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-naïve patients were enrolled in these studies, and 664 patients received at least one 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 three initial monthly doses; and 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 (2) doses spaced 16 weeks apart, or three (3) 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-naïve, 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 non- inferiority 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 2, Figure 1, and Figure 2 below. The clinical efficacy for the second year of the study has not been reviewed.

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.