TENAYA and LUCERNE: Rationale and Design for the Phase 3 Clinical Trials of Faricimab for Neovascular Age-Related Macular Degeneration

Abstract

Purpose: To describe the design and rationale of the phase 3 TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) trials that aimed to assess efficacy, safety, and durability of faricimab, the first bispecific antibody for intraocular use, which independently binds and neutralizes both angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A) versus aflibercept in patients with neovascular age-related macular degeneration (nAMD).

Design: Identical, global, double-masked, randomized, controlled, phase 3 clinical trials.

Participants: Adults with treatment-naïve nAMD.

Methods: These trials were designed to evaluate patients randomized to receive faricimab 6.0 mg up to every 16 weeks after 4 initial every-4-week doses or aflibercept 2.0 mg every 8 weeks after 3 initial every-4-week doses. The initial doses in the faricimab arm were followed by individualized fixed treatment intervals up to week 60, based on disease activity assessment at weeks 20 and 24, guided by central subfield thickness, best-corrected visual acuity (BCVA), and investigator assessment. The primary efficacy end point was BCVA change from baseline averaged over weeks 40, 44, and 48. Secondary end points included the proportion of patients receiving every-8-week, every-12-week, and every-16-week faricimab and anatomic outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. From week 60, faricimab-treated patients followed a personalized treatment interval (PTI), a novel protocol-driven treat-and-extend regimen with interval adjustment from every 8 weeks to every 16 weeks based on individualized treatment response measured by anatomic criteria, functional criteria, and investigator assessment of patients' disease activity.

Main outcome measures: Rationale for trial design and PTI approach.

Results: The TENAYA and LUCERNE trials were the first registrational trials in nAMD to test fixed dosing regimens up to every 16 weeks based on patients' disease activity in year 1 and incorporate a PTI paradigm during year 2. The PTI approach was designed to tailor treatment intervals to individual patient needs, to reflect clinical practice treatment practice, and to reduce treatment burden.

Conclusions: The innovative trial design rationale for the TENAYA and LUCERNE trials included maximizing the benefits of angiopoietin-2 blockade through dosing up to every 16 weeks and PTI regimens based on patients' disease activity while fulfilling health authority requirements for potential registrational efforts.

Keywords: Anti-VEGF therapy; BCVA, best-corrected visual acuity; CNV, choroidal neovascularization; CRC, central reading center; CST, central subfield thickness; FFA, fundus fluorescein angiography; Faricimab; Neovascular age-related macular degeneration; PTI, personalized treatment interval; Personalized treatment interval; T&E, treat-and-extend; VEGF, vascular endothelial growth factor; nAMD, neovascular age-related macular degeneration.

© 2021 by the American Academy of Ophthalmology.

Figures

Figure 1

Diagram showing (A) study profile and (B) study design of the TENAYA and LUCERNE trials. ∗Protocol-defined assessment of disease activity at weeks 20 and 24. Patients with anatomic or functional signs of disease activity at these time points received treatment every 8 weeks (Q8W) or every 12 weeks, respectively. †Change from baseline in best-corrected visual acuity (BCVA), as measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 m, based on an average of the week 40, 44, and 48 visits. ‡Personalized treatment interval (PTI): interactive voice or web-based response systemguided flexible dosing in the faricimab arms starting at week 60. From week 60 onward, patients in the faricimab arm are treated according to a PTI dosing regimen between Q8W and every 16 weeks (Q16W). CST = central subfield thickness; nAMD = neovascular age-related macular degeneration; R = randomized.

Figure 2

Personalized treatment interval (PTI) scenario examples. A, Disease activity resulting from best-corrected visual acuity (BCVA) met at week 24 and patient dosed every 12 weeks (Q12W) until week 60; at week 60, based on PTI assessment, patient meets the criteria for interval extension from Q12W to every 16 weeks (Q16W). B, No disease activity observed at weeks 20 and 24 and patient dosed Q16W until week 60; patient meets the PTI criteria for interval reduction at week 60, and interval reduced from Q16W to Q12W because of a 10-letter decrease in BCVA at week 60 compared with the highest on-study drug dosing measurement that is attributable to neovascular age-related macular degeneration disease activity. C, Active disease at week 20 resulting from both BCVA decrease and central subfield thickness (CST) increase compared with the previous 2 visits, resulting in the patient being dosed every 8 weeks (Q8W) until week 60; during the week 60 PTI assessment, patient meets the interval extension criteria from Q8W to Q12W. ETDRS = Early Treatment Diabetic Retinopathy Study.