Description
Faricimab is a humanized bispecific antibody that acts through inhibition of two pathways by binding to vascular endothelial growth factor A (VEGF-A) and angiopoietin 2 (Ang-2). By inhibiting VEGF-A, faricimab suppresses endothelial cell proliferation, neovascularization and vascular permeability. By inhibiting Ang-2, faricimab is thought to promote vascular stability and desensitize blood vessels to the effects of VEGF-A. Ang-2 levels are increased in some patients with nAMD and DME. The contribution of Ang-2 inhibition to the treatment effect and clinical response for nAMD and DME has yet to be established.

Policy
Initial Criteria

1. Member has one of the following diagnoses:
   1. Neovascular (wet) age-related macular degeneration (nAMD)
   2. Diabetic macular edema (DME), AND
2. Prescribed by or in consultation with an ophthalmologist, AND
3. Member does not have ocular or periocular infection, AND
4. Member does not have active intraocular inflammation, AND
5. Trial and failure, contraindication, or intolerance to ONE of the following:
   1. Compounded Avastin* prepared by a 503(B) Outsourcing Facility, or
   2. Lucentis (ranibizumab)

Auth duration: 6 months

Reauthorization Criteria

1. Documentation of positive clinical response to therapy (such as: Improvement in Best Corrected Visual Acuity (BCVA) compared to baseline, stable vision)

Auth duration: 12 months

Rationale
This medical policy was developed in June 2022 and is based on the clinical studies provided to the U.S. Food and Drug Administration for approval.

Neovascular (wet) Age-Related Macular Degeneration (nAMD) (1)
The safety and efficacy of Vabysmo were assessed in two randomized, multi-center, double-masked, active comparator-controlled, 2-year studies (TENAYA - NCT03823287 and LUCERNE - NCT03823300) in patients with nAMD.

A total of 1,329 newly diagnosed, treatment-naive patients were enrolled in these studies, and 664 patients received at least 1 dose of Vabysmo. Patient ages ranged from 50 to 99 with a mean of 75.9 years. The studies were identically designed two-year studies. Patients were randomized in a 1:1 ratio to one of two treatment arms: 1) aflibercept 2 mg administered fixed every 8 weeks (Q8W) after 3 initial monthly doses; and 2) Vabysmo 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection every 4 weeks (approximately every 28 ± 7 days, monthly) for the first 4 doses, followed by optical coherence tomography and visual acuity evaluations 8 and 12 weeks later to determine whether to give a 6 mg (0.05 mL of 120 mg/mL solution) dose via intravitreal injection on one of the following three regimens: 1) Weeks 28 and 44; (also referred to as Q16W dosing); 2) Weeks 24, 36 and 48 (also referred to as Q12W dosing); or 3) Weeks 20, 28, 36 and 44 (also referred to as Q8W dosing). However, the utility of these criteria to guide dosing intervals has not been established.

At week 48, after 4 initial monthly doses in the Vabysmo arm, 45% of patients received the Weeks 28 and 44 dosing, 33% of patients received the Weeks 24, 36 and 48 dosing, and the remaining 22% of patients received dosing every 8 weeks. These percentages are reflective of what happened within the conduct of these trials and indicate that some patients did well on two doses spaced 16 weeks apart, or three doses spaced 12 weeks apart, but the percentages may not be generalizable to a broader nAMD population for a variety of reasons. The inclusion/exclusion criteria limited enrollment to a select subset of treatment naive, newly diagnosed nAMD patients and there is no empirical data that a similar magnitude would be observed if eligibility criteria allowed for broader enrollment. The disease activity criteria, which was instrumental in determining dose frequency, is unvalidated. Stricter criteria would have changed how patients were treated resulting in different percentages of subjects in each dose interval cohort. There was not a similarly dosed aflibercept arm for comparison, which makes the percentages difficult to interpret.

Both studies demonstrated non-inferiority to the comparator control (aflibercept) at the primary endpoint, defined as the mean change from baseline in Best Corrected Visual Acuity (BCVA) when averaged over the week 40, 44, and 48 visits and measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter chart. The primary endpoint analysis was a noninferiority comparison for the mean change in BCVA between the aflibercept and the Vabysmo arm. The lower bound of the 95% confidence interval for the mean change in BCVA could not be lower than minus 4 letters to declare non-inferiority. In both studies, Vabysmo treated patients had a non-inferior mean change from baseline in BCVA compared to patients treated with aflibercept. Detailed results of both studies are shown in Table 1, Figure 1, and Figure 2 below. The clinical efficacy for the second year of the study has not been reviewed.

