addition, the CrIs for between-group comparisons were wide, often including the potential that either treatment being compared could be favoured.

Studies Addressing Gaps in the Evidence From the Systematic Review

Sixteen studies were submitted by the sponsor to address gaps in the RCTs submitted for faricimab for the treatment of RVO. These studies were excluded from the report because patients enrolled across studies included nAMD and DME populations, which differ from the sponsor-submitted reimbursement population. One matched cohort study, which matched patients with RVO from 2 registries (Vestrum and Medisoft) with the baseline characteristics of patients enrolled in the 2 pivotal trials submitted for this review (BALATON and COMINO trials), was also submitted by the sponsor. However, given that the therapies evaluated, in association with the outcomes of interest, did not include faricimab, the study was excluded from the report.

Conclusion

Two phase III, randomized, multicentre, double-masked, active comparator–controlled, parallel-group, 2-part trials were submitted for this review. Part 1 evaluated the efficacy, safety, and pharmacokinetics of intravitreal faricimab 6 mg every 4 weeks compared with intravitreal aflibercept 2 mg every 4 weeks in patients with macular edema secondary to BRVO (in the BALATON trial) or CRVO or HRVO (in the COMINO trial) from day 1 through week 24 (24 weeks of treatment). Part 2 evaluated the efficacy, durability, safety, and pharmacokinetics of faricimab administered at masked treatment intervals of every 4, 8, 12, or 16 weeks based on personalized treatment interval dosing criteria, without an active control from week 24 through week 72 (48 weeks of treatment). Based on input from patients and clinicians, visual acuity, anatomic outcomes, vision-related functioning and HRQoL, and treatment interval are important outcomes. The studies demonstrated that 24 weeks of treatment with intravitreal faricimab results in little to no difference in visual acuity when compared with intravitreal aflibercept, based on change from baseline in BCVA and the proportion of patients gaining 15 letters or greater in BCVA. Faricimab was statistically noninferior, but not superior, to aflibercept for change from baseline in BCVA. The studies also suggested that 24 weeks of treatment with faricimab likely results in little to no difference in anatomic outcomes when compared with aflibercept, based on the change from baseline in CST, the proportion of patients with an absence of macular edema, and the proportion of patients with an absence of both intraretinal and subretinal fluid. Overall, uncertainty in these efficacy end point results showing little to no difference in treatment effect was primarily due to concerns of risk of bias due to missing outcome data and imprecision of the 95% CIs. The studies also suggested that 24 weeks of treatment with faricimab results in little to no difference in vision-related functioning and HRQoL when compared with aflibercept, based on change from baseline in the NEI-VFQ-25 composite score. The evidence informed by the trials is very uncertain about the effect of faricimab on an extended treatment interval (i.e., every 8 to 16 weeks) at week 68 when compared with any active comparator, primarily due to the absence of a relevant comparison group. Further, there are concerns with the generalizability of the results because the criteria used to determine a personalized treatment interval dosing regimen are not used uniformly by clinicians in Canada.

Indirect evidence from the sponsor-submitted NMA provided evidence for faricimab relative to anti-VEGFs other than aflibercept. The evidence from the NMA suggested that faricimab may have little to no difference in treatment effect (in BCVA and CST) compared to other anti-VEGF therapies administered as needed in patients with macular edema secondary to RVO. However, there is uncertainty in the NMA results due to wide 95% CrIs, uncertain plausibility of the homogeneity assumption (i.e., variability in potential effect modifiers), a sparse network of evidence, and a potential for risk of bias in the included studies (e.g., uncertain handling of missing data).

With regard to safety, the frequency of AEs through week 24 was generally similar between the faricimab and aflibercept groups from each trial and was considered relatively low. The studies suggested that 24 weeks of treatment with faricimab may result in little to no difference in endophthalmitis when compared with aflibercept. Although endophthalmitis can be assessed within 3 to 4 days of injection, uncertainty in this safety end point remained primarily due to concerns of imprecision because there were few to no events observed to inform a higher-certainty judgment. Evidence from the NMA was insufficient to inform on the relative harms of faricimab compared with other anti-VEGFs.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of faricimab 6 mg/0.05 mL solution for intravitreal injection for the treatment of RVO.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

RVO is a multifactorial disease that develops when a thrombus blocks the venous outflow of the retina, affecting the branch retinal veins, central vein, or hemicentral vein resulting in macula edema (fluid accumulation at the back of the eye).³ Macula edema can lead to significant retinal thickening, hemorrhage, and leakage.^4,5 Patients with RVO typically experience acute, painless visual symptoms (vision loss or varying degrees of visual alteration) due to the edema.^4-6 If left untreated, macula edema may cause blurred vision, eventually leading to blindness. RVO represents a significant cause of visual disability, frequently associated with systemic cardiovascular pathologies.^5,18

There are 3 forms of RVO, classified according to the location of the occlusion: branch (involving a complete or partial obstruction at a branch or tributary of the central retinal vein), central (involving obstruction of the retinal vein at or posterior to the optic nerve head), and hemicentral RVO (involving occlusion occurring at the disc that commonly involves half of the neurosensory retinal venous drainage, either the superior or inferior hemifield).^4,6 RVO can be further subclassified as ischemic RVO or nonischemic RVO, depending on the degree of blockage and blood supply restriction. Ischemic RVO is a serious form of RVO involving inadequate blood supply (ischemia) to the retina, with substantial and often irreversible damage. Nonischemic RVO is less serious, occurring when there is still adequate blood supply to the retina, which is associated with better outcomes.^5,19

In Canada, the yearly incidence rate of visual impairment caused by macular edema secondary to BRVO and CRVO was 0.056% and 0.021%, respectively (56 and 21 per 100,000).⁷ Globally, there were about 28 million persons with RVO in 2015, with BRVO and CRVO accounting for 83.3% and 16.7% of cases, respectively.²⁰ While Canadian prevalence data for RVO is difficult to source, pooled data from 11 population-based studies from the US, Europe, Asia, and Australia showed prevalence rates of approximately 0.52% for any RVO, 0.44% for BRVO, and 0.08% for CRVO corresponding to 520, 440, and 80 people per 100,000 respectively.⁸

RVO is diagnosed based on clinical assessments and imaging techniques, including eye exams, blood pressure and glucose tests, a complete blood count, and an erythrocyte sedimentation rate analysis.⁶ Common retinal imaging techniques used in practice include OCT, which is crucial for evaluating neovascularization and the extent of macula edema in the disease; OCT angiography; and fluorescein angiography. The Optimal Treatment of Retinal Vein Occlusion: Canadian Expert Consensus recommends using OCT angiography alongside OCT, and fluorescein angiography is recommended at initial assessment.⁷ Fluorescein angiography is also valuable for an in-depth diagnosis and classification of RVO because it offers detailed views of the retinal circulation, pinpointing capillary nonperfusion areas and assisting in distinguishing between ischemic and nonischemic RVO types.²

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

The Optimal Treatment of Retinal Vein Occlusion: Canadian Expert Consensus (published in 2015) advises on the following:⁷

BRVO with OCT evidence of macular edema: If visual acuity is greater than 20/40, then observation and close follow-up are suggested. Alternatively, anti-VEGF therapy can be considered in patients with relatively good functional vision and OCT evidence of minimal subclinical macular edema (i.e., 1 to 2 small intraretinal cysts). If there is no foveal involvement, then focal laser therapy is also an option. If visual acuity is less than 20/40 with subfoveal involvement, then treatment with anti-VEGF monotherapy is advised.⁷

If vision is stable and/or there is no OCT evidence of fluid after 3 monthly intravitreal injections of anti-VEGF, then as-needed treatment with frequent monitoring is advised. If there is some improvement in vision and/or OCT evidence of fluid after 3 monthly intravitreal injections of an anti-VEGF, continuation with anti-VEGF therapy for 3 monthly doses is advised. If there is no improvement or a worsening in vision after 3 monthly intravitreal injections of an anti-VEGF, then fluorescein angiography is advised to assess for ischemia and other complications and/or causes of a suboptimal treatment response to guide subsequent therapeutic approaches (i.e., sector panretinal photocoagulation, focal macular laser, switching the anti-VEGF, steroids).⁷ The clinical expert consulted for this review noted that with the introduction of anti-VEGF therapy, laser treatment is used less frequently for BRVO in practice but may still be used as an adjunct to anti-VEGF therapy to reduce the number of injections.

According to the Optimal Treatment of Retinal Vein Occlusion: Canadian Expert Consensus, most clinicians manage macular edema secondary to HRVO similarly to BRVO.⁷

CRVO with OCT evidence of macular edema: If visual acuity is greater than 20/40, then observation and close follow-up are suggested. Otherwise, treatment with anti-VEGF monotherapy is advised.⁷

If vision is stable and/or there is no OCT evidence of fluid after 3 monthly intravitreal injections of an anti-VEGF, then as-needed treatment with frequent monitoring is advised. If there is some improvement in vision and/or OCT evidence of fluid after 3 monthly intravitreal injections of an anti-VEGF, continuation with anti-VEGF therapy is advised, with consideration for assessment using fluorescein angiography to guide subsequent therapeutic approaches (i.e., panretinal photocoagulation, focal macular laser, switching the anti-VEGF). If there is no improvement or worsening in vision after 3 monthly intravitreal injections of an anti-VEGF, then intravitreal steroids or switching the anti-VEGF can be considered.⁷ The clinical expert indicated that laser therapy is not usually used for CRVO in practice.

The clinical expert advised that the mainstay of treatment for macular edema associated with RVO is anti-VEGF therapy. The clinical expert indicated that all anti-VEGF drugs (aflibercept, ranibizumab and its biosimilars, bevacizumab) are generally effective (i.e., they reduce macular edema and improve visual acuity in a majority of patients), with a relatively low and acceptable risk of complications. The clinical expert further indicated that continued injections at a reduced frequency are needed in most patients with RVO.

The clinical expert noted that triamcinolone suspension or dexamethasone implant, which are commonly associated with complications such as cataract and elevated intraocular pressure, are used infrequently (i.e., primarily for a suboptimal response to anti-VEGF therapy).

Based on the clinical expert input, the most important goal of therapy is to improve vision, thereby improving the HRQoL of patients with macular edema secondary to RVO. In addition to improving visual acuity, based on the clinician group input, the goals of therapy include extending the treatment intervals, reducing macular edema, preserving visual acuity, reducing VEGF levels, and preventing neovascularization and neovascular glaucoma.

Drug Under Review

Key characteristics of faricimab are summarized in Table 4 with other treatments available for RVO.

Faricimab is a humanized bispecific immunoglobulin G1 antibody that acts through the inhibition of both Ang-2 and VEGF-A. Faricimab suppresses endothelial cell proliferation, neovascularization, and vascular permeability by inhibiting VEGF-A. By inhibiting Ang-2, faricimab is thought to increase vascular stability and desensitize blood vessels to the effects of VEGF-A. Ang-2 levels are increased in some patients with wet age-related macular degeneration, DME, and RVO.¹

The recommended dose of faricimab for RVO is 6 mg (0.05 mL), administered intravitreally every 4 weeks (approximately every 28 days plus or minus 7 days) for 6 months. Patients are required to be assessed regularly. Monitoring between the dosing visits should be scheduled based on the patient’s status and at the physician’s discretion.¹

Faricimab was reviewed by Health Canada for the treatment of macular edema secondary to RVO and granted a Notice of Compliance on July 24, 2024. Faricimab was previously reviewed for nAMD and DME. Faricimab has been approved by the FDA for the treatment of macular edema following RVO and is currently under review by the European Medicines Agency.

Table 4: Key Characteristics of Faricimab, Aflibercept 2 mg, Ranibizumab, and Bevacizumab

ATE = arterial thromboembolic event; BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion; IOP = intraocular pressure; IVT = intravitreal; mAb = monoclonal antibody; ME = macular edema; PlGF = placental growth factor; RVO = retinal vein occlusion; VA = visual acuity.

^aHealth Canada–approved indication.

^bBevacizumab is used off label in the treatment of RVO.

Sources: Product monograph for Vabysmo,¹ Eylea,²¹ Lucentis,²² and Avastin.²³

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

Input from a joint patient group comprising 3 not-for-profit organizations (Fighting Blindness Canada, Canadian Council of the Blind, and Vision Loss Rehabilitation Canada) was summarized for this report. The 3 organizations cater to research and activities promoting vision health and the well-being of patients with RVO and other vision-related conditions. Information from this input was summarized from the results of an online survey made available from March to April 2024 to people in Canada living with RVO, supplemented with qualitative interviews with 3 patients diagnosed with RVO that were conducted in March and April 2024.

