Clinical biomarkers
Significant optical coherence tomography (OCT) imaging biomarkers associated with nAMD activity and progression include intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachment (PED), subretinal hyperreflective material (SHRM), new macular haemorrhage, and HRF [26]. Intraretinal fluid is considered the most relevant in terms of impact (progression or improvement) on visual outcome [26]. In eyes treated with anti-VEGF for nAMD, persistent IRF is associated with worse long-term visual acuity compared with resolved IRF, while early resolution of SRF is associated with a greater improvement in visual acuity [26–28].
Signs of nAMD disease activity that guide retreatment decisions include: new or increased retinal fluid (IRF, SRF or subretinal pigment epithelium fluid) on OCT; increased PED size; new or persistent macular haemorrhage; new or increased SHRM; or decreased visual acuity of ≥ 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters attributable to choroidal neovascularisation activity [29, 30]. Fluorescein leakage or increase in lesion size on FFA may also indicate active disease [31]. Guidance from the National Institute for Health and Care Excellence (NICE) underscores the importance of monitoring of both eyes when one eye only is being treated for nAMD [32].
Clinicians mostly treat nAMD using a flexible T&E dosing regimen after an initial monthly treatment phase (i.e., loading) [7, 29, 33]. Treatment interval extension is considered appropriate when there is no retinal fluid or other OCT biomarkers of active nAMD, with stable or better visual acuity or if visual acuity loss is not considered due to nAMD disease activity [33]. Visual acuity measurements within high throughput real-world services may not provide an accurate assessment of disease activity status.
Determining treatment response
A patient whose visual acuity declines due to persistent exudative disease activity despite an optimally delivered treatment regimen is considered a non-responder [34]. The original diagnosis should be re-evaluated, and the treating clinician should assess protocol adherence to rule out undertreatment [34]. A suboptimal response to anti-VEGF treatment may be considered as presence of macular fluid after the initiation phase of consecutive monthly anti-VEGF injections or persistent/residual macular fluid at any time post the initial loading phase [35]. Mettu et al. defined incomplete response to anti-VEGF therapy in nAMD as persistent disease activity (characterised by persistent fluid, unresolved or new haemorrhage, or progressive lesion fibrosis) and/or suboptimal visual recovery (failure to achieve visual acuity of ≥ 70 ETDRS letters or ≥ 20/40 Snellen equivalent) despite sustained treatment [36]. Refractory nAMD is generally defined by the presence of IRF or SRF on OCT despite maximal (monthly) or prolonged anti-VEGF dosing [37].
Options for switching from initial anti-VEGF to faricimab in nAMD
Current practice in treating nAMD is to actively consider switch alternatives for non-response and suboptimal response to previous anti-VEGF therapy at any time after the initial treatment loading phase and for high-need patients being treated regularly every 4 to 7 weeks (Q4W–Q7W, ~ 7–12 injections each year). A change may also be considered for treatment-resistant or recalcitrant nAMD, e.g., worsening visual outcomes, or persistent or recurrent retinal fluid on OCT, despite continued timely anti-VEGF injections over a 12-month or longer period [38]. Patients maintained on every-8-week (Q8W) anti-VEGF treatment (~ 6 injections each year), who cannot be extended further, and patients who are not able to maintain intervals longer than 10 or 12 weeks (~ 4–5 injections per year), may be offered or request the option of a switch to potentially longer-acting treatment, if suitable.
Switching decisions may either be disease activity driven (anatomic control supplemented by visual acuity response) or based on insufficient durability of response per clinician and patient decision. Local service models, disease characteristics and patient-related factors including likely visit adherence may impact clinician decision-making on alternative effective treatment options.
For patients with suboptimal improvement after initial monthly loading and for patients with persistent retinal fluid or other signs of active disease on continued Q4W–Q7W dosing intervals, clinicians should consider initiating the treatment switch to faricimab with a loading phase of four consecutive monthly injections, if possible. Among patients previously treated with anti-VEGF at maximum every-4-week (Q4W) intervals, initial loading with monthly faricimab injections may continue to improve anatomic response.
Among patients considered unable to extend beyond Q8W treatment intervals, a treatment switch to faricimab may be initiated by matching the previous interval, or with initial monthly injections per clinician discretion, followed thereafter by flexible dosing using a T&E regimen. Patients who are interval matched but who fail to respond sufficiently on first clinic review post switch may benefit from a new initiation phase of consecutive monthly injections. Figure 2 provides an overview of guidance for switching to faricimab T&E in previously treated nAMD.
