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HomemieyecareDual Pathway Inhibition Clinical Trial Findings with Vabysmo

Dual Pathway Inhibition Clinical Trial Findings with Vabysmo

Vabysmo became a new arrow in the ophthalmologists’ quiver when it was listed on the Pharmaceutical Benefits Scheme (PBS) this year. Dr Long Phan, Dr Thomas Hong, and Associate Professor Andrew Chang review the current studies and look forward to real world data.

Vabysmo (faricimab) is the first approved bispecific antibody that targets two separate pathways involved in the pathogenesis of both neovascular age-related macular degeneration (nAMD) and diabetic macular oedema (DMO).

Vabysmo… targets two separate pathways involved in the pathogenesis of both neovascular age-related macular degeneration (nAMD) and diabetic macular oedema (DMO)

Exudation of fluid from abnormal retinal microvessels is a key feature representing activity in both diseases. In nAMD, this is typically a result of choroidal neovascularisation, whereas, in DMO, intraretinal fluid occurs due to increased vascular permeability following a breakdown of the blood-retinal barrier.

Although their underlying pathophysiological mechanisms may differ, upregulation or abnormal expression of the signalling protein vascular endothelial growth factor (VEGF) is the common mediator driving disease activity in both states.1, 2

Anti-VEGF therapeutics, given as an intravitreal injection into the eye, block the biologic effects of VEGF-A, the main isoform involved in angiogenesis and regulation of vascular permeability.

Compared to previous treatment modalities, the introduction of anti-VEGF was revolutionary as alongside preventing further exudation, it provided opportunities for vision gains following the resolution of existing fluid. However, while being the standard of care for nAMD and DMO for the past decade, not all patients respond equally to treatment. While a large proportion of patients experience good immediate outcomes, some subgroups do not achieve complete fluid resolution (25–35%) and/or experience significant declines in visual acuity (5–10%) over their first year of therapy.3 In addition to these early responses, further treatment variation occurs over time, with some patients experiencing gradual declines in vision and/or fluid recurrence despite demonstrating a good initial response.4,5

There is also a differing outcome found within the real world, as post-marketing trials and clinical studies find larger proportions of patients who lose vision compared to the Phase 3 randomised control trials.

One reason for this could be that continuous VEGF inhibition is often required to maintain suppression of disease activity. Given the chronic nature of these diseases, ongoing treatment and medical visits are required, which can place considerable treatment burdens on patients and their carers in terms of quality of life and economic aspects.6,7

As a further consequence, high levels of non-adherence, which may occur even within the first year of treatment, may compromise the potential to achieve good long-term anatomic and visual outcomes.8,9

In terms of safety, faricimab was well tolerated throughout the duration of all studies

Relieving Patient Burdens

Flexible treatment strategies, and more durable therapeutics capable of relieving patient burdens, have now become a major focus in the current management of nAMD and DMO. From a clinical perspective, the goal of relieving the burden of treatment can be achieved via flexible treatment patterns such as the pro-re-nata and treat-and-extend dosing strategies, which aim to maximise the duration of action of each anti-VEGF dose per patient.

As these personalised approaches are based upon individual disease activity status, reductions in treatment frequency can occur without compromising visual and anatomic outcomes compared to fixed dosing intervals.10,11

Meanwhile, from a pharmaceutical point of view, alternative drug delivery methods have been explored. These aim to provide minimally invasive and/or sustained exposures to therapeutics over more extended periods of time in the form of drug reservoirs and sustained release implants. A notable example is the Susvimo implant for nAMD, a port delivery system currently in Phase 3 clinical development, which is designed to continuously deliver a customised formulation of ranibizumab (100 mg/ml) for up to six months in individuals with nAMD.12,13

Another possible contributor to sub-optimal responses is that current therapeutics used to treat nAMD and DMO only target the VEGF pathway. Given these diseases’ multifactorial pathophysiology, alternative signalling pathways are likely simultaneously involved in producing neovascularization and vascular leakage.14

Recently, the focus has been on a second key target, the angiopoietin/tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains (Ang/Tie) pathway. Tie2 is a tyrosine kinase receptor expressed on endothelial cells of blood vessels which binds a family of growth factors including Ang-1 and Ang-2. Ang-1 binding activates the Tie2 receptor, stabilising newly formed and mature blood vessels by promoting endothelial cell survival, pericyte recruitment, and improved endothelial barrier function; effectively acting as a ‘molecular brake’ to prevent leakage and inflammation.15 Meanwhile, Ang-2 is also a weak agonist of Tie2 under baseline homeostatic conditions, however, it acts as a competitive antagonist of Tie2 after becoming upregulated under hypoxic and hyperglycemic conditions.16

This change in signalling, or ‘angiogenic switch’, disrupts Ang-1 signalling and conversely results in the promotion of vessel leakage, inflammation, and neovascularisation instead. Ang-2 also appears to increase the sensitivity of deep retinal capillaries to VEGF-A, to further increase vascular permeability and promote angiogenesis.17 While much of the current understanding of this pathophysiology is based on preclinical models, elevated intraocular levels of Ang-2 have also been observed in patients with nAMD and diabetic retinopathy.18,19

The Vabysmo Difference

Vabysmo is a bispecific antibody designed to inhibit mediators from two separate pathways, VEGF and Ang/Tie. Alongside a single Fc region, each antibody molecule contains two Fab arms, allowing simultaneous binding and inhibition of Ang-2 and VEGF-A. TENAYA/ LUCERNE and RHINE/YOSEMITE were the two-year randomised, multicentre, double-masked, sister Phase 3 studies that compared faricimab to aflibercept (Eylea) in patients with nAMD and DMO respectively.