The joint survey gathered information about patient-lived experiences, associated vision loss, and current treatments for RVO. In total, 32 patients living in Canada (62.5% of respondents with central RVO, 21.9% with branch RVO, and 15.6% who did not know what type of RVO they were diagnosed with) responded to the survey. The mean age of respondents was 69 years and most respondents (71.0%) had RVO in 1 eye only. A total of 51.9% of respondents were from Ontario followed by British Columbia (22.2%) and Alberta (11.1%). The remaining respondents were from Newfoundland, Nova Scotia, Quebec, and Saskatchewan (3.7% each). Overall, 70% of respondents lived in urban areas. Most respondents worried about vision worsening (53%). Respondents to the survey revealed that RVO significantly impacted their day-to-day lives and psychological well-being. Some respondents expressed being anxious about their RVO diagnosis, while others expressed feelings of fear, isolation, anger, and/or loss of confidence or self-worth. Due to the sudden nature of RVO and its severity, respondents expressed ongoing fear of progression or that the unaffected eye may 1 day be affected. Patients noted that RVO diagnosis is lengthy and complicated because an ophthalmologist may not be the first point of contact. Respondents of working age expressed concerns about the lack of treatment coverage and difficulties attending multiple appointments, coupled with the negative impact that vision loss may have on their careers.

Overall, 60.0% of respondents indicated they had received anti-VEGF injections for their condition, 20.0% indicated they had received eye injections but were unable to identify the drug, 26.7% indicated they had also received laser treatment, and 13.3% stated they had never received treatment for RVO. When patients were asked how they felt about their current ongoing treatments, 78% of those who received injections reported feeling pain or discomfort 24 hours following treatment, and 52.1% of respondents found it stressful or difficult to attend appointments. The main reasons for the stress were anxiety about injections (83%), symptoms from the injections (50%), and travel to appointments (33%). Overall, 68% of respondents with experience with eye injections were satisfied with the injections. Respondents primarily expressed that treatment improved their vision or that treatment made their vision stable. Respondents who indicated dissatisfaction with their treatment listed pain or side effects after injections, lack of vision improvement, and the lack of coverage by drug plans as reasons.

Respondents to the survey highlighted the need for new treatments that prevent or slow down further vision loss and restore vision. Patients also expressed that they would like treatments that lower out-of-pocket costs, lower side effects, require fewer injections, and are effective. Four of the survey respondents and 2 of the individuals interviewed had experience with faricimab. One patient who had switched from another anti-VEGF did not notice a difference after 1 injection but noted that their doctor saw a difference on an OCT scan. Another interviewee expressed hope after treatment because they had experienced fewer blind spots following treatment.

The joint patient group input noted that RVO leads to visual complications that render certain daily activities — such as reading or driving — either problematic or impossible. In addition to causing diminishing visual acuity, RVO can present acute emotional and psychological burdens. When asked about their experience of the disease and its treatment, patients noted that treatments with less demanding injection regimes would help ease some of the burden associated with RVO. The joint input noted that while the current anti-VEGF treatments on the market have shown high levels of effectiveness in slowing or halting vision loss, they also come with highly burdensome regular intravitreal injections, creating challenges for many patients, such as painfulness of the injection, both during and after the procedure, and making it difficult to manage their bidirectional commute for their appointments. The group expressed challenges, especially for patients living in rural areas and remote parts of the country, such as travelling significantly long distances to their appointments and the frequent inaccessibility of transportation for low-vision individuals, both of which may lead to reliance and dependency on caregivers for travelling to and from appointments. They also noted challenges in managing daily living and tasks that are rendered very difficult by RVO, and short-term visual complications due to intravitreal injections. Patients expressed that they preferred treatment options that could be administered less frequently and supported treatments that could be made available to patients regardless of their province.

Clinician Input

Input From the Clinical Expert Consulted

All review teams include at least 1 clinical specialist with expertise regarding 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., 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 macular edema secondary to RVO.

Unmet Needs

The clinical expert identified the need for therapies to treat patients whose condition does not respond to available treatments or becomes refractory to current treatment options. They also noted the need for treatments that can reverse the course of disease (none currently exist) and address key outcomes, and for treatments that are better tolerated and improve adherence and convenience. Additionally, the clinical expert indicated that treatments that reduce treatment frequency and associated socioeconomic burden (i.e., treatment burden for clinicians and associated costs for patients and their families, such as transportation costs and lost income due to missed workdays) are needed.

Place in Therapy

The clinical expert indicated that the anticipated place of faricimab in therapy is as an alternative to other currently available anti-VEGF therapies (i.e., the clinical expert did not expect a shift in the current treatment paradigm for macular edema secondary to RVO). The clinical expert noted that clinical practice, treatment history (suboptimal response with other treatments), access, and drug costs can influence treatment decisions.

Patient Population

The clinical expert indicated that the anticipated target population for faricimab includes all patients with RVO, regardless of subtype, severity, symptoms, and so forth. Additionally, the clinical expert indicated that patients currently being treated with another anti-VEGF therapy may also be considered candidates for treatment with faricimab.

Per the clinical expert input, the diagnosis of RVO involves a detailed retinal examination. To determine the subtype of RVO, supplementary information is required, including an OCT, OCT angiography, and fluorescein angiography. OCT is used to diagnose and quantify macular edema, while OCT angiography and fluorescein angiography are used to assess the degree of ischemia and identify whether there is a need for panretinal photocoagulation.

Assessing Treatment Response

The clinical expert acknowledged the goal of treatment is to improve visual acuity; however, in practice, the clinical expert indicated that the OCT quantitative measurement of macular edema (measurement of CST) is the most important outcome used to assess response to treatment. The clinical expert noted that some clinicians also use qualitative parameters to assess treatment response, such as the presence and size of cystoid spaces.

For visual acuity, the clinical expert indicated that a difference of more than 1 Snellen line of acuity is typically considered clinically meaningful (in the context of a comparison with a similar treatment). However, depending on variability in the light conditions, technician factors, and patient concentration, the clinical expert indicated that a difference of at least 2 Snellen lines can be considered clinically meaningful.

For macular edema measured by OCT, the clinical expert indicated that a difference of 10% is typically considered clinically meaningful.

The clinical expert indicated that assessment of treatment response usually coincides with treatment schedule (i.e., initially, once per month). When the condition is stabilized and the patient enters into the treat-and-extend phase, the clinical expert indicated that both the treatment and response assessment are extended accordingly.

Discontinuing Treatment

The clinical expert suggested the following scenarios in which the discontinuation of faricimab could be considered:

• When the underlying pathology has resolved (in some cases, there may be disease resolution due to recanalization of the thrombotic process).

• When the presence or absence of macular edema shows no difference in acuity due to retinal atrophy, chronic cystoid degeneration, or macular ischemia.

• When the treat-and-extend protocol allows an extension to more than 4 to 6 months between injections.

Prescribing Considerations

Based on clinical expert input, the diagnosis of RVO and treatment with faricimab should ideally be performed by a retina specialist. In situations where a retina specialist is not available, such as in remote areas, the clinical expert advised that the diagnosis of RVO and treatment with faricimab should ideally be performed by a well-trained general ophthalmologist.

The clinical expert further advised that an outpatient setting that is well equipped for ophthalmic examination and OCT imaging is an appropriate setting for treatment with faricimab.

Clinician Group Input

This section was prepared by the review team based on the input provided by the clinician groups.

Inputs from 4 clinician groups were summarized for this review: Toronto Retina Institute (comprising a group of 10 retina specialists in multiple locations across the Greater Toronto Area), Southeastern Ontario Community Ophthalmologists (comprising 2 practising ophthalmologists with a community practice in Southeastern Ontario), Southwestern Ontario Community Ophthalmologists (comprising community-based ophthalmologists practising in Southwestern Ontario), and Northeastern Ontario Community Ophthalmologists (comprising ophthalmologists practising in Northeastern Ontario). In total, 19 ophthalmologists contributed to the clinician input submission. Input across groups was generally sourced from virtual meetings and discussions, emails, and phone calls.

The treatment goals highlighted for RVO were similar across the participating clinician groups. These goals included extending the treatment intervals, reducing macular edema, preserving visual acuity, improving visual acuity, reducing VEGF levels, and preventing neovascularization and neovascular glaucoma in patients with RVO. According to the groups, an ideal treatment is 1 with demonstrated efficacy in sustaining improvements in visual acuity over the long-term and is durable in reducing the treatment burden associated with repetitive intravitreal therapy (i.e., requiring fewer injections, reducing the frequency of patient visits, and lowering costs and the burden on the health care system). According to the clinician groups, the current treatments options for RVO in practice include anti-VEGF treatments (aflibercept 2 mg, ranibizumab, and bevacizumab) and steroids (including dexamethasone and subtenon Kenalog). The clinician groups noted that RVO has a large inflammatory component, and some studies have demonstrated that the Ang-2 pathway is more active in patients with RVO.

The unmet needs identified in the clinician group input submissions were also consistent across groups. The groups highlighted that RVO treatment requires repeated visits (every 4, 5, 6, 7, or 8 weeks) regardless of the type of treatment, which poses a significant burden to patients. There is an unmet need for patients whose condition does not achieve durable responses to existing treatment options. Therefore, there is a need for efficacious, durable, and long-lasting treatments that can minimize treatment burden compared with existing therapies and extend treatment intervals while maintaining efficacy. The clinician groups anticipate that faricimab will offer a valuable additional anti-VEGF and Ang-2 option to potentially extend the treatment interval.

The clinician groups anticipate that faricimab will be used as a first-line option for patients newly diagnosed with RVO based on its bispecific action mechanism. The clinician groups anticipate that faricimab will likely expand treatment options for patients with RVO that fails other anti-VEGF treatments. According to the clinician groups, faricimab would be suited for any patient with RVO, particularly those whose condition has failed to respond to other treatment options, although caution would be exercised for patients who have inflammation from other pre-existing conditions. The clinician groups did not anticipate any misdiagnoses because fluid in the retina is identifiable through OCT; thus, the introduction of faricimab will not impact diagnostic paradigms.

According to the clinician groups, any improvement in swelling, determined with an OCT scan, was considered a clinically meaningful improvement. The groups listed the following outcomes to assess whether a patient’s condition has responded to treatment: stable or improved visual acuity (improved vision); reduced presence of fluid assessed by an OCT scan; improved clinical exam measures of retinal hemorrhages, ischemia, and neovascularization; and fewer injections required and/or an increased interval between injections.

One clinician group highlighted that clinicians use a treat-and-extend protocol to determine whether the interval between treatments can be adjusted and whether treatment response approaches are fairly standardized across the retinal medical community. The clinician groups highlighted that the factors considered for treatment discontinuation would be similar to those considered for currently approved therapies. These include no response or the presence of irreversible macular damage. One group highlighted that if a patient responds well and the treatment extension has increased to 4 months or more, clinicians would assess whether to stop treatment and would ensure the patient undergoes reasonably close observation. However, a new treatment option would be considered if the patient’s treatment interval declines, or they experience progressive vision loss. Another group noted that the discontinuing of faricimab may occur due to patient-related factors such as better perceived efficacy on another therapy or difficulty travelling to the clinic for treatment. According to the groups, faricimab can be administered in any outpatient setting and should preferably be administered by a trained retina specialist.

Drug Program Input

The drug programs provide input on each drug being reviewed through the Reimbursement Review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical expert consulted are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

AMD = age-related macular degeneration; BRVO = branch retinal vein occlusion; CDEC = Canadian Drug Expert Committee; DME = diabetic macular edema; pCPA = pan-Canadian Pharmaceutical Alliance; PM = pathologic myopia; q.12.w. = every 12 weeks; q.16.w. = every 16 weeks; RVO = retinal vein occlusion.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of faricimab 6 mg/0.05 mL solution for intravitreal injection in the treatment of macular edema secondary to RVO. The focus will be placed on comparing faricimab injection with relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of faricimab injection is presented in 2 sections, with the review team’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. The review team’s assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes indirect evidence from the sponsor.

Included Studies

Clinical evidence from the following is included in the review and appraised in this document:

• 2 pivotal studies identified in the systematic review

• 1 ITC.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Description of Studies

Characteristics of the included studies, BALATON and COMINO, are summarized in Table 6.

BALATON and COMINO were phase III, multicentre, randomized, double-masked, active comparator–controlled, parallel-group, 2-part studies. The first part of the studies (day 1 through week 24) evaluated the efficacy, safety, and pharmacokinetics of faricimab every 4 weeks compared with aflibercept every 4 weeks in patients with macular edema secondary to BRVO (in the BALATON trial) or CRVO or HRVO (in the COMINO trial). The second part of the studies (week 24 through week 72) evaluated the efficacy, durability, safety, and pharmacokinetics of faricimab administered at masked treatment intervals of every 4, 8, 12, or 16 weeks based on personalized treatment interval dosing criteria, without an active control. Of note, there was no comparator in part 2 of the studies because all patients from part 1 received faricimab intravitreal injections according to a personalized treatment interval dosing regimen, plus sham procedures to maintain masking of the treatment intervals. The study design is depicted in Figure 1.