SWITCHING GUIDANCE FOR SUBOPTIMAL ANTI-VEGF RESPONSE IN DMO
Clinical biomarkers
Early and sustained control of central subfield thickness (CST) and fluid resolution are both important for optimising vision outcomes in DMO [39, 40]. Additional biomarkers associated with treatment response in DMO include intraretinal cysts, large outer nuclear layer cyst, disorganisation of retinal inner layers (DRIL), ellipsoid zone disruption, and amount and location of HRF [41].
Retreatment decisions in the management of DMO are based mainly on comparison of OCT features and visual acuity over recent visits. Change in OCT CST/central retinal thickness (CRT) should be assessed against the lowest CST/CRT achieved and visual acuity change against the best-achieved score in response to treatment, which usually occur following the monthly treatment phase but may be following further intensive treatment [42]. Extension of treatment interval using a personalised T&E regimen is considered appropriate once CST/CRT on OCT and visual acuity are stable [42].
Determining treatment response
Non-response to treatment for DMO may be considered where there is worsening visual outcomes, or unchanged/ increased CST/CRT, despite an optimally delivered treatment regimen. As for nAMD, diagnosis should be re-evaluated for eyes that are non-responsive to initial intravitreal treatment. A suboptimal clinical response at ≥ 12 weeks from treatment initiation may be considered where there is < 20% reduction from reference OCT CST/CRT (machine matched for comparisons) and unchanged (≤ 5–letter improvement) or reduced visual acuity due to DMO with residual disease activity. The panel suggested a practical threshold for defining insufficient anatomic response as a reduction of less than 20% in reference CST/CRT (documented for example at time of diagnosis) and/or retinal thickness above an indicative absolute CST/CRT value or threshold as determined by the treating clinician (e.g., 390 µm if NICE guidance recommendation of CRT criterion of ≥ 400 µm was used to initiate anti-VEGF treatment) [43]. Treatment-resistant or refractory DMO is generally considered as persistent DMO, increased retinal thickness, or reduced visual acuity attributable to DMO, despite continued anti-VEGF treatment over a 12-month or longer period [44].
Options for switching from initial anti-VEGF to faricimab in DMO
Clinicians may consider switching to faricimab in patients with DMO who are either non-responsive or considered suboptimal responders after monthly loading with anti-VEGF monotherapy, and for patients with persistent active disease following regular anti-VEGF treatment post loading. Other options for these patients include intravitreal corticosteroid implant treatment or supplemental focal laser.
In DMO, clinical management is focused predominantly on achieving effective disease control by continuing to treat until resolution of macular oedema, with an early switch considered for a poor or incomplete response with persistent DMO. High retreatment burden, patient-related factors including adherence restrictions or disease-related characteristics (e.g., unresolved maculopathy) may impact clinical decisions on appropriate switch options and timings. Patients who are maintained stable with controlled diabetic maculopathy on longer dosing intervals of every 10 or 12 weeks are thought most likely to transition to a pro re nata (PRN, as needed) treatment plan with continued unchanged therapy. The Diabetic Retinopathy Clinical Research Network Protocol I study showed that the need for intravitreal anti-VEGF injections in DMO decreases annually over 5 years [45].
Ideally all suitable patients with previously treated DMO who are switched to faricimab would receive an initial monthly loading phase where possible, followed thereafter by a personalised T&E approach. Extension increments of 4 weeks are considered suitable, but there is flexibility for shorter adjustment increments at the discretion of the treating clinician.
Adjunctive macular laser or change to intravitreal corticosteroid treatment may be appropriate in eyes with suboptimal response to anti-VEGF agents. It is recommended that clinicians consider intravitreal corticosteroid treatment if suitable based on inadequate response after 12 months or after 2 years based on burden of injections at this stage [46, 47]. Intravitreal corticosteroid treatment may also be considered in DMO eyes with contraindications to anti-VEGF [46]. Vitrectomy should be considered for DMO patients who do not respond to anti-VEGF treatment with evidence of vitreomacular traction or presumed ERM-related oedema [46]. Figure 3 provides an overview of guidance for switching to faricimab T&E in previously treated DMO.
Different treatment plans for each eye are feasible for patients with bilateral DMO (e.g., intravitreal corticosteroid treatment in one eye and anti-VEGF for the other).
The panel recommended non-ophthalmic physician review for all patients, especially those with uncontrolled diabetes and for patients with progressive retinopathy or resistant maculopathy, to address all treatable systemic risk factors. Routine access to support from diabetologists or general practitioners is recommended.