Investigative antibody shows sustained efficacy in retinal disease studies
Results from Phase 3 trials of bispecific antibody faricimab demonstrate that it is more durable than currently available agents, and it has a good safety profile.
Reviewed by Dr Arshad M. Khanani.
Extensive preclinical data show that inhibition of the protein angiopoietin-2 (Ang-2) can lead to reduced endothelial barrier breakdown, vascular leakage, inflammatory responses and neovascularisation, as well as increased pericyte coverage.1,2 An investigational bispecific antibody, faricimab (Roche), works by neutralising Ang-2 and vascular endothelial growth factor A (VEGF-A) via simultaneous and independent binding. This dual approach might offer benefits beyond anti-VEGF monotherapy in the management of chronic retinal disease.
Primary 1-year results from global Phase 3 comparator-controlled trials investigating faricimab in diabetic macular oedema (DMO) and neovascular age-related macular degeneration (nAMD) were presented during Bascom Palmer Eye Institute’s Angiogenesis, Exudation, and Degeneration 2021 Meeting in February and further reviewed in presentations at The Association for Research in Vision and Ophthalmology (ARVO) 2021 Annual Meeting.
The drug candidate demonstrated sustained efficacy and the potential for extended durability, with the majority of participants on treatment intervals of at least every 12 weeks at 1 year (Table 1).3-6 The studies supporting these findings are discussed as follows.
1Averaged over Weeks 48, 52, 56;
2Averaged over Weeks 40, 44, 48;
Data quality and integrity were of acceptable standard for filing despite COVID-19 pandemic.
Abbreviations: BCVA, best corrected visual acuity; DMO, diabetic macular oedema; nAMD, neovascular age-related macular degeneration; PTI, personalised treatment interval; Q12W, every 12 weeks; Q16W, every 16 weeks.
DMO studies
The YOSEMITE and RHINE DMO trials, enrolling 1,891 participants across 353 study sites, met the primary endpoint for vision change from baseline at 1 year. Gains in best-corrected visual acuity (BCVA) from baseline (averaged over Weeks 48, 52 and 56) with faricimab 6 mg, dosed every 8 weeks (Q8W) after four monthly loading doses—or personalised treatment interval (PTI) up to every 16 weeks (Q16W) after six loading doses—were non-inferior to aflibercept (Eylea, Regeneron) 2 mg administered Q8W after five loading doses in patients with DMO.
Although neither faricimab treatment arm demonstrated superiority over aflibercept for vision change, improved anatomic outcomes were observed. Change in central subfield thickness (CST) from baseline consistently favoured faricimab, and more faricimab-treated patients achieved absence of both DMO and intraretinal fluid. Rates of absence of subretinal fluid were high and comparable between faricimab and aflibercept, and the proportion of patients showing improvement in diabetic retinopathy severity was similar across treatments.
Patients in the faricimab PTI arm were treated using a standardised objective regimen based on the treat-and-extend concept, with dosing interval adjusted (4-week increments up to a maximum of 16 weeks) based on treatment response as measured by CST and BCVA. In the faricimab PTI arm, 72% were on quarterly or longer dosing intervals, with 52% on 4-monthly dosing intervals, at Week 52. Across both Phase 3 studies throughout Year 1, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and the potential for extended dosing using the PTI algorithm.
nAMD studies
TENAYA and LUCERNE are global Phase 3 studies evaluating the efficacy and safety of faricimab dosed up to Q16W after four initial monthly doses compared with aflibercept given Q8W after three monthly loading doses in 1,329 treatment-naive patients with choroidal neovascularisation secondary to AMD. The trials are taking place across 271 sites worldwide.
aCST values obtained at site will be entered into the interactive voice or web-based response system (IxRS) at Weeks 12, 16, 20 and 24.
Abbreviations: BCVA, best-corrected visual acuity; CST, central subfield thickness; nAMD, neovascular age-related macular degeneration; OCT, optical coherence tomography.
The studies have two treatment arms: faricimab 6 mg given at fixed intervals of every 8, 12 or 16 weeks after four monthly loading doses, based on disease activity assessment (BCVA and CST criteria as well as investigator’s evaluation) at Weeks 20 and 24, and aflibercept 2 mg given at fixed Q8W intervals after three initial monthly doses (Table 2).7 After assignment to the respective treatment interval group, no subsequent interval adjustments nor rescue injections were permitted.