Table 6: Details of Studies Included in the Systematic Review

AE = adverse event; BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; C3F8 = octafluoropropane (perfluoropropane); CRC = central reading centre; CRVO = central retinal vein occlusion; CST = central subfield thickness; DME = diabetic macular edema; DR = diabetic retinopathy; ETDRS = Early Treatment Diabetic Retinopathy Study; FFA = fundus fluorescein angiography; HRVO = hemiretinal vein occlusion; nAMD = neovascular age-related macular degeneration; NEI-VFQ-25 = National Eye Institute Visual Functioning Questionnaire–25; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; q.12.w. = every 12 weeks; q.16.w. = every 16 weeks; RVO = retinal vein occlusion; SD-OCT = spectral-domain optical coherence tomography; SS-OCT = swept-source optical coherence tomography.

^aBRVO was defined by retinal hemorrhages, telangiectatic capillary bed, dilated venous system, or other biomicroscopic evidence of RVO (neovascularization, vitreous hemorrhages) in no more than 1 quadrant of the retina drained by the affected vein.

^bCRVO and HRVO were defined by retinal hemorrhages, telangiectatic capillary bed, dilated venous system or other biomicroscopic evidence of RVO (neovascularization, vitreous hemorrhages) in the entire retina (CRVO) or 2 quadrants of the retina (HRVO).

^cCST was defined as the distance (measured in µm) between the internal limiting membrane and Bruch membrane, as assessed by CRC.

^dCST for Cirrus SD-OCT and Topcon SD-OCT were standardized to Spectralis SD-OCT by the CRC.

^eTreatment intervals at week 68 were defined as the treatment interval decision followed at week 68.

^fAbsence was defined as an area of ischemic nonperfusion within the macula of 0 mm² to 0.1 mm².

^gAbsence was defined as an area of leakage within the macular of 0 mm².

Sources: Primary Clinical Study Reports for GR41984 (BALATON)¹⁴ and GR41986 (COMINO),¹⁶ final Clinical Study Report for GR41984 (BALATON),¹⁵ updated Clinical Study Report for GR41986 (COMINO),¹⁷ and version 1 of the statistical analysis plan for GR41984 and GR41986.²⁴ Details included in the table are from the sponsor’s summary of clinical evidence.²

Figure 1: Design of the BALATON and COMINO Studies

IVT = intravitreal; PTI = personalized treatment interval; Q4W = every 4 weeks; W = week.

Sources: Version 2 of the study protocols for GR41984 (BALATON)²⁵ and GR41986 (COMINO).²⁶

Patients were assessed for eligibility during screening, including through the review of colour fundus photographs and SD-OCT (or swept-source OCT) scans by the central reading centre. The diagnosis of macular edema due to RVO was confirmed by the central reading centre. Only 1 eye was assigned as the study eye. If both eyes were eligible, then the eye with the worse BCVA at screening was selected as the study eye.

In part 1 of each study, eligible patients were randomized in a 1:1 ratio through an interactive web-based response system to receive either faricimab 6 mg intravitreal injections every 4 weeks or aflibercept 2 mg intravitreal injections every 4 weeks. Randomization was stratified by the baseline BCVA ETDRS letter score (≥ 55 letters versus ≤ 54 letters in the BALATON trial and (≤ 34 letters, 35 to 54 letters, and ≥ 55 letters in the COMINO trial) and region (US and Canada, Asia, and the rest of the world). Notably, there were no study sites in Canada. In part 2 of each study, all patients received faricimab 6 mg intravitreal injections according to a personalized treatment interval dosing regimen (i.e., no active control was administered during this period). Study visits were scheduled at every 4 weeks for the entire study duration of 72 weeks.

An independent data monitoring committee (DMC) monitored safety and study conduct until the primary analysis was completed. A DMC evaluation of unmasked ocular and systemic safety events was prepared by an independent data coordinating centre every 6 months to provide recommendations to the sponsor regarding ongoing study conduct (e.g., stopping the study early for safety reasons).

Ophthalmology imaging and grading charters and a reading centre charter were prepared to outline the methods and procedures for independently grading medical images and supportive clinical data; the design, conduct, and reporting of grading imaging data; and the roles and responsibilities of the centre. Three central reading centres were used to conduct masked ocular imaging analyses and for storage.

An extension of the global enrolment phase specifically for China could be established (prespecified in the protocol) because patient recruitment was expected to take longer in China. After the global enrolment phase of the COMINO study was completed for the planned sample size for the primary analysis, additional patients continued to be enrolled at sites in China to reach sufficient enrolment to support registration in that country. The COMINO study’s China extension was ongoing at the time of the sponsor’s submission; therefore, data from patients enrolled during the China extension were not included in the primary analyses. However, all patients who were enrolled at sites in China during the global enrolment phase of COMINO were included in the primary analysis. A China extension was not needed for the BALATON trial because sufficient enrolment to support registration in China was reached before the global enrolment phase was completed.

The BALATON and COMINO studies were ongoing at the time of the primary analysis; the present report reflects a data cut-off date of July 6, 2022, and August 9, 2022, respectively, when all patients from the global enrolment phase had either completed the study through week 24 or had discontinued from the study before week 24.

The present report also presents data from the final analysis through week 72, corresponding to the last patient last visit date of June 12, 2023, in the BALATON trial and July 12, 2023, in the COMINO trial (global enrolment phase only).

Populations

Inclusion and Exclusion Criteria

Both the BALATON and COMINO studies included patients aged 18 years and older with foveal centre–involved macular edema secondary to BRVO (in the BALATON trial) or CRVO or HRVO (in the COMINO trial) diagnosed no longer than 4 months before screening and confirmed by the central reading centre based on SD-OCT (or swept-source OCT) images. The BCVA of the study eye had to be 73 to 19 letters, inclusive, as assessed on the ETDRS visual acuity chart at a starting test distance of 4 m on day 1. Further, the CST of the study eye at screening had to be 325 μm or greater, as measured on Spectralis SD-OCT, or 315 μm or greater, as measured on Cirrus SD-OCT or Topcon SD-OCT.

Both the BALATON and COMINO studies excluded patients with a history of retinal detachment or a macular hole (stage 3 or 4) in the study eye. Further, patients were excluded if they had received any prior treatment, or were receiving any current treatment, in the study eye for macular edema due to RVO or for other causes, macular neovascularization, or vitreomacular-interface abnormalities, or intravitreal treatment for any other retinal diseases that can lead to macular edema complications, or prior macular laser. Additionally, patients with a nonfunctioning fellow eye, defined as either BCVA of 20/320 or worse, or no physical presence of a fellow eye were excluded from the trials.

Interventions

Study Treatments

All intravitreal injections of the study drug were performed onsite. Investigators and patients were masked to treatment assignment in part 1 and to both the original treatment assignment and faricimab treatment interval in part 2.

At least 2 investigators were required per site to fulfill the masking requirements. One investigator was masked to treatment assignment and performed ocular assessments, including predose assessments and assessments at screening, at day 7, and at the final or early termination visit. One other investigator was unmasked and performed study treatments as well as post-dose administration safety assessments (i.e., finger counting, hand-motion and/or light-perception tests, intraocular pressure measurements) and treatment of AEs that occurred during or shortly after study treatment administration. Depending on the masked investigator’s decision, patients could self-administer predose and postdose antimicrobials.

Part 1 of the BALATON and COMINO Trials: Day 1 Through Week 24

Patients received intravitreal injections of either faricimab 6 mg or aflibercept 2 mg every 4 weeks for a total of 6 injections.

Dose modifications for faricimab and aflibercept were not permitted in the study. Study treatment interruption and patient discontinuation from study treatment due to AEs were permitted according to the prespecified criteria listed in the protocol.

Part 2 of the BALATON and COMINO Trials: Week 24 Through Week 72

All patients received faricimab 6 mg intravitreal injections every 4, 8, 12, or 16 weeks according to a personalized treatment interval dosing regimen for a total of 3 to 12 injections.

Starting at week 24, all patients received faricimab every 4 weeks until their CST value met the predefined threshold of less than 325 µm for Spectralis SD-OCT or less than 315 µm for Cirrcus SD-OCT and Topcon SD-OCT (initial reference CST), as determined by the central reading centre. If the established reference CST value was stable (i.e., did not increase or decrease by > 10%) with no associated loss of vision of 10 letters or greater relative to their reference BCVA (defined as the mean of the 3 best BCVA scores obtained at any prior dosing visit), then the patient was eligible to have their faricimab dosing interval extended. Thereafter, the treatment intervals were maintained or adjusted based on changes from the reference CST and BCVA values at the faricimab dosing visits. Decisions on the personalized treatment interval were automatically determined by the interactive web-based response system according to the criteria presented in Table 7.

If a patient’s dosing interval, previously extended, needed shortening due to disease progression, the patient was generally not permitted to return to a longer interval later in the study. For example, if the interval was reduced from every 12 weeks to every 8 weeks, then the interval was not extended beyond every 8 weeks for the remainder of the treatment period. However, if a patient’s interval was reduced to every 4 weeks, it could be extended again, but by no more than 4 weeks shorter than the patient’s maximum prior extension. For example, if the interval was reduced from every 16 weeks to every 4 weeks, then the interval could be extended up to every 12 weeks but could not be extended back to every 16 weeks.

Throughout the 72-week study duration, all patients were scheduled for study visits every 4 weeks. To maintain masking of the faricimab treatment intervals, a sham procedure that mimicked an intravitreal injection was conducted during visits when no faricimab injection was administered, per their personalized treatment interval regimen. The sham procedure involved the blunt end of an empty syringe, without a needle, being pressed against an anesthetized eye.

Permitted Therapies

The therapies permitted during the study included maintenance therapies, including, but not limited to, the following:

• Treatment for onset of ocular hypertension or glaucoma in the study eye, as indicated.

• Vitrectomy could be performed at the discretion of the masked investigator in the event that the study eye developed a sight-threatening vitreous hemorrhage or retinal detachment. These conditions were recorded as SAEs and the study treatment would be interrupted and restarted based on patient status, after discussion with the medical monitor.

• Treatment for the onset of cataract or posterior capsular opacification in either eye, as indicated, was permitted. Dose interruption criteria could apply with cataract surgery.

• The short-term use of topical ocular corticosteroids after cataract surgery, yttrium-aluminum-garnet capsulotomy, peripheral iridotomy, argon or selective laser trabeculoplasty, or the presence of ocular allergic conditions in either eye was allowed.

• Complete, sector, or local panretinal photocoagulation in either eye was permitted if needed for the treatment of ischemic RVO or new peripheral neovascularization, after discussion with the medical monitor. Both conditions were recorded as SAEs.

• At the discretion of the masked investigator, the fellow eye could be treated with an anti-VEGF therapy licensed for ocular use if the patient were diagnosed with an ocular condition for which the selected anti-VEGF therapy had been approved by the country’s regulatory agency. Masking was maintained by having the unmasked physician administer treatment with an anti-VEGF if it was to be provided to the fellow eye at the same visit as the study eye treatment.

Table 7: Algorithm for the IxRS-Determined Faricimab Personalized Treatment Interval Dosing Regimen in Part 2 of the BALATON and COMINO Studies

BCVA = best-corrected visual acuity; CST = central subfield thickness; IxRS = interactive web-based response system; SD-OCT = spectral-domain optical coherence tomography.

Notes: The algorithm used by the IxRS for interval decision-making is presented in the preceding table. The criteria were based on the relative change of the CST and BCVA values at the faricimab dosing visits compared with the reference CST and BCVA values.

The initial reference CST value was defined as the CST value when the CST threshold was initially met (< 325 µm for Spectralis SD-OCT or < 315 µm for Cirrcus SD-OCT and Topcon SD-OCT, as determined by the central reading centre), but no earlier than week 20. Reference CST was adjusted if CST decreased by > 10% from the previous reference CST for 2 consecutive faricimab 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.

The reference BCVA was defined as the mean of the 3 best BCVA scores obtained at any prior dosing visit.

Sources: Version 2 protocols for the GR41984 (BALATON)²⁵ and GR41986 (COMINO)²⁶ studies.

Prohibited Therapies

The therapies prohibited during the study included the following:

• systemic anti-VEGF therapy

• bevacizumab (highlighted by the investigator because it is not licensed for ophthalmic use in any participating country)

• systemic drugs known to cause macular edema (fingolimod and tamoxifen)

• intravitreal anti-VEGF drugs other than study-assigned aflibercept and faricimab in the study eye

• intravitreal or periocular steroid implants, or chronic topical ocular corticosteroids in the study eye

• treatment with verteporfin in the study eye

• administration of micropulse and focal or grid laser in the study eye

• other experimental therapies, with the exception of vitamins and minerals.

Outcomes

A list of the efficacy end points assessed in this Clinical Review Report is provided in Table 8 followed by descriptions of the outcome measures. The summarized end points are based on the outcomes included in the sponsor’s summary of clinical evidence as well as any outcomes identified as important to this review, according to the clinical expert consulted, and input from the patient and clinician groups and public drug plans. Using the same considerations, the review team selected end points that were considered to be most relevant to inform expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All of the efficacy end points that were summarized were assessed using GRADE. Select notable harms outcomes considered important for informing expert committee deliberations were also assessed using GRADE.

The following outcome measures and their measurement properties are presented in Table 9.