Clinicians now have access to Vabysmo funded by the PBS

All studies met their primary efficacy endpoints of non-inferiority in best-corrected visual acuity (BCVA) change following one year of treatment, which was maintained through to the end of the study. What was of particular interest was that these outcomes were achieved in faricimab-treated arms, which incorporated treat-and-extend based dosing administered up to every 16 weeks (Q16W) compared to fixed dosing of aflibercept every eight weeks (Q8W). In TENAYA and LUCERNE, approximately 78% of faricimab-treated patients were eligible for extended dosing intervals beyond Q8W, with 63% reaching the maximal Q16W interval by the second year. In these studies, faricimab-treated patients received a median of 10 injections over two years, compared to aflibercept-treated patients who received a median of 15 injections.20

It should also be noted that true flexible dosing in the faricimab-treated arm was not applied until the second year of study, as fixed dosing with either Q8W, Q12W or Q16W was performed through to week 60 based on protocol-defined disease activity criteria held at weeks 20/24. Similar benefits were seen in RHINE and YOSEMITE, with 78% of faricimab-treated patients on either Q12W or Q16W, receiving a median of 11 injections through year two, compared to 14 injections in the aflibercept group.21

Although changes in central subfield thickness (CST) were comparable, faricimabtreated patients appeared to achieve total fluid (sub-retinal fluid, intra-retinal fluid, and DMO) resolution faster and with fewer injections than patients treated with aflibercept during post hoc analysis.20,21 Some of these differences could be seen as early as the loading phase when both therapies were administered at the same dosing interval.20,21

In terms of safety, faricimab was well tolerated throughout the duration of all studies, with a profile comparable to aflibercept. Notably, there were no cases of retinal vasculitis or intraocular inflammation associated with retinal occlusive events.

Trial Case Studies

The following illustrative cases were patients at our trial site participating in the Phase 3 studies of faricimab.
Figure 1 presents an 80-year-old female with nAMD in her left eye who participated in the LUCERNE study. There was an initial improvement in visual acuity which continued to improve for the first 12 months and was maintained for the remainder of the study duration despite some retinal fluid fluctuation over the study.

Figure 1. Optical coherence tomography imaging, best-corrected visual acuity, and central macular thickness of a patient with nAMD enrolled in the LUCERNE study.

Figure 2 presents a 60-year-old female with DMO in her left eye who participated in the RHINE study. Alongside immediate improvements in visual acuity, consistent anatomic improvements were demonstrated throughout the study, with complete fluid resolution occurring at Week 56. The macula remained free of oedema until the end of the study after two years.

Figure 2. Optical coherence tomography imaging, best-corrected visual acuity, and central macular thickness of a patient with DMO enrolled in the RHINE study.

Looking to the Future

Clinicians now have access to Vabysmo funded by the PBS, so what comes next?

Despite the promising clinical results so far, and potential for reductions in treatment burdens to occur, we should look forward to the accumulation of data from the real-world usage of Vabysmo for several reasons. Since the disease activity criteria, which underlined the personalized treatment interval decisions in the Phase 3 studies, were based on discrete BCVA and CST criteria, this may not have entirely reflected real-world treatment patterns, as ophthalmologists typically also take into consideration retinal morphology such as fluid type to determine disease activity.

More importantly, we should look forward to studies exploring the effects of Vabysmo in previously treated, or rather patients considered to be ‘treatment-resistant’ as these patients were excluded from the Phase 3 trials (nAMD) or were capped at 25% (DMO) and are currently those who stand to gain the most benefit from the bispecific function and durability aspects of faricimab. Finally, and most importantly, ongoing evaluations and caution is required to ensure that these benefits are not at the expense of patient safety and long-term visual function. RPE atrophy and subretinal fibrosis are major causes of loss of vision as we look towards further therapies that will address these unmet needs in patients with macular degeneration.

Associate Professor Andrew Chang MBBS(Hons) PhD FRANZCO FRACS is a vitreoretinal surgeon and ophthalmologist. He holds an academic appointment of Clinical Associate Professor at the University of Sydney. He is a consultant ophthalmologist and the Head of the Sydney Eye Hospital and Head of the Retinal Unit. Assoc. Prof Chang is also the Medical Director of Sydney Retina Clinic and Secretary General of the Asia-Pacific Vitreoretinal Society.

Dr Thomas Hong graduated from the University of Sydney and was awarded a BAppSc (Orthoptics) in 2001, a MScMed (Clinical Epidemiology) in 2009, a PhD in 2015, and completed an MBA in 2019. He has accumulated more than 20 years of clinical and research experience in epidemiological and clinical research. Dr Hong manages CUREOS, a clinical research network conducting trials in ophthalmology.

Dr Long Phan is a research officer at CUREOS, a clinical research network conducting ophthalmology trials. Dr Long graduated with a Bachelor of Pharmacy from the University of Sydney in 2016, and a Master of Orthoptics from the University of Technology Sydney in 2018. He subsequently completed a PhD in myopia research, investigating the measurement of risk factors using quantitative measures.

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