Table 1. Primary Endpoint Results^a in the TENAYA and LUCERNE Studies

^a Average of weeks 40, 44 and 48.

BCVA: best corrected visual acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; CI: confidence interval; LS: least square.

Figure 1. Mean Change in Visual Acuity from Baseline to Week 48 in TENAYA

Figure 2. Mean Change in Visual Acuity from Baseline to Week 48 in LUCERNE

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline visual acuity) in each study were consistent with the results in the overall population.

Diabetic Macular Edema (1)
The safety and efficacy of Vabysmo were assessed in 2 randomized, multi-center, double-masked, active comparator-controlled 2-year studies (YOSEMITE - NCT03622580 and RHINE - NCT03622593) in patients with DME.

A total of 1,891 diabetic patients were enrolled in the two studies with a total of 1,262 patients treated with at least 1 dose of Vabysmo. Patient ages ranged from 24 to 91 with a mean of 62.2 years. The overall population included both anti-VEGF naive patients (78%) and patients who had been previously treated with a VEGF inhibitor prior to study participation (22%).

The studies were identically designed 2-year studies. Patients were randomized in a 1:1:1 ratio to 1 of 3 treatment regimens: 1) aflibercept Q8W, patients received fixed aflibercept 2 mg administered every 8 weeks (Q8W) after the first 5 monthly doses; 2) Vabysmo Q8W, patients received fixed Vabysmo 6 mg administered Q8W after the first 6 monthly doses; and 3) Vabysmo Variable, patients received Vabysmo 6 mg administered every 4 weeks for at least 4 doses and until the central subfield thickness (CST) of the macula measured by optical coherence tomography was less than approximately 325 microns, then the interval of dosing was modified by up to 4-week interval extensions or reductions in up to 8 week interval increments based on CST and visual acuity disease activity criteria at study drug dosing visits. However, the utility of these disease activity criteria to guide dosing intervals has not been established.

After 4 initial monthly doses, the patients in the Vabysmo variable arm could have received between the minimum of three and the maximum of 11 total injections through Week 56 inclusive. At Week 56, 32% of patients had completed at least one Q12W interval followed by one full Q16W interval. Seventeen percent (17%) of patients were treated on Q8W and/or Q4W dosing intervals through Week 56 (7% only on Q4W). Sustainability of the Q16W dosing interval cannot be determined based on year 1 data alone. These percentages are reflective of what happened within the conduct of these trials, but the percentages are not generalizable to a broader DME population for a variety of reasons. The inclusion/exclusion criteria limited enrollment to a select subset of DME patients and there is no empirical data that a similar magnitude would be observed if eligibility criteria allowed for broader enrollment. The disease activity criteria, which was instrumental in determining dose frequency, is unvalidated. Stricter criteria would have changed how patients were treated resulting in different percentages of subjects in each dose interval cohort. There was not a similarly dosed aflibercept arm for comparison which makes the percentages difficult to interpret.

Both studies demonstrated non-inferiority to the comparator control (aflibercept) at the primary endpoint, defined as the primary endpoint, defined as the mean change from baseline in BCVA at year 1 (average of the week 48, 52 and 56 visits), measured by the ETDRS Letter Score. The primary endpoint analysis was a non-inferiority comparison for the mean change in BCVA between the aflibercept and Vabysmo groups. The lower bound of the 97.5% confidence interval for the mean change in BCVA could not be lower than minus 4 letters to declare noninferiority. In both studies, Vabysmo Q8W and Vabysmo Variable treated patients had a mean change from baseline in BCVA that was non-inferior to the patients treated with aflibercept Q8W. Detailed results of both studies are shown in Table 2, Figure 3 and Figure 4 below. The clinical efficacy for the second year of the study has not been reviewed.

Table 2. Primary Endpoint Results^a in the YOSEMITE and RHINE Studies

^a Average of weeks 48, 52, 56.

Q8W: Every 8 weeks; BCVA: best corrected visual acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; CI: confidence interval; LS: least square.

