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HomemieyecareFaricimab Real World Treatment for AMD and DMO

Faricimab Real World Treatment for AMD and DMO

From 1 January 2023, the Pharmaceutical Benefits Scheme (PBS) approved the reimbursement of faricimab (Vabysmo, Roche/ Genentech) for the management of neovascular age related macular degeneration (nAMD) and diabetic macular oedema (DMO). It’s another proven tool for ophthalmologists.

In this article, Dr Alexander Newman and Associate Professor Anthony Kwan review the current real-world treatment of nAMD and DMO and look at what’s on the horizon.

Both nAMD and DMO are leading causes of treatable vision loss in the Australian population, predominantly affecting those of middle and advanced age groups.1,2 Common to both diseases is the implication of multiple pro-angiogenic cytokines, which regulate vascular permeability and angiogenesis. Since the regulatory approval of ranibizumab in 2006, the mainstay of treatment has been targeting the biological effects of vascular endothelial growth factor-A (VEGF-A) via intravitreal injection. Agents that inhibit VEGF-A have shown both anatomic improvements in retinal exudation and functional benefits by stabilising or even improving patients’ visual acuity.

The success of intravitreal injection has been due to the ability to provide outpatient therapy, minimise systemic toxicity, and achieve therapeutic drug concentrations in the retinal compartments by mechanically bypassing the physiological barriers which limit bioavailability.3 With an increased understanding in disease pathogenesis and molecular clarification of retinal vascular and degenerative diseases, current treatment strategies aim to maximise patient-centred results while minimising treatment burden and cumulative treatment risk.

In addition to VEGF-A, Angiopoetin-2 (Ang-2) upregulation is observed in DMO and nAMD.4 Ang-2 dysregulation, in synergy with VEGF-A, is involved in a constellation of microvascular abnormalities including angiogenesis, enhanced vascular permeability, inflammation, and disruption of the blood-retinal barrier.5 Although inhibition of both Ang-2 and VEGF-A targets two distinct disease pathways, both cytokines are involved in the pathophysiology of nAMD and DMO where choroidal neovascularisation and disruption of the retinal microcirculation are implicated respectively. Acknowledging the multifactorial aetiology of these diseases, faricimab is the first bispecific antibody approved for use in the management of nAMD and DMO.

Long term cross-sectional data for nAMD indicates that even after seven years following treatment initiation, almost half of eyes were still receiving injections and two-thirds of eyes had active exudation.6 Results from this analysis also indicate a trend toward better vision in those who maintained a higher frequency of injections.6,7 Some reported trial results for DMO also show that up to one in five DMO patients will still have persistent macular exudation despite monthly or bi-monthly anti-VEGF treatments for several years.8,9 The cumulative and relentless treatment burden drives therapeutic innovation to minimise the number of procedures while maintaining patient outcomes and safety.

Compared with clinical trial results, real-world management often results in underutilisation of medications and poorer visual outcomes.7,10 Individualised management utilising flexible treatment regimens is often employed in a clinical setting to achieve the best possible visual and anatomic outcomes while minimising the number of treatments. These include treat-and-extend (TAE) or pro-re-nata (PRN) schedules, which have been shown to maintain the visual and anatomic success of treatment while administering fewer injections compared with fixed-dosing schedules.11

ANOTHER PROVEN TOOL FOR OPHTHALMOLOGISTS

The performance of faricimab in seminal trials is well reported for both nAMD and DMO. TENAYA/LUCERNE12 and RHINE/ YOSEMITE13 were Phase 3 randomised, double masked, non-inferiority sister studies, each conducted over two years. One of the randomised treatment arms in each study received faricimab at a personalised treatment interval, allowing protocol-based extension to an injection interval of up to 16 weeks. TENAYA/LUCERNE participants were exclusively treatment naïve, with RHINE/ YOSEMITE only permitting up to 25% of recruited subjects to have been previously treated with anti-VEGF for DMO, however not within the preceding three months.

Analysis from both sister studies showed that over two years, personalised faricimab dosing performed as well as fixed-dose aflibercept, considering both visual acuity and central subfield thickness (CST). MACULAR DISEASE ISSUE 14,15 The analyses additionally revealed the extended durability of faricimab; more than three-quarters of the patients achieved a 12-week or 16-week dosing interval for both nAMD and DMO. These faricimab studies have consistently demonstrated a similar safety profile to aflibercept, with neither study reporting occlusive retinal vasculitis events.

REAL-WORLD EXPERIENCE

Real-world data is relied upon to build confidence in the safety and performance of new treatments. The Phase 3 clinical trials described above demonstrate the benefits of treat and extend faricimab in primarily treatment naïve populations, showing sustained anatomic and functional improvements with fewer injections. Given these results, there is reasonable motivation to assess faricimab’s real-world performance, not just in those starting treatment for the first time, but also in patients who have not achieved a desirable outcome on other established therapies. These patient groups are not limited to, but include those who are unable to achieve disease control despite maximal therapy, or those who remain dependent on long-term frequent injections to maintain their macular function.16 To date, a consensus definition of a suboptimal treatment outcome has not been made to guide clinicians on an optimal time to switch medications, however, between three to six injections are typically reported in study protocols.17

Below, we provide a snapshot of the published literature to date, regarding the real-word performance and safety of faricimab.

Neovascular Age-Related Macular Degeneration

The TRUCKEE trial is an ongoing multicentre, retrospective series of both naïve and previously treated nAMD patients, treated with at least one injection of faricimab.18 For the published six-month results of 376 eyes, approximately 10% of enrolled patients were treatment naïve. Even following a single injection of faricimab, overall, there were significant improvements in both macular thickness and visual acuity. Ninety-four eyes were then analysed following three faricimab injections, again showing improvements in vision and macular exudation for both naïve and previously treated patients. Concerning safety, there were two cases of intraocular inflammation: mild anterior uveitis that responded to topical therapy, and infectious endophthalmitis. There were no reports of occlusive retinal vasculitis. Short-term favourable outcomes were also demonstrated in a smaller United Kingdom-based cohort of 11 eyes, which enrolled a mix of switch and naïve eyes.19

Real-world management of treatment naïve patients has been reported in two Japanese cohorts, including patients with macular neovascularisation and polypoidal choroidal vasculopathy (PCV), enrolling 40 and 62 eyes, respectively.20,21 Although the studies were only conducted over 12 and 16 weeks, robust improvements in visual acuity and macular exudation were noted and more than half of polypoidal lesions demonstrated complete regression. One case of vitritis without vision loss, and two cases of retinal pigment epithelial tear, were cumulatively reported.

Specific analyses of medication-switch patients with non-favourable outcomes on conventional agents, consistently show an improvement in macular exudation and stable or improved visual acuity. A retrospective series of 63 eyes22 from the United Kingdom, and 13 eyes23 from the United States corroborate these findings. The largest published observational series of 190 eyes demonstrated significant improvement in functional and structural parameters, with acceptable safety over 34 weeks.24 The observation period was sufficient to demonstrate the durability of faricimab, with the extension of the injection interval compared with both ranibizumab and aflibercept utilising a treat and extend protocol. Another study of 55 patients found that in addition to a structural improvement, a greater proportion