Table 8: Outcomes Summarized From the BALATON and COMINO Studies

BCVA = best-corrected visual acuity; CST = central subfield thickness; NEI-VFQ-25 = National Eye Institute Visual Functioning Questionnaire–25; 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-OCT = spectral-domain optical coherence tomography.

^aCST was defined as the distance between the internal limiting membrane and Bruch membrane as assessed by the central reading centre.

^bCST for Cirrus SD-OCT or Topcon SD-OCT were standardized to Spectralis SD-OCT by the central reading centre.

^cIntraretinal fluid and subretinal fluid were as measured in the central subfield (centre 1 mm).

^dTreatment intervals at week 68 were defined as the treatment interval decision followed at week 68.

Sources: Version 1 of the statistical analysis plan for the GR41984 (BALATON) and GR41986 (COMINO) studies.²⁴ Details included in the table are from the sponsor’s summary of clinical evidence.²

Table 9: Summary of Outcome Measures and Their Measurement Properties

CST = central subfield thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; MID = minimal important difference; NEI-VFQ-25 = National Eye Institute Visual Functioning Questionnaire–25; OCT = optical coherence tomography; RVO = retinal vein occlusion; SD-OCT = spectral-domain optical coherence tomography; TD-OCT = time-domain optical coherence tomography.

Visual Acuity

The assessments of visual acuity that were determined to be the most relevant for this review were change in BCVA and the proportion of patients with an improvement in BCVA. These outcomes provide information on the degree of improvement in visual acuity and the proportion of patients with an improvement in visual acuity, respectively.

Change from baseline in BCVA at week 24 was the primary end point, and the proportion of patients gaining 15 letters or greater in BCVA at week 24 was a secondary end point in both studies. At each study visit, BCVA was assessed by masked examiners using the ETDRS visual acuity chart at a starting test distance of 4 m for both eyes. Scores are based on the number of letters read correctly on the ETDRS chart, with higher scores indicating better visual acuity (the maximum score is 100 letters).

Anatomic

The assessments of the anatomy of the study eye that were determined to be the most relevant for this review were change in CST as measured by OCT and the proportion of patients with an absence of macular edema and fluid. Based on the clinical expert input, these outcomes provide information on the extent of improvement in tissue swelling or edema, the physiological environment (i.e., re-establishment of the blood–retina barrier), and the presence or absence of cystoid spaces, respectively.

Change from baseline in the CST at week 24, the proportion of patients with an absence of macular edema (defined as CST of < 325 µm) at week 24, and the proportion of patients with an absence of both intraretinal fluid and subretinal fluid (as measured in the central subfield; centre 1 mm) at week 24 were secondary end points in both studies. CST was defined as the distance measured between the internal limiting membrane and Bruch membrane, standardized to Spectralis SD-OCT. SD-OCT (or swept-source OCT, if applicable) imaging was performed for both eyes at each study visit by masked OCT technicians. Images were forwarded to the central reading centres for independent analysis; the analysis was based on the same type of scan and evaluated over time within a patient. The data resulting from this masked review of ocular images were forwarded to the sponsor and the SD-OCT CST values were forwarded to the interactive web-based response system for the determination of the treatment interval.

Vision-Related Functioning and HRQoL

The assessment of vision-related functioning and HRQoL that was determined to be the most relevant for this review was the change in the NEI-VFQ-25 composite score. The NEI-VFQ-25 is used to assess a patient’s perception of vision-related functioning and HRQoL. The questionnaire comprises 11 vision-related subscales (25 items) and a question on general health (1 item). Subscales include general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, colour vision, and peripheral vision. Specific to the BALATON and COMINO studies, an additional 6 appendix items were included in the near activities and distance activities subscales.

Change from baseline in the NEI-VFQ-25 composite score at week 24 was a secondary end point in both studies. The NEI-VFQ-25 was administered by the masked site staff at the clinic or over the telephone. Specifically, the NEI-VFQ-25 was administered before the patient received their disease status, the performance of other assessments, and the administration of study treatment, unless otherwise specified. The composite and subscale scores range from 0 to 100, with higher scores indicating better vision-related functioning and HRQoL.

Treatment Intervals

Treatment interval was identified as a relevant outcome for this review because the clinician groups indicated that an ideal treatment demonstrates a durable effect (i.e., demonstrates efficacy in sustaining improvement in visual acuity over the long-term) as measured by a reduction in the treatment burden associated with repetitive intravitreal injections.

The proportion of patients on each treatment interval of every 4, 8, 12, or 16 weeks at week 68 was a secondary end point in both studies. The treatment intervals at week 68 were defined as the treatment interval decision followed at week 68. The algorithm for the interactive web-based response system that determined the personalized treatment interval dosing regimen for faricimab in part 2 of the BALATON and COMINO studies is presented in Table 7 and discussed in detail in the preceding interventions section.

Safety

Safety assessments consisted of monitoring and recording AEs, including SAEs and AEs of special interest; performing protocol-specified safety laboratory assessments; measuring protocol-specified vital signs; and conducting other protocol-specified tests. AEs were assessed at each study visit.

An independent clinical events coding committee adjudicated the thromboembolic events reported during the study. APTC events were defined as nonfatal strokes or nonfatal myocardial infarctions or vascular deaths (including deaths of unknown cause).

Statistical Analysis

Statistical Hypotheses and Multiple Testing Procedure

Two hypotheses on the primary end point of change from baseline in BCVA at week 24 were tested in the following order:

• The noninferiority of faricimab every 4 weeks compared with aflibercept every 4 weeks at week 24 in the intention-to-treat (ITT) population at a 1-sided significance level of 0.02485.

• The superiority of faricimab every 4 weeks compared with aflibercept every 4 weeks at week 24 in the ITT population at a 2-sided significance level of 0.0497.

If statistical significance was achieved on the noninferiority test, then the test for superiority could proceed.

If the lower bound of a 2-sided 95.03% CI for the difference between treatments was greater than –4 letters (noninferiority margin), intravitreal faricimab 6 mg every 4 weeks was considered noninferior to intravitreal aflibercept 2 mg every 4 weeks.

If the lower bound of a 2-sided 95.03% CI for the difference between treatments was greater than 0 letters, then the test was considered positive, and intravitreal faricimab 6 mg every 4 weeks was considered superior to intravitreal aflibercept 2 mg every 4 weeks.

Statistical testing for the secondary end points was undertaken without adjustment for multiple testing.

A nominal type I error penalty of 0.0001 (2-sided) was applied for each time the DMC reviewed unmasked data before the formal analysis of the primary efficacy end point. The investigators did not anticipate that this type I error adjustment would impact sample size and power. At the time of the primary analysis, it was estimated the DMC would conduct 3 reviews of interim safety data; therefore, the efficacy analyses would be performed with a familywise significance level of 0.0497. The actual adjustment was dependent on the actual number of interim safety reviews conducted by the DMC.

Noninferiority Margin

The 4-letter noninferiority margin was selected based on the statistical rationale for preserving approximately 50% of the benefit compared with sham control, as estimated by the lower limit of a 95% CI, based on the aflibercept pivotal trials in BRVO and CRVO.^33-35 More specifically, based on the results of the aflibercept pivotal trials, the 4-letter noninferiority margin preserved between 44% and 77% of the least estimated benefit of aflibercept relative to a control (sham or grid laser).

Sample Size and Power Calculation

The sample size was determined based on the number of patients enrolled in the global enrolment phase; approximately 570 patients for the BALATON trial and 750 patients for the COMINO trial were planned and then randomized in a 1:1 ratio to receive treatment with either faricimab or aflibercept.

The investigators indicated that a sample size of 285 patients per group for the BALATON trial and 375 patients per group for the COMINO trial would provide greater than 90% power to demonstrate the noninferiority of faricimab to aflibercept based on change in BCVA at week 24 in the ITT population, using the 4-letter noninferiority margin and under the following assumptions:

• no difference in the mean change from baseline in BCVA between the treatment groups

• an SD of 13 letters for the BALATON trial and 15 letters for the COMINO trial for the change from baseline in BCVA at week 24

• 2-sample t tests

• 2.5% 1-sided type I error rate

• 10% dropout rate.

Further, the investigators indicated that the planned sample sizes would provide greater than 80% power to demonstrate a superiority of 3.5 letters for faricimab over aflibercept, under the same SD, test, and dropout assumptions as shown in the preceding list, and a 2-sided type I error rate of 5%.

The investigators also indicated that the planned sample size would provide adequate power for the PP analysis accounting for the potential impact of COVID-19; however, the sponsor decided to stop recruitment at an under-recruitment level of 3% because the impact of COVID-19 was less than anticipated. Enrolment ended after 553 patients were enrolled in the BALATON trial and 730 patients were enrolled in the COMINO trial. The final sample size provided greater than 90% power for the noninferiority assessment and greater than 80% power for the superiority test.

For the China extension, the investigators anticipated that 62 patients would be enrolled in the BALATON trial and 82 patients would be enrolled in the COMINO trial; this included patients who had already been enrolled during the global enrolment phase. The data from patients enrolled at study sites in China during the global enrolment phase of the study were included in the primary analysis; although the data from the patients enrolled at study sites in China during the China extension were not included in the primary analyses, these data will be included in the China subpopulation analysis.

Statistical Model

General Considerations

The analyses described in this section were based on the patients enrolled during the global enrolment phase, excluding the China extension, unless otherwise specified. The efficacy analysis at the primary analysis was based on data through week 24; the efficacy end points at week 24 were measured before the week 24 injection and were included in the comparative analysis.

The analyses of the efficacy outcome measures were stratified by baseline BCVA ETDRS letter score as assessed on day 1 (≥ 55 letters versus ≤ 54 letters for the BALATON trial; ≤ 34 letters versus 35 to 54 letters versus ≥ 55 letters for the COMINO trial) and region (US and Canada, Asia, and the rest of the world).

Continuous outcomes were analyzed using an MMRM. The binary secondary end points were analyzed using a stratified estimation for binomial proportions. The estimates and associated CIs were provided for the mean for continuous variables and the proportion for binary variables for each treatment group, and for the respective differences between aflibercept and faricimab, where applicable. All CIs were 2-sided and at the 95.03% level.

Invalid BCVA values that were confirmed to be inaccurate because the BCVA test was performed incorrectly were excluded from the analyses. Nonstandard BCVA data were included in the analyses, including as assessed by ETDRS BCVA testing with prior visit refraction, and a BCVA test performed by an unmasked certified ETDRS BCVA assessor or by an uncertified experienced ETDRS BCVA assessor. A supplementary PP analysis was performed with the nonstandard BCVA data excluded.

Intercurrent events were defined as the discontinuation of study treatment due to AEs or a lack of efficacy, and the use of any prohibited systemic treatment or prohibited therapy in the study eye, as per protocol. For the primary and secondary end points, intercurrent events were handled by applying a treatment policy strategy.

Primary End Point Analysis

The main analysis for the primary end point of change from baseline in BCVA at week 24 was performed using an MMRM. The model included the following categorical covariates as fixed effects: treatment group, visit, visit by treatment group interactions, baseline BCVA (continuous), and randomization stratification factors. The MMRM model assumed an unstructured covariance structure. It there were convergence problems in the model, then a heterogenous compound symmetry or an autoregressive covariance structure could be fitted.

No interim efficacy or futility analyses were planned or conducted.

Data Imputation Methods

Data for patients with missing baseline assessments were not imputed.

Specific to the primary end point, missing data were implicitly imputed by the MMRM model assuming missing at random.

Sensitivity Analysis

To evaluate the robustness of the main analysis finding, a sensitivity analysis using multiple imputation was performed for the primary efficacy end point (a different approach to handling missing data). Missing BCVA data were assumed to be missing not at random. Each group was imputed separately for patients with missing BCVA data at week 24. An approximate Bayesian bootstrap method was used for imputation. These patients were assumed to have worse outcomes compared with the rest of the population and were imputed from patients with nonmissing BCVA data with the worst outcomes. The number of imputations was set to 100. The analysis was performed using an analysis of covariance model with adjustment for the following covariates: treatment group, baseline BCVA (continuous), and randomization stratification factors.

Supplementary Analyses

To further the understanding of treatment effect, the following supplementary analyses were performed for the primary efficacy end point: a PP analysis, an analysis distinguishing COVID-19–related and non-COVID-19–related intercurrent events, and an analysis using a hypothetical strategy for all intercurrent events.

Of interest to this review were the PP analysis and the analysis using a hypothetical strategy for all intercurrent events.

• The PP analysis was based on the PP population; patients with major protocol deviations that impacted the efficacy evaluation were excluded from the analysis.

• In the analysis using a hypothetical strategy for all intercurrent events, all values were censored after the occurrence of the intercurrent event to estimate a treatment effect in the absence of intercurrent events. Data censored after intercurrent events as per the hypothetical strategy, and missing data due to reasons other than intercurrent events were both implicitly imputed by the MMRM model assuming missing at random.