Figure 3. Mean Change in Visual Acuity from Baseline to Year 1 (Week 56) in YOSEMITE

Figure 4. Mean Change in Visual Acuity from Baseline to Year 1 (Week 56) in RHINE

Treatment effects in the subgroup of patients who were anti-VEGF naive prior to study participation were similar to those observed in the overall population. Treatment effects in evaluable subgroups (e.g., by age, gender, race, baseline HbA1c, baseline visual acuity) in each study were generally consistent with the results in the overall population.

Summary of Evidence
Based on the clinical studies provided to the U.S. Food and Drug Administration for approval, faricimab-svoa (Vabysmo™) may be medically necessary for the treatment of patients with neovascular (wet) age-related macular degeneration (nARMD) or diabetic macular edema (DME). All other indications are considered experimental, investigational and/or unproven due to lack of clinical evidence.

References

1. U.S. Food and Drug Administration. Highlights of Prescribing Information. Vabysmo™ (faricimab-svoa). January 2022. Available at: <www.accessdata.fda.gov>. Accessed June 10, 2022.
2. Vabysmo [package insert]. South San Francisco, CA; Genentech, Inc.; January 2022. Accessed January 2022.
3. Solomon SD, Chew E, Duh EJ, et al. Diabetic Retinopathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017 Mar;40(3):412-418.
4. American Academy of Ophthalmology-Preferred Practice Patterns (AAO-PPP) Retina/Vitreous Panel, Hoskins Center for Quality Eye Care. Diabetic Retinopathy PPP – Update 2017. Nov 2017.
5. American Academy of Ophthalmology-Preferred Practice Patterns (AAO-PPP) Retina/Vitreous Panel, Hoskins Center for Quality Eye Care. Retinal Vein Occlusions PPP – Update 2017. Nov 2017.
6. American Academy of Ophthalmology-Preferred Practice Patterns (AAO-PPP) Retina/Vitreous Panel, Hoskins Center for Quality Eye Care. Age-Related Macular Degeneration PPP – Update 2017. Nov 2017.
7. Royal College of Ophthalmologists. Clinical Guidelines – Retinal Vein Occlusion (RVO) Guidelines – July 2015. Accessed at https://www.rcophth.ac.uk/standards-publications-research/clinical-guidelines.
8. Heier JS, Khanani AM, Quezada et al; TENAYA and LUCERNE Investigators. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet. 2022 Jan 21. pii: S0140-6736(22)00010-1. doi: 10.1016/S0140-6736(22)00010-1.
9. Wykoff CC, Abreu F, Adamis AP, et al; YOSEMITE and RHINE Investigators. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials. Lancet. 2022 Jan 21. pii: S0140-6736(22)00018-6. doi: 10.1016/S0140-6736(22)00018-6.
10. Vabysmo [package insert]. South San Francisco, CA; Genentech, Inc.; January 2022. Accessed January 2022.
11. Solomon SD, Chew E, Duh EJ, et al. Diabetic Retinopathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017 Mar;40(3):412-418.
12. American Academy of Ophthalmology-Preferred Practice Patterns (AAO-PPP) Retina/Vitreous Panel, Hoskins Center for Quality Eye Care. Diabetic Retinopathy PPP – Update 2017. Nov 2017.
13. American Academy of Ophthalmology-Preferred Practice Patterns (AAO-PPP) Retina/Vitreous Panel, Hoskins Center for Quality Eye Care. Retinal Vein Occlusions PPP – Update 2017. Nov 2017.
14. American Academy of Ophthalmology-Preferred Practice Patterns (AAO-PPP) Retina/Vitreous Panel, Hoskins Center for Quality Eye Care. Age-Related Macular Degeneration PPP – Update 2017. Nov 2017.
15. Royal College of Ophthalmologists. Clinical Guidelines – Retinal Vein Occlusion (RVO) Guidelines –July 2015. Accessed at https://www.rcophth.ac.uk/standards-publicationsresearch/clinical-guidelines.
16. Heier JS, Khanani AM, Quezada et al; TENAYA and LUCERNE Investigators. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular agerelated macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet. 2022 Jan 21. pii: S0140-6736(22)00010-1. doi:10.1016/S0140-6736(22)00010-1.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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