The faricimab treatment protocol was informed by results from the Phase 2 STAIRWAY clinical trial for nAMD, where 65% of faricimab-treated patients had no disease activity 12 weeks after the last loading dose.8 Vision gains were fully maintained up until Week 52 with faricimab dosed up to Q16W and Q12W and were comparable to monthly ranibizumab, suggesting extended disease stability after faricimab treatment.
In TENAYA and LUCERNE, mean gains in BCVA from baseline for faricimab dosed up to Q16W were non-inferior to aflibercept Q8W in patients with nAMD at 1 year, averaged over Weeks 40, 44 and 48: +5.8 letters versus +5.1 letters respectively in TENAYA and +6.6 letters for both treatments in LUCERNE. A comparable proportion of patients gained or maintained vision with faricimab and aflibercept, with meaningful and comparable reductions in CST from baseline until Week 48.
The proportion of faricimab patients on at least Q12W dosing intervals was 79% and the proportion on Q16W dosing intervals was 45% during the first year. The median number of injections was six with faricimab and eight with aflibercept.
Vitreo-retinal specialist Dr Arshad M. Khanani commented: “For me, the biggest unmet need in patients with nAMD is durability. Data from numerous studies reveal that patients with nAMD are not receiving the injections they need in the real world, with undertreatment and inferior vision outcomes compared with clinical trials.”
He added: “Data from the global Phase 3 trials of faricimab in nAMD demonstrate better durability than the current available anti-VEGF agents, with eight out of ten patients achieving sustained vision gains on quarterly or longer treatment intervals and with a well-tolerated safety profile. This is great news for physicians and patients that we may have a more durable option in the future to decrease treatment burden for patients with nAMD.”
Future long-term outcome data, including second-year results from the faricimab Phase 3 programme and the planned 2-year extension studies, will provide additional important insights into better understanding the benefits of dual Ang-2/VEGF inhibition and resulting vascular stability.
References
1. Regula JT, Lundh von Leithner P, Foxton R, et al. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol Med. 2016;8:1265-1288. Erratum: EMBO Mol Med. 2019;11:e10666.
2. Joussen AM, Ricci F, Paris LP, et al. Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data. Eye (Lond). 2021;35:1305-1316.
3. Wykoff CC, Abreu F, Basu K, et al. Faricimab in diabetic macular edema (DME): YOSEMITE and RHINE study results. Presentated at: Bascom Palmer Eye Institute Angiogenesis, Exudation, and Degeneration. 12–13 February 2021; virtual.
4. Heier JS, Basu K, Ives J, et al. Faricimab in neovascular age-related macular degeneration: TENAYA and LUCERNE study results. Presentated at: Bascom Palmer Eye Institute Angiogenesis, Exudation, and Degeneration. 12–13 February 2021; virtual.
5. Wells JA, Wykoff CC, Willis JR, et al. Efficacy, durability, and safety of faricimab in diabetic macular edema (DME): one-year results from the phase 3 YOSEMITE and RHINE trials. Presented at: The Association for Research in Vision and Ophthalmology. 1–7 May 2021; virtual.
6. Khanani AM, Heier J, Ruiz CQ, et al. Faricimab in neovascular age-related macular degeneration: 1-year efficacy, safety, and durability in the phase 3 TENAYA and LUCERNE trials. Presented at: The Association for Research in Vision and Ophthalmology. 1–7 May 2021; virtual.
7. Guymer RH, Ruiz CQ, Willis JR, et al. Dual angiopoietin-2 and VEGF-A inhibition with faricimab in neovascular age-related macular degeneration: phase 3 TENAYA and LUCERNE trial design. Presented at: The Association for Research in Vision and Ophthalmology. 1–7 May 2021; virtual.
8. Khanani AM, Patel SS, Ferrone PJ, et al. Efficacy of every four monthly and quarterly dosing of faricimab vs ranibizumab in neovascular age-related macular degeneration: the STAIRWAY phase 2 randomized clinical trial. JAMA Ophthalmol. 2020;138:964-972.
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