Subgroup Analyses

The following subgroups were analyzed with respect to the primary end point using the same method described previously:

• baseline BCVA (note that the baseline covariate consisting of the BCVA stratification factor was removed from the model)

  • BALATON trial (BRVO): 54 letters or fewer and 55 letters or greater

  • COMINO trial (CRVO and HRVO): 34 letters or fewer, 35 to 54 letters, and 55 letters or greater

  • low vision of 23 letters or fewer and 24 letters or greater (analysis was performed if a sufficient sample size was available to draw meaningful conclusions)

• region (note that baseline covariate consisting of region stratification factor was removed from the model)

  • US and Canada, Asia, and the rest of the world

• baseline age: younger than 65 years and 65 years and older

• sex: female and male

• race: white, Asian, and other

• baseline RVO status (CRVO and HRVO; applicable only to the COMINO trial).

A forest plot was presented to summarize the results. The subgroup categories could be combined if there was insufficient representation of a specific subpopulation.

Of the subgroups listed previously, baseline RVO status was identified as the most relevant for the purpose of this review to inform expert committee deliberations.

Secondary Outcomes

No formal superiority test was performed for secondary end points. No sensitivity analysis was performed for any secondary end points.

Secondary End Points at the Primary Analysis

At the primary analysis, nominal superiority P values were provided for secondary end points, where applicable, for reference purposes only.

The continuous secondary end points at the primary analysis were analyzed using the same analysis methods used for the main analysis of the primary end point, except for change from baseline in the NEI-VFQ-25 composite score, which was analyzed using an analysis of covariance. The missing data for the change from baseline in the NEI-VFQ-25 composite score at week 24 were not imputed; all observed available data were included in the analysis regardless of intercurrent events.

Binary secondary end points at the primary analysis were analyzed using Cochran-Mantel-Haenszel. The proportion of patients in each treatment group and the difference in proportions between treatment groups were estimated using the weighted average of the observed proportions and the differences in observed proportions over the strata defined by the randomization stratification factor for the baseline BCVA score and region using the Cochran-Mantel-Haenszel weights.^36,37 The CIs were calculated using the normal approximation to the weighted proportions.³⁸ If the response rate was low, an unstratified analysis could be performed. Missing data were imputed using LOCF.

For the proportion of patients gaining 15 letters or greater in BCVA from baseline at week 24, which was a secondary end point, a supplementary analysis was also performed at the primary analysis. The supplementary analysis was performed using the same estimand and analysis method that was used for the main analysis of the binary secondary end points but with the following differences:

• Handling of intercurrent events: A composite variable strategy was applied in which it was assumed that the disease of those patients with an intercurrent event had failed treatment after the intercurrent event.

• Handling of missing data (without intercurrent events): If BCVA at weeks 16, 20, and 24 were all missing, then the disease of those patients was assumed to have failed treatment at week 24; otherwise, missing data were imputed using LOCF.

Secondary End Points at the Final Analysis

At the final analysis, no comparisons between treatment groups were made because all patients received faricimab during part 2 of each study. The proportions of patients on a treatment interval of every 4 weeks, every 8 weeks, every 12 weeks, and every 16 weeks at week 68 were analyzed using descriptive statistics, with the percentage based on the patients who had not discontinued the study at week 68.

Safety Analysis

At the primary analysis, safety was assessed through a descriptive summary based on data obtained before week 24 and the assessments at week 24 that were measured before the administration of the week 24 injection (i.e., data through week 24).

At the final analysis, safety was assessed through a descriptive summary based on data through week 72 according to the following groups: faricimab every 4 weeks before week 24, aflibercept every 4 weeks before week 24, faricimab personalized treatment interval (faricimab every 4 weeks in part 1) on and after week 24, faricimab personalized treatment interval (aflibercept every 4 weeks in part 1) on and after the first dose of faricimab, and all patients who had received at least 1 dose of faricimab with safety data on and after the first dose of faricimab.

In consultation with the clinical expert, no notable harm (in the context of RVO and faricimab) monitored at week 72 was identified. As such, the safety summary through week 72 was not included in this report.

Analysis Populations

Efficacy analyses were based on the ITT population, defined as all patients who were randomized in the study. Supplementary analysis of the primary end point was based on the PP population, defined as all patients randomized in the study who received at least 1 dose of the study treatment and who did not have a major protocol deviation that impacted the efficacy evaluation. Before study unmasking, protocol deviations were reviewed and a determination of the definition of the population for PP analysis was made.

Results

Patient Disposition

A summary of patient disposition through week 24 and week 72 from the BALATON and COMINO studies is presented in Table 12 and Table 13, respectively.

BALATON Trial

A total of 768 patients were screened, of which 215 patients were not randomized in the study due to screening failure; the reasons for screening failure were not reported.

Table 10: Statistical Analysis of Efficacy End Points From the BALATON and COMINO Studies

ANCOVA = analysis of covariance; BCVA = best-corrected visual acuity; CMH = Cochran-Mantel-Haenszel; CST = central subfield thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; LOCF = last observation carried forward; MMRM = mixed model for repeated measures; NEI-VFQ-25 = National Eye Institute Visual Functioning Questionnaire–25; q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; q.12.w. = every 12 weeks; q.16.w. = every 16 weeks; vs. = versus.

Sources: Version 1 of the statistical analysis plan for GR41984 (BALATON) and GR41986 (COMINO).²⁴ Details included in the table are from the sponsor’s summary of clinical evidence.²

A total of 276 patients were randomized to receive faricimab every 4 weeks and 277 patients were randomized to receive aflibercept every 4 weeks. Of those who were randomized, 1.4% (4 patients) in the faricimab group and 1.1% (3 patients) in the aflibercept group discontinued the study before week 24. Each reason for early discontinuation from the study, including lost to follow-up, AEs, withdrawal by patient, and protocol deviation, was reported in less than 2.0% of patients who were randomized in each group. Of those who were randomized, 11.2% (31 patients) in the group of patients who were randomized to receive faricimab in part 1 and 11.9% (33 patients) in the group of patients who were randomized to receive aflibercept in part 1 discontinued the study before week 72. Each reason for early discontinuation from the study was reported in approximately 5.0% of patients or less who were randomized in each group for part 1 of the study.

Table 11: Analysis Populations of the BALATON and COMINO Studies

PP = per protocol; ITT = intention to treat.

^aPatients were grouped according to the treatment assigned at randomization. Patients who were incorrectly randomized to 1 study, discontinued without treatment, and were then randomized to the other study (COMINO or BALATON), were included in the latter study only.

^bPatients were grouped according to the actual treatment received through week 20. If, by error, a patient received a combination of different active study drugs (faricimab and aflibercept) in the study eye, the patient’s treatment group was as randomized.

^cBefore study unmasking, protocol deviations were reviewed and a determination of the definition of the population for PP analysis was made.

Sources: Version 1 of the statistical analysis plan for the GR41984 (BALATON) and GR41986 (COMINO) trials.²⁴ Details included in the table are from the sponsor’s summary of clinical evidence.²

Of those who received treatment, 3.3% (9 of 276 patients) in the faricimab group and 1.1% (3 of 274 patients) in the aflibercept group discontinued study treatment in their study eye before week 24. Each reason for early discontinuation of the study treatment, including lost to follow-up, withdrawal by patient, AEs, and death, was reported in less than 2.0% of patients who received treatment in each group. Of those who received treatment, 11.6% (32 patients) in the group of patients who were randomized to receive faricimab in part 1 and 10.2% (28 patients) in the group of patients who were randomized to receive aflibercept in part 1 discontinued study treatment in their study eye before week 72. Each reason for early discontinuation of the study treatment was reported in approximately 5.0% of patients or less who received treatment in each group.

COMINO Trial

A total of 1,004 patients were screened, of which 274 patients were not randomized in the study due to screening failure; the reasons for screening failure were not reported.

A total of 366 patients were randomized to receive faricimab every 4 weeks and 363 patients were randomized to receive aflibercept every 4 weeks. Of those who were randomized, 1.6% (6 patients) in the faricimab group and 2.8% (10 patients) in the aflibercept group discontinued from the study before week 24. Each reason for early discontinuation, including lost to follow-up, AEs, withdrawal by patient, protocol deviation, death, noncompliance with study drug, physician decision, and other reasons, was reported in less than 2.0% of patients who were randomized in each group. Of those who were randomized, 9.0% (33 patients) in the group of patients who were randomized to receive faricimab in part 1 and 11.0% (40 patients) in the group of patients who were randomized to receive aflibercept in part 1 discontinued the study before week 72. Each reason for early discontinuation from the study was reported in less than 5.0% of patients who were randomized in each group for part 1 of the study.

Of those who received treatment, 3.0% (11 of 365 patients) in the faricimab group and 4.2% (15 of 361 patients) in the aflibercept group discontinued the study treatment in their study eye before week 24. Each reason for early discontinuation of the study treatment, including lost to follow-up, withdrawal by patient, AEs, death, physician decision, noncompliance with study drug, and other reasons, was reported in less than 2.0% of patients who received treatment in each group. Of those who received treatment, 9.9% (36 patients) in the group of patients who were randomized to receive faricimab in part 1 and 11.6% (42 patients) in the group of patients who were randomized to receive aflibercept in part 1 discontinued study treatment in their study eye before week 72. Each reason for early discontinuation of the study treatment was reported in less than 5.0% of patients who received treatment in each group.

Table 12: Summary of Patient Disposition Through Week 24 From the BALATON and COMINO Studies

ITT = intention to treat; NR = not reported; PP = per protocol.

Note: The data presented in the preceding table include discontinuations occurring before day 154 (first day of week 24 analysis visit window).

^aPercentages are based on number of patients treated.

^bPercentages are based on number of patients randomized.

Sources: Primary Clinical Study Reports for GR41984 (BALATON)¹⁴ and GR41986 (COMINO).¹⁶ Details included in the table are from the sponsor’s summary of clinical evidence.²

Table 13: Summary of Patient Disposition Through Week 72 From the BALATON and COMINO Studies

PTI = personalized treatment interval; q.4.w. = every 4 weeks.

Note: The data presented in the preceding table include the discontinuations that occurred through the end of each study.

^aPercentages are based on number of patients treated.

^bPercentages are based on number of patients randomized.

Sources: Final Clinical Study Report for GR41984 (BALATON)¹⁵ and updated Clinical Study Report for GR41986 (COMINO).¹⁷

Protocol Deviations

A summary of protocol deviations through week 24 and week 72 from the BALATON and COMINO studies is presented in Table 14 and Table 15, respectively.

BALATON Trial

A total of 27.2% of patients (75 of 276 patients) randomized to receive faricimab every 4 weeks and 26.4% of patients (73 of 277 patients) randomized to receive aflibercept every 4 weeks had at least 1 major protocol deviation through week 24. The most frequently reported category of protocol deviation was procedural-related, reported for 25.7% of patients (71 patients) in the faricimab group and 24.5% of patients (68 patients) in the aflibercept group. The most common procedural-related protocol deviations (frequency > 5.0% of patients in either group), including missing weeks 20 and 24 and major issues with images of the study eye, were each reported in less than 8.0% of patients in each group. Other categories of major protocol deviations, relating to medication and inclusion and exclusion criteria, were each reported in less than 2.0% of patients in each group.

A total of 52.9% of patients (146 of 276 patients) randomized to receive faricimab in part 1 and 50.9% of patients (141 of 277 patients) randomized to receive aflibercept in part 1 had at least 1 major protocol deviation through week 72. The most frequently reported category of protocol deviation continued to be procedural-related, which was reported for 131 patients (47.5%) randomized to receive faricimab in part 1 and 123 patients (44.4%) randomized to receive aflibercept in part 1. The most common procedural-related protocol deviations were each reported in less than 15.0% of patients in each group. Other categories of major protocol deviations, relating to medication and inclusion and exclusion criteria, were each reported in less than 9.0% of patients in each group.

COMINO Trial

A total of 27.3% of patients (100 of 366 patients) randomized to receive faricimab every 4 weeks and 32.2% of patients (117 of 363 patients) randomized to receive aflibercept every 4 weeks had at least 1 major protocol deviation through week 24. The most frequently reported category of protocol deviation was procedural-related, reported for 25.4% of patients (93 patients) in the faricimab group and 30.6% of patients (111 patients) in the aflibercept group. The most common procedural-related protocol deviations (frequency > 5.0% of patients in either group), including missing weeks 20 and 24 and major issues with images of the study eye, were each reported in less than 6.0% of patients in each group. Other categories of major protocol deviations, relating to medication and inclusion and exclusion criteria, were each reported in approximately 2.0% of patients or less in each group.

Table 14: Summary of Protocol Deviations Through Week 24 From the BALATON and COMINO Studies (ITT Population)

ITT = intention to treat.

Note: Multiple occurrences of the same deviation in an individual patient were counted only once.

^aFrequency greater than 5.0% of patients in either group.

^bMajor issues with images included images not acquired according to study protocol, images not acquired at an attended study visit, and images not submitted to or rejected by reading centre, imaging performed by non–study-certified personnel.

^cNo major protocol deviation was reported in greater than 5.0% of patients in either group.

Sources: Primary Clinical Study Reports for GR41984 (BALATON)¹⁴ and GR41986 (COMINO).¹⁶

Table 15: Summary of Protocol Deviations Through Week 72 From the BALATON and COMINO Studies (ITT Population)

ITT = intention to treat; PTI = personalized treatment interval; q.4.w. = every 4 weeks.

Note: Multiple occurrences of the same deviation in an individual patient were counted only once.

^aFrequency greater than 5.0% of patients in either group.

^bMajor issues with images included images not acquired according to study protocol, images not acquired at an attended study visit, images not submitted to or rejected by reading centre, and imaging performed by non–study-certified personnel.

^cNo major protocol deviation was reported in greater than 5.0% of patients in either group.

Sources: Final Clinical Study Report for GR41984 (BALATON)¹⁵ and updated Clinical Study Report for GR41986 (COMINO).¹⁷

A total of 50.8% of patients (186 of 366 patients) randomized to receive faricimab in part 1 and 54.8% of patients (199 of 363 patients) randomized to receive aflibercept in part 1 had at least 1 major protocol deviation through week 72. The most frequently reported category of protocol deviation continued to be procedural-related, which was reported for 172 patients (47.0%) randomized to receive faricimab in part 1 and 179 patients (49.3%) randomized to receive aflibercept in part 1. The most common procedural-related protocol deviations were each reported in less than 14.0% of patients in each group. Other categories of major protocol deviations, relating to medication and inclusion and exclusion criteria, were each reported in approximately 11.0% of patients or less in each group.

Baseline Characteristics

The baseline characteristics outlined in Table 16 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

BALATON Trial

The mean age of patients was 64.3 years (SD = 10.7 years; range, 35 to 93 years) in the faricimab group and 63.8 years (SD = 10.6 years; range, 28 to 88 years) in the aflibercept group. The distribution of patients by age based on a cut-off of 65 years was well balanced between groups; approximately 50.0% of patients were in each age group (< 65 years and ≥ 65 years). The mean time since RVO diagnosis in the study eye was 1.26 months (SD = 1.88 months; range, 0.2 to 27.7 months) in the faricimab group and 1.65 months (SD = 7.27 months; range, 0.1 to 120.6 months) in the aflibercept group.

The mean BCVA in the study eye was 57.50 letters (SD = 13.04 letters; range, 19.0 to 76.0 letters) in the faricimab group and 57.64 letters (SD = 12.15 letters; range, 21.0 to 73.0 letters) in the aflibercept group. The mean CST in the study eye was 558.32 µm (SD = 177.03 µm; range, 281.0 µm to 1,154.0 µm) in the faricimab group and 558.12 µm (SD = 180.26 µm; range, 290.0 µm to 1,208.0 µm) in the aflibercept group.

The mean intraocular pressure in the study eye was 14.57 mm Hg (SD = 2.88 mm Hg; range, 7.0 mm Hg to 21.0 mm Hg) in the faricimab group and 14.48 mm Hg (SD = 2.94 mm Hg; range, 7.0 mm Hg to 22.0 mm Hg) in the aflibercept group. A total of 1.8% of patients (5 of 276 patients) randomized to receive faricimab and 1.4% of patients (4 of 277 patients) randomized to receive aflibercept were reported with nonproliferative diabetic retinopathy in the study eye. A total of 0.4% of patients (1 patient) randomized to receive faricimab and no patients randomized to receive aflibercept were reported with proliferative diabetic retinopathy in the study eye. A total of 5.8% of patients (16 patients) randomized to receive faricimab and 5.4% of patients (15 patients) randomized to receive aflibercept were reported with glaucoma in the study eye.

The distribution of patients by blood pressure categories (> 160 systolic or > 90 diastolic, ≤ 140 systolic and ≤ 85 diastolic, ≤ 120 systolic and ≤ 80 diastolic) was well balanced between groups, with approximately 20.0%, 50.0%, and 9.0% of patients in each category, respectively. A total of 17.8% of patients (49 of 276 patients) randomized to receive faricimab and 16.6% of patients (46 of 277 patients) randomized to receive aflibercept were reported with type 2 diabetes.

COMINO Trial

The mean age of patients was 65.6 years (SD = 13.1 years; range, 22 to 100 years) in the faricimab group and 64.7 years (SD = 13.3 years; range, 27 to 95 years) in the aflibercept group. The distribution of patients by age based on a cut-off of 65 years was well balanced between groups; approximately 55.0% of patients were aged 65 years and older. The mean time since RVO diagnosis in the study eye was 1.57 months (SD = 6.39 months; range, 0.1 to 120.3 months) in the faricimab group and 1.10 months (SD = 0.95 months; range, 0.1 to 8.9 months) in the aflibercept group. A total of 83.0% of patients (303 of 366 patients) randomized to receive faricimab and 81.9% of patients (294 of 363 patients) randomized to receive aflibercept were reported with CRVO. A total of 17.0% of patients (62 patients) randomized to receive faricimab and 18.1% of patients (65 patients) randomized to receive aflibercept were reported with HRVO.

The mean BCVA in the study eye was 50.25 letters (SD = 16.25 letters; range, 19.0 to 87.0 letters) in the faricimab group and 50.71 letters (SD = 16.34 letters; range, 19.0 to 73.0 letters) in the aflibercept group. The mean CST in the study eye was 702.21 µm (SD = 244.00 µm; range, 266.0 µm to 1,500.0 µm) in the faricimab group and 721.07 µm (SD = 242.86 µm; range, 281.0 µm to 1,419.0 µm) in the aflibercept group.

The mean intraocular pressure in the study eye was 14.89 mm Hg (SD = 3.06 mm Hg; range, 7.0 mm Hg to 25.0 mm Hg) in the faricimab group and 14.97 mm Hg (SD = 3.17 mm Hg; range, 7.0 mm Hg to 26.0 mm Hg) in the aflibercept group. A total of 2.5% of patients (9 of 366 patients) randomized to receive faricimab and 2.5% of patients (9 of 363 patients) randomized to receive aflibercept were reported with nonproliferative diabetic retinopathy in the study eye. A total of 0.3% of patients (1 patient) randomized to receive faricimab and no patients randomized to receive aflibercept were reported with proliferative diabetic retinopathy in the study eye. A total of 10.7% of patients (39 patients) randomized to receive faricimab and 9.4% of patients (34 patients) randomized to receive aflibercept were reported with glaucoma in the study eye.

The distribution of patients by blood pressure categories (> 160 systolic or > 90 diastolic, ≤ 140 systolic and ≤ 85 diastolic, ≤ 120 systolic and ≤ 80 diastolic) was well balanced between groups, with approximately 16.0%, 54.0%, and 14.0% of patients in each category, respectively. A total of 20.2% of patients (74 of 366 patients) randomized to receive faricimab and 21.8% of patients (79 of 363 patients) randomized to receive aflibercept were reported with type 2 diabetes.

Table 16: Summary of Baseline Characteristics From the BALATON and COMINO Studies (ITT Population)

AMD = age-related macular degeneration; BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion; CST = central subfield thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; HRVO = hemiretinal vein occlusion; ITT = intention to treat; NR = not reported; RVO = retinal vein occlusion; SD = standard deviation.

^aNonstandard BCVA data, such as assessed by ETDRS BCVA testing with prior visit refraction and BCVA test performed by an unmasked certified ETDRS BCVA assessor or by an uncertified experienced ETDRS BCVA assessor, were included in the analyses.

^bFrequency greater than 5.0% of patients in either group.

Sources: Primary Clinical Study Reports for GR41984 (BALATON)¹⁴ and GR41986 (COMINO).¹⁶ Details included in the table are from the sponsor’s summary of clinical evidence.²

Prior Ocular Medications

A summary of prior ocular therapies and surgeries from the BALATON and COMINO studies is presented in Table 17.

BALATON Trial

A total of 2.9% of patients (8 of 276 patients) randomized to receive faricimab and 5.8% of patients (16 of 277 patients) randomized to receive aflibercept used at least 1 targeted ocular therapy or treatment in the study eye before the start of the trial. Each applicable therapy or treatment (topical steroids, panretinal photocoagulation laser, dietary supplement, other laser photocoagulation, and all other therapies and treatments) was reported in less than 5.0% of patients in each group.

A total of 17.4% of patients (48 patients) randomized to receive faricimab and 16.6% of patients (46 patients) randomized to receive aflibercept underwent at least 1 ocular surgery or procedure in the study eye before the start of the trial. The most common surgery or procedure (frequency > 5.0% of patients in either group) was cataract surgery, reported for 14.5% of patients (40 patients) in the faricimab group and 11.9% of patients (33 patients) in the aflibercept group.

COMINO Trial

A total of 5.7% of patients (21 of 366 patients) randomized to receive faricimab and 5.0% of patients (18 of 363 patients) randomized to receive aflibercept used at least 1 targeted ocular therapy or treatment in the study eye before the start of the trial. Each applicable therapy or treatment (topical steroids, panretinal photocoagulation laser, dietary supplement, other laser photocoagulation, and all other therapies and treatments) was reported in less than 5.0% of patients of patients in each group.

A total of 17.5% of patients (64 patients) randomized to receive faricimab and 15.2% of patients (55 patients) randomized to receive aflibercept underwent at least 1 ocular surgery or procedure in the study eye before the start of the trial. The most common surgery or procedure (frequency > 5.0% of patients of patients in either group) was cataract surgery, reported for 15.0% of patients (55 patients) in the faricimab group and 11.6% of patients (42 patients) in the aflibercept group.

Table 17: Summary of Prior Ocular Therapies and Surgeries From the BALATON and COMINO Studies (ITT Population)

ITT = intention to treat.

Note: Multiple occurrences of the same therapy, treatment, surgery, or procedure in an individual patient were counted only once.

^aFrequency greater than 5.0% of patients in either group.

Sources: Primary Clinical Study Reports for GR41984 (BALATON)¹⁴ and GR41986 (COMINO).¹⁶

Exposure to Study Treatments

A summary of study treatment exposure in the study eye through week 24 and week 72 from the BALATON and COMINO studies is presented in Table 18 and Table 19, respectively.

BALATON Trial

The mean number of study drug administrations through week 24 was 5.8 administrations (SD = 0.72 administrations; range, 1 to 6 administrations) in the faricimab every 4 weeks group and 5.8 administrations (SD = 0.46 administrations; range, 3 to 6 administrations) in the aflibercept every 4 weeks group. Of the patients who received at least 1 injection of the study drug in the study eye, 1.1% (3 of 276 patients) in the faricimab group and 1.8% (5 of 274 patients) in the aflibercept group had at least 1 interrupted dose through week 24.

The mean number of study drug administrations through week 72 was 10.3 administrations (SD = 3.01 administrations; range, 1 to 18 administrations) in the group of patients who were randomized to receive faricimab in part 1 and 10.6 administrations (SD = 2.96 administrations; range, 4 to 18 administrations) in the group of patients who were randomized to receive aflibercept in part 1. Of the patients who received at least 1 injection of the study drug in the study eye, 6.5% (18 patients) in the group of patients who were randomized to receive faricimab in part 1 and 6.9% (19 patients) in the group of patients who were randomized to receive aflibercept in part 1 had at least 1 interrupted dose through week 72. Each specific reason for an interrupted dose listed in Table 19 was reported in less than 1.0% of patients in each group, while “other” reasons were reported in 4.3% (12 patients) of the patients in the faricimab group and 6.6% (18 patients) of the patients in the aflibercept group.

COMINO Trial

The mean number of study drug administrations through week 24 was 5.7 administrations (SD = 0.68 administrations; range, 1 to 6 administrations) in the faricimab every 4 weeks group and 5.7 administrations (SD = 0.72 administrations; range, 1 to 6 administrations) in the aflibercept every 4 weeks group. Of the patients who received at least 1 injection of the study drug in the study eye, a total of 4.1% (15 of 365 patients) of patients in the faricimab group and 3.0% (11 of 361 patients) of patients in the aflibercept group had at least 1 interrupted dose through week 24.

The mean number of study drug administrations through week 72 was 11.2 administrations (SD = 3.29 administrations; range, 1 to 18 administrations) in the group of patients who were randomized to receive faricimab in part 1 and 10.9 administrations (SD = 3.31 administrations; range, 1 to 18 administrations) in the group of patients who were randomized to receive aflibercept in part 1. Of the patients who received at least 1 injection of the study drug in the study eye, 15.3% (56 patients) in the group of patients who were randomized to receive faricimab in part 1 and 10.8% (39 patients) in the group of patients who were randomized to receive aflibercept in part 1 had at least 1 interrupted dose through week 72. Each specific reason for an interrupted dose listed in Table 19 was reported in less than approximately 2.0% of patients in each group, while “other” reasons were reported in 11.2% (41 patients) and 8.0% (29 patients) of patients in the faricimab and aflibercept groups, respectively.

Table 18: Summary of Study Treatment Exposure in the Study Eye Through Week 24 From the BALATON and COMINO Studies (Safety-Evaluable Population)

BCVA = best-corrected visual acuity; SD = standard deviation.

Sources: Primary Clinical Study Reports for GR41984 (BALATON)¹⁴ and GR41986 (COMINO).¹⁶ Details included in the table are from the sponsor’s summary of clinical evidence.²

Table 19: Summary of Study Treatment Exposure in the Study Eye Through Week 72 From the BALATON and COMINO Studies (Safety-Evaluable Population)

BCVA = best-corrected visual acuity; NR = not reported; PTI = personalized treatment interval; q.4.w. = every 4 weeks; SD = standard deviation.

Sources: Final Clinical Study Report for GR41984 (BALATON)¹⁵ and updated Clinical Study Report for GR41986 (COMINO).¹⁷

Concomitant Ocular Medications

A summary of concomitant therapies and surgeries through week 24 and week 72 from the BALATON and COMINO studies is presented in Table 20 and Table 21, respectively.

BALATON Trial

Of the patients who received at least 1 injection of the study drug in the study eye, 13.8% (38 of 276 patients) randomized to receive faricimab and 20.1% (55 of 274 patients) randomized to receive aflibercept also received at least 1 concomitant ocular medication in the study eye through week 24. Through week 72, 24.3% of patients (67 patients) randomized to receive faricimab in part 1 and 26.3% of patients (72 patients) randomized to receive aflibercept in part 1 received at least 1 concomitant ocular medication in the study eye. No single type of concomitant ocular medication was reported in greater than 5.0% of patients in either group.

A total of 1.1% of patients (3 of 276 patients) randomized to receive faricimab and no patients randomized to receive aflibercept had at least 1 concurrent ocular surgery or procedure in the study eye through week 24. No single type of concurrent ocular surgery or procedure was reported in greater than 5.0% of patients in either group; no patients underwent a vitrectomy. In part 2 of the studies, 3.7% of patients (10 of 270 patients) randomized to receive faricimab in part 1 and 2.6% of patients (7 of 274 patients) randomized to receive aflibercept in part 1 had at least 1 concurrent ocular surgery or procedure in the study eye through week 72. No single type of concurrent ocular surgery or procedure was reported in greater than 5.0% of patients in either group; only 0.4% of patients (1 patient) randomized to receive faricimab in part 1 underwent a vitrectomy.

Of the patients who received at least 1 injection of the study drug in the study eye, 85.9% (237 patients) randomized to receive faricimab and 86.9% (238 patients) randomized to receive aflibercept also received at least 1 concomitant nonocular medication through week 24. Of note, 13.8% (38 patients) and 17.2% (47 patients) of patients, respectively, used at least 1 drug for diabetes. The most common drugs used for diabetes (frequency > 5.0% of patients in either group) were metformin, used by 3.6% of patients (10 patients) in the faricimab group and 8.4% of patients (23 patients) in the aflibercept group, and metformin hydrochloride, used by 5.1% (14 patients) and 4.7% (13 patients) of patients, respectively. The most common drugs used for diabetes (frequency > 5.0% of patients in either group) continued to be metformin and metformin hydrochloride through week 72.

COMINO Trial

Of the patients who received at least 1 injection of the study drug in the study eye, 24.7% (90 of 365 patients) randomized to receive faricimab and 25.2% (91 of 361 patients) randomized to receive aflibercept also received at least 1 concomitant ocular medication in the study eye through week 24. No single type of concomitant ocular medication was reported in greater than 5.0% of patients in either group. Through week 72, 38.4% of patients (140 patients) randomized to receive faricimab in part 1 and 37.7% of patients (136 patients) randomized to receive aflibercept in part 1 received at least 1 concomitant ocular medication in the study eye. The most common concomitant ocular medications used in the study eye (frequency > 5.0% of patients in either group) were dorzolamide hydrochloride plus timolol maleate, and latanoprost.

A total of 1.4% of patients (5 of 366 patients) randomized to receive faricimab and 3.3% of patients (12 of 361 patients) randomized to receive aflibercept had at least 1 concurrent ocular surgery or procedure in the study eye through week 24. No single type of concurrent ocular surgery or procedure was reported in greater than 5.0% of patients in either group; vitrectomy was reported in 0.3% of patients (1 patient) in each group. In part 2 of the studies, 4.2% of patients (15 of 359 patients) randomized to receive faricimab in part 1 and 4.5% of patients (16 of 352 patients) randomized to receive aflibercept in part 1 had at least 1 concurrent ocular surgery or procedure in the study eye through week 72. No single type of concurrent ocular surgery or procedure was reported in greater than 5.0% of patients in either group; 0.3% of patients (1 patient) in each group underwent vitrectomy.

Table 20: Summary of Concomitant Therapies and Surgeries Through Week 24 From the BALATON and COMINO Studies (Safety-Evaluable Population)

ITT = intention to treat.

^aNo single type of treatment or procedure was reported in greater than 5.0% of patients in either group.

^bKey ocular surgery and procedure or key nonocular medication identified by the clinical expert consulted for this review. The clinical expert advised that anti-VEGF therapies are less effective after vitrectomy and consequently can impact treatment decision-making (i.e., extending the treatment interval would be difficult). The clinical expert also advised that drugs used for the treatment of diabetes can cause macular edema.

^cAnti-VEGF treatments before baseline were excluded.

^dFrequency greater than 5.0% of patients in either group.

Sources: Primary Clinical Study Reports for GR41984 (BALATON)¹⁴ and GR41986 (COMINO),¹⁶ and final Clinical Study Report for GR41984 (BALATON).¹⁵

Of the patients who received at least 1 injection of the study drug in the study eye, 85.8% (313 patients) randomized to receive faricimab and 87.3% (315 patients) randomized to receive aflibercept also received at least 1 concomitant nonocular medication through week 24. Of note, a total of 20.5% (75 patients) and 21.6% (78 patients) of patients, respectively, used at least 1 drug for diabetes. The most common drugs used for diabetes (frequency > 5.0% of patients in either group) were metformin, used by 9.9% (36 patients) and 9.1% (33 patients) of patients in the faricimab and aflibercept groups, respectively, and metformin hydrochloride, used by 6.0% (22 patients) and 5.8% (21 patients) of patients in the faricimab and aflibercept groups, respectively. The most common drugs used for diabetes (frequency > 5.0% of patients in either group) continued to be metformin and metformin hydrochloride through week 72.

Efficacy

A summary of key efficacy results from the BALATON (in patients with BRVO) and COMINO (in patients with CRVO and HRVO) studies is presented in Table 22 and Table 23.

Visual Acuity Outcomes

BALATON Trial

The treatment difference in the mean change from baseline in BCVA in the study eye at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −0.6 letters (95% CI, −2.2 to 1.1 letters; P value for superiority test = 0.4978). Based on the analysis for noninferiority followed by the test for superiority, faricimab was statistically noninferior, but not superior, to aflibercept for this end point. A sensitivity analysis was performed for this outcome using multiple imputation to handle missing data differently. Two supplementary analyses were also performed: a PP analysis of the PP population and an analysis using a hypothetical strategy for all intercurrent events. The sensitivity and supplementary analysis results were generally supportive of the primary analysis results.

The treatment difference in the estimated proportion of patients with a gain in BCVA of 15 letters or greater in the study eye from baseline at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −4.3% (95% CI, −12.3% to 3.8%; P = 0.3023). The supplementary analysis result was generally supportive of the primary analysis result.

COMINO Trial

The treatment difference in the mean change from baseline in BCVA in the study eye at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −0.4 letters (95% CI, −2.5 to 1.6 letters; P value for superiority test = 0.6715). Three analyses were performed for this outcome: a sensitivity analysis using multiple imputation to handle missing data differently, a supplementary analysis of the PP analysis population, and a supplementary analysis using a hypothetical strategy for all intercurrent events. The sensitivity and supplementary analysis results were generally supportive of the primary analysis results.

Table 21: Summary of Concomitant Ocular Therapies and Surgeries Through Week 72 From the BALATON and COMINO Studies (Safety-Evaluable Population)

ITT = intention to treat; PTI = personalized treatment interval; q.4.w. = every 4 weeks.

Notes: Part 1 included procedures performed before week 24 treatment or dose hold or, if no dose hold, performed before day 168 (target day of week 24 visit).

Part 2, for the faricimab q.4.w. to faricimab PTI arm, included procedures performed on or after the week 24 treatment or dose hold or, if no dose hold, performed on or after day 168 through week 72. Part 2 for the aflibercept q.4.w. to faricimab PTI arm included procedures performed on or after the date of the first faricimab dose through week 72.

^aFrequency greater than 5.0% of patients in either group.

^bNo single type of treatment or procedure was reported in greater than 5.0% of patients in either group.

^cKey ocular surgery and procedure, or key nonocular medication, identified by the clinical expert consulted for this review. The clinical expert advised that anti-VEGF therapies are less effective after vitrectomy and consequently can impact treatment decision-making (i.e., extending the treatment interval would be difficult). The clinical expert also advised that drugs used for the treatment of diabetes can cause macular edema.

^dAnti-VEGF treatments before baseline were excluded.

Sources: Final Clinical Study Report for GR41984 (BALATON)¹⁵ and updated Clinical Study Report for GR41986 (COMINO).¹⁷

A summary of the relevant subgroup (based on baseline RVO status) analysis results for the primary end point from the COMINO study is presented in Table 24. In the subgroup of patients with CRVO, the treatment difference in the mean change from baseline in BCVA in the study eye at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was 0.2 letters (95% CI, −2.1 to 2.6 letters). In the subgroup of patients with HRVO, the treatment difference in the mean change from baseline in BCVA in the study eye at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −3.8 letters (95% CI, −7.3 to −0.4 letters).

The treatment difference in the estimated proportion of patients with a gain in BCVA of 15 letters or greater in the study eye from baseline at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −1.5% (95% CI, −8.4% to 5.3%; P value = 0.6661). The supplementary analysis result was generally supportive of the primary analysis result.

Anatomic Outcomes

BALATON Trial

The treatment difference in the mean change from baseline in CST in the study eye at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −7.0 µm (95% CI, −14.1 µm to 0.0 µm; P value for superiority test = 0.0495).

The treatment difference in the estimated proportion of patients with an absence of macular edema (defined as CST < 325 µm) at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was 1.4% (95% CI, −2.3% to 5.0%; P value for superiority test = 0.4742).

Table 22: Summary of Key Efficacy Results From the BALATON and COMINO Studies (ITT Population)

AE = adverse event; ANCOVA = analysis of covariance; BCVA = best-corrected visual acuity; CDA-AMC = Canada’s Drug Agency; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; CST = central subfield thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; ITT = intention to treat; LOCF = last observation carried forward; MMRM = mixed model for repeated measures; NEI-VFQ-25 = National Eye Institute Visual Function Questionnaire-25; PP = per protocol; PTI = personalized treatment interval; q.4.w. = every 4 weeks; SE = standard error; vs. = versus.

Note: For missing outcomes that were not due to early study discontinuation, reasons for missing data include study visits missed, and outcomes not measured although patients attended the visit.

^aFor the primary analysis, an MMRM analysis was performed; the model was adjusted for treatment group, visit, visit by treatment group interaction, baseline BCVA (continuous), baseline BCVA (≤ 54 letters vs. ≥ 55 letters in the BALATON trial and ≤ 34 letters, 35 to 54 letters, and ≥ 55 letters in the COMINO trial), and region (US and Canada, Asia, and the rest of the world). An unstructured covariance structure was used. Observed BCVA assessments were used regardless of the occurrence of intercurrent events (i.e., discontinued study treatment due to AEs or lack of efficacy or received any prohibited systemic treatment or prohibited therapy in the study eye). Missing data were implicitly imputed by MMRM. Invalid BCVA values were excluded from analysis. The 95% CI was a rounding of 95.03% CI.

^bFor the primary analysis, if the lower bound of the 2-sided 95% CI for the difference in the adjusted means of the 2 treatments was greater than −4 letters (the noninferiority margin), then faricimab was considered noninferior to aflibercept.

^cThe weighted estimate was based on CMH weights stratified by baseline BCVA score (≤ 54 letters vs. ≥ 55 letters in the BALATON trial and ≤ 34 letters, 35 to 54 letters, and ≥ 55 letters in the COMINO trial) and region (US and Canada, Asia, and the rest of the world). All observed values were used regardless of the occurrence of the intercurrent event. Missing assessments were imputed by LOCF. Proportion was calculated after LOCF imputation. CI was a rounding of 95.03% CI and estimates below 0% or above 100% were imputed as 0% or 100%, respectively. Invalid BCVA values were excluded from the analysis. Absence of macular edema was defined as CST < 325 µm. Intraretinal fluid and subretinal fluid were as measured in the central subfield (centre 1 mm).

^dNo formal superiority test was performed for secondary end points. At the primary analysis, nominal superiority P values were provided for secondary end points, where applicable, for reference purposes only.

^eFor the MMRM analysis, the model was adjusted for treatment group, visit, visit by treatment group interaction, baseline CST (continuous), baseline BCVA score (≤ 54 letters vs. ≥ 55 letters in the BALATON trial and ≤ 34 letters, 35 to 54 letters, and ≥ 55 letters in the COMINO trial) and region (US and Canada, Asia, and the rest of the world). An unstructured covariance structure was used. Observed assessments were used regardless of the occurrence of intercurrent events. Missing data were implicitly imputed by MMRM. The 95% CI was a rounding of 95.03% CI. CST was defined as the distance between the internal limiting membrane and Bruch membrane as assessed by the central reading centre.

^fFor the ANCOVA analysis, the model used the nonmissing change from baseline in the NEI-VFQ-25 composite score at week 24 as the response variables adjusted for the treatment group, baseline NEI-VFQ-25 composite score (continuous), baseline BCVA score (≤ 54 letters vs. ≥ 55 letters in the BALATON trial and ≤ 34 letters, 35 to 54 letters, and ≥ 55 letters in the COMINO trial), and region (US and Canada, Asia, and the rest of the world). Observed NEI-VFQ-25 assessments were used regardless of the occurrence of intercurrent events. Missing data were not imputed. Two patients discontinued the COMINO study before week 24; however, they completed the NEI-VFQ-25 assessment at their end-of-study visit; therefore, they were counted as patients with available data. The 95% CI was a rounding of the 95.03% CI.

Sources: Primary Clinical Study Reports for GR41984 (BALATON trial)¹⁴ and GR41986 (COMINO trial),¹⁶ final Clinical Study Report for GR41984 (BALATON trial),¹⁵ updated Clinical Study Report for GR41986 (COMINO trial),¹⁷ and the sponsor’s October 21, 2024, response to the request by CDA-AMC on October 16, 2024, for additional information.³⁹ Details included in the table are from the sponsor’s summary of clinical evidence.²

Table 23: Summary of Personalized Treatment Interval Outcome at Week 68 From the BALATON and COMINO Studies (ITT Population)

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

^aPercentages were based on patients who were randomized and who had not discontinued the study at week 68. Proportions are descriptive and were unadjusted. The treatment interval at week 68 was defined as the treatment interval decision followed at that visit. Patients received either intravitreal faricimab 6 mg q.4.w. or intravitreal aflibercept 2 mg q.4.w. to week 20. From week 24 (when all patients were scheduled to receive faricimab) onward, patients were treated according to the PTI dosing regimen up to week 68. The 95% CI was a rounding of the 95.03% CI.

Sources: Primary Clinical Study Reports for GR41984 (BALATON trial)¹⁴ and GR41986 (COMINO trial),¹⁶ final Clinical Study Report for GR41984 (BALATON trial),¹⁵ updated Clinical Study Report for GR41986 (COMINO trial),¹⁷ and the sponsor’s October 21, 2024, response to the request by CDA-AMC on October 16, 2024, for additional information.³⁹ Details included in the table are from the sponsor’s summary of clinical evidence.²

Table 24: Summary of Subgroup Analysis Results of the Primary End Point From the COMINO Study (ITT Population)

BCVA = best-corrected visual acuity; CI = confidence interval; CRVO = central retinal vein occlusion; ETDRS = Early Treatment Diabetic Retinopathy Study; HRVO = hemiretinal vein occlusion; MMRM = mixed model for repeated measures; ITT = intention to treat; q.4.w. = every 4 weeks; SE = standard error; vs. = versus.

Note: For the MMRM analysis, the model was adjusted for treatment group, visit, visit by treatment group interaction, baseline BCVA (continuous), baseline BCVA (≤ 34 letters, 35 to 54 letters, and ≥ 55 letters), and region (US and Canada, Asia, and the rest of the world). An unstructured covariance structure was used. Observed BCVA assessments were used regardless of the occurrence of intercurrent events. Missing data were implicitly imputed by MMRM. Invalid BCVA values were excluded from the analysis. The 95% CI was a rounding of the 95.03% CI.

^aThe P value for the superiority test was not adjusted for multiple comparisons.

Source: Primary Clinical Study Report for GR41986 (COMINO).¹⁶

The treatment difference in the estimated proportion of patients with an absence of both intraretinal fluid and subretinal fluid (as measured in the central subfield; centre 1 mm) at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was 5.3% (95% CI, −2.7% to 13.3%; P value for superiority test = 0.1967).

COMINO Trial

The treatment difference in the mean change from baseline in CST in the study eye at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −12.8 µm (95% CI, −26.7 µm to 1.0 µm; P value for superiority test = 0.0684).

The treatment difference in the estimated proportion of patients with an absence of macular edema (defined as CST < 325 µm) at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was 1.7% (95% CI, −2.0% to 5.4%; P value for superiority test = 0.3589).

The treatment difference in the estimated proportion of patients with an absence of both intraretinal fluid and subretinal fluid (as measured in the central subfield; centre 1 mm) at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was 6.5% (95% CI, 0.1% to 13.0%; P value for superiority test = 0.0489).

Vision-Related Functioning and Health-Related Quality of Life Outcome

BALATON Trial

The treatment difference in the mean change from baseline in the NEI-VFQ-25 composite score at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −0.4 (95% CI, −1.9 to 1.1; P value for superiority test = 0.6370).

COMINO Trial

The treatment difference in the mean change from baseline in the NEI-VFQ-25 composite score at week 24 between faricimab every 4 weeks versus aflibercept every 4 weeks was −1.2 (95% CI, −2.7 to 0.3; P value for superiority test = 0.1088).

Treatment Interval Outcomes

BALATON Trial

The proportion of patients on an extended treatment interval at week 68 were as follows (patients randomized to receive faricimab every 4 weeks in part 1 and patients randomized to receive aflibercept every 4 weeks in part 1):

• Faricimab every 8 weeks: 13.3% (95% CI, 9.1% to 17.5%) and 18.0% (95% CI, 13.2% to 22.9%), respectively.

• Faricimab every 12 weeks: 11.7% (95% CI, 7.7% to 15.7%) and 9.4% (95% CI, 5.8% to 13.1%), respectively.

• Faricimab every 16 weeks: 52.4% (95% CI, 46.2% to 58.6%) and 47.5% (95% CI, 41.3% to 53.8%), respectively.

COMINO Trial

The proportion of patients on an extended treatment interval at week 68 were as follows (patients randomized to receive faricimab every 4 weeks in part 1 and patients randomized to receive aflibercept every 4 weeks in part 1):

• Faricimab every 8 weeks: 20.0% (95% CI, 15.7% to 24.3%) and 17.5% (95% CI, 13.3% to 21.7%), respectively.

• Faricimab every 12 weeks: 8.5% (95% CI, 5.5% to 11.5%) and 11.1% (95% CI, 7.6% to 14.6%), respectively.

• Faricimab every 16 weeks: 37.0% (95% CI, 31.8% to 42.2%) and 39.0% (95% CI, 33.7% to 44.4%), respectively.

Harms

A summary of safety results through week 24 from the BALATON and COMINO studies is presented in Table 25.

Additionally, a summary of safety results from baseline through week 72 from the BALATON and COMINO studies is presented in Table 26. Note that there was no comparison group because all patients received faricimab 6 mg intravitreal injections (and sham procedures to maintain masking of the treatment intervals) according to a personalized treatment interval dosing regimen in part 2 of the studies.

AEs Through Week 24

BALATON Trial

Of the patients who received at least 1 injection of the active study drug in the study eye, 16.3% (45 of 276 patients) randomized to receive faricimab and 20.4% (56 of 274 patients) randomized to receive aflibercept were reported with at least 1 ocular AE in the study eye. Each ocular AE in the study eye was reported in less than 4.0% of patients in each group.

Of the patients who received at least 1 injection of the active study drug in the study eye, 1.1% (3 patients) randomized to receive faricimab and 1.5% (4 patients) randomized to receive aflibercept were reported with at least 1 adjudicated APTC-defined AE. Each adjudicated APTC-defined AE was reported in less than 1.0% of patients in each group.

COMINO Trial

Of the patients who received at least 1 injection of the active study drug in the study eye, 23.0% (84 of 365 patients) randomized to receive faricimab and 27.7% (100 of 361 patients) randomized to receive aflibercept were reported with at least 1 ocular AE in the study eye. Each ocular AE in the study eye was reported in less than 4.0% of patients in each group.

Of the patients who received at least 1 injection of the active study drug in the study eye, 1.1% (4 patients) randomized to receive faricimab and 1.4% (5 patients) randomized to receive aflibercept were reported with at least 1 adjudicated APTC-defined AE. Each adjudicated APTC-defined AE was reported in less than 1.0% of patients in each group.

Serious Ocular AEs Through Week 24

BALATON Trial

Of the patients who received at least 1 injection of the active study drug in the study eye, 1.1% (3 patients) randomized to receive faricimab and 0.7% (2 patients) randomized to receive aflibercept were reported with at least 1 serious ocular AE in the study eye. Each serious ocular AE in the study eye was reported in less than 1.0% of patients in each group.

COMINO Trial

Of the patients who received at least 1 injection of the active study drug in the study eye, 2.5% (9 patients) randomized to receive faricimab and 3.3% (12 patients) randomized to receive aflibercept were reported with at least 1 serious ocular AE in the study eye. Each serious ocular AE in the study eye was reported in less than 1.0% of patients in each group.

Withdrawals Due to AEs Through Week 24

BALATON Trial

Of the patients who received at least 1 injection of the active study drug in the study eye, no patients stopped study treatment due to ocular AEs.

COMINO Trial

Of the patients who received at least 1 injection of the active study drug in the study eye, 0.8% (3 patients) randomized to receive faricimab and 0.6% (2 patients) randomized to receive aflibercept stopped study treatment due to ocular AEs. Each ocular AE that led to a patient stopping their study treatment was reported in less than 1.0% of patients in each group.

Mortality Through Week 24

BALATON Trial

Of the patients who received at least 1 injection of the active study drug in the study eye, 0.4% (1 patient due to cerebrovascular accident) randomized to receive faricimab and no patients randomized to receive aflibercept died during the study through week 24.

COMINO Trial

Of the patients who received at least 1 injection of the active study drug in the study eye, 0.3% (1 patient due to pneumonia) randomized to receive faricimab and 0.6% (2 patients due to myocardial infarction) randomized to receive aflibercept died during the study through week 24.

Notable Harms Through Week 24

BALATON Trial

Of the patients who received at least 1 injection of the active study drug in the study eye, no patients were reported with endophthalmitis in the study eye.

COMINO Trial

Of the patients who received at least 1 injection of the active study drug in the study eye, no patients randomized to receive faricimab and 0.3% (1 patient) randomized to receive aflibercept were reported with endophthalmitis in the study eye.

Table 25: Summary of Harms Results Through Week 24 From the BALATON and COMINO Studies (Safety-Evaluable Population)

AE = adverse event; APTC = Antiplatelet Trialists’ Collaboration; MI = myocardial infarctions; NR = not reported; SAE = serious adverse event.

Notes: Multiple occurrences of the same AE in 1 individual patient were counted only once.

Includes AEs with onset before week 24 treatment or dose hold or, if no dose hold, before day 168.

^aFrequency ≥ 1% in any study drug group.

^bTiming of the event was not specified (i.e., unknown if this was chronic increase in intraocular pressure). Intraocular pressure was measured in the study eye at 30 minutes by the unmasked investigator after the study treatment was performed. If the intraocular pressure value was of concern to the unmasked investigator, the patient remained in the clinic and was managed according to the clinical judgment of the unmasked investigator.

^cFrequency ≥ 2% in any study drug group.

^dFrequency ≥ 0.5% in any study drug group.

^eAPTC events were defined as nonfatal strokes or nonfatal myocardial infarctions or vascular deaths (including deaths of unknown cause). If no events occurred for a certain category, the category was not presented.

Sources: Primary Clinical Study Reports for GR41984 (BALATON)¹⁴ and GR41986 (COMINO).¹⁶ Details included in the table are from the sponsor’s summary of clinical evidence.²

Critical Appraisal

Internal Validity

In general, part 1 of the BALATON and COMINO studies were appropriately designed and powered to evaluate the efficacy of faricimab relative to aflibercept. Methods for randomization and allocation concealment were appropriate and there were no notable imbalances in baseline patient disease and demographic characteristics and prior and concomitant ocular therapies and surgeries through week 24. The exception was that patients in the BALATON study had relatively greater baseline BCVA and lower CST values compared with patients in the COMINO study. The investigator indicated these observed baseline ocular differences between patients with BRVO and CRVO or HRVO were expected based on historical pivotal trials in RVO; the clinical expert agreed with this statement. As such, it was concluded that the risk of bias arising from the randomization process is unlikely. In contrast to part 1 of the studies, part 2 of the studies did not have a relevant comparison group; therefore, conclusions about the number of injections relative to aflibercept or any other active comparator could not be drawn (i.e., challenges the ability to draw causal inferences).

Table 26: Summary of Harms Results From Baseline Through Week 72 From the BALATON and COMINO Studies (Safety-Evaluable Population)