Clinical Studies:
YOSEMITE (1 YEAR RESULTS)
Citation: Abreu, F., Adamis, A. P., Eichenbaum, D. A., Haskova, Z., Lin, H., Loewenstein, A., Mohan, S., Wells, J. A., Willis, J. R., Aaberg, T., Alam, S., Amini, P., Antoszyk, A., Asaria, R., Avila, M., Awh, C. C., Bafalluy, J., Bator, G., Burgess, S., … Zatorska, B. (2022). 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. The Lancet (British Edition), 399(10326), 741–755
Key Points
- YOSEMITE was a randomized, double-masked, non-inferiority global trial comparing aflibercept 2mg every 8 weeks, faricimab 6mg every 8 weeks, and faricimab 6mg per personalized treatment interval (PTI) up to week 100.
- PTI dosing interval was extended, maintained, or reduced every 4 weeks up to 16 weeks based on disease activity.
- The primary end-point was mean change in BCVA at 1 year and non-inferiority was achieved between 6 mg faricimab q8weeks, 6 mg faricimab PTI and aflibercept 2mg q8 weeks.
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Objective
To study the safety and efficacy of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody, vs aflibercept in patients with DME.
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Study Design
Randomized, multi-center, double-masked, non-inferiority, phase 3 clinical trial.
Study Subjects
- Major Inclusion Criteria:
- Age 18 and older with center involving macular edema secondary to diabetes type 1 or 2
- Central subfield thickness (CST) of 325 micrometers or more AND BCVA of 25-73 ETDRS
- Anti-VEGF treatment naïve eyes or previously treated greater than 3 months prior to day 1 of the study
- Major Exclusion Criteria:
- High Risk PDR, tractional retinal detachment, preretinal fibrosis, or ERM
- Intravitreal anti-VEGF, PRP, macular laser, or cataract surgery within 3 months of study
- Other causes of macular edema
- Uncontrolled glaucoma
Randomization Scheme/Study Interventions
- Randomized 1:1:1 to:
- Intravitreal faricimab 6mg every 8 weeks (6 initial injections q4 weeks, then q8)
- Intravitreal faricimab 6mg per personalized treatment interval (PTI) (4 initial injections, then PTI)
- Intravitreal aflibercept 2mg every 8 weeks (5 initial injections q4, then q8)
- PTI regimen: automated, protocol-driven dosing regimen based on treat and extend. PTI group received q4week injections until CST < 325 microns at or after week 12.
Endpoints
- Primary Outcome: Mean change from baseline in BCVA at 1 year, averaged at 48, 52, and 56 weeks.
- Secondary Outcomes:
- Proportion of patients in the faricimab PTI group receiving dosing at 4, 8, 12, and 16 weeks at week 52
- Mean Change in CST at primary endpoint and over time
- Proportion of patients without protocol defined diabetic macular edema over time
- Patients with absence of intraretinal fluid over time
- Two-step improvement in Diabetic Retinopathy Severity Scale (DRSS) at week 52
- Safety endpoints: incidence and severity of ocular and non-ocular adverse events
Results
- Study Population: 940 patients enrolled (n = 315 faricimab q8 weeks, n= 313 faricimab PTI, n = 312 aflibercept q8 weeks). 937 (99.7%) in YOSEMITE received at least one dose of study treatment.
- Primary Outcome Results:
- Primary endpoint of noninferiority of mean change in ETDRS from baseline to year 1 was met between faricimab q8weeks or PTI and aflibercept q8weeks.
- Mean change in ETDRS letters from baseline to primary endpoint: 10.7 in faricimab every 8 weeks group, 11.6 in faricimab PTI group, 10.9 in aflibercept q8weeks.
- Secondary Outcome Results:
- Durability in faricimab PTI group: 151 (53%) patients achieved dosing every 16 weeks and 60 (21%) patients achieved dosing every 12 weeks. 194 (68%) of patients achieved q12 or q16 week intervals at week 52 without an intervention reduction.
- Greater reductions in CST in faricimab groups compared to aflibercept q8weeks: -206.6 in faricimab q8weeks, -196.5 in faricimab PTI group, -170.3 in aflibercept q8weeks.
- Higher proportion of patients with absence of protocol defined macular edema in faricimab groups compared to aflibercept (77-87% of faricimab every 8 weeks, 80-82% of faricimab PTI, 64-71% of aflibercept q8weeks).
- Higher proportion of patients with absence of intraretinal fluid (42-48% of faricimab q8week, 34-43% of faricimab PTI group, 22-25% of aflibercept every 8 weeks group).
- Rates of two-step improvement in DRSS: 46% of faricimab q8weeks, 42.5% of faricimab PTI group, 35.8% of aflibercept every 8 weeks.
- Safety Outcome Results:
- Incidence of ocular events and serious ocular adverse events were similar between faricimab and aflibercept.
- Incidence of intraocular inflammation was numerically higher in the faricimab group compared to aflibercept (n=5 (1.6%) faricimab q8 weeks and n=7 (2.2%) PTI versus n=3 (1%) aflibercept q8 weeks). Two cases in PTI group were severe uveitis (1 patient with uveitis and KP with BCVA loss of 30 ETDRS letter, 1 patient with uveitis/chorioretinitis with BCVA loss of 15 ETDRS or more) and 1 case of severe vitritis in faricimab q8 weeks without BCVA loss and with resolution.
Conclusions
- This study demonstrated non-inferiority in vision gains between faricimab every 8 weeks and PTI versus aflibercept, improved anatomical outcomes, and increased durability at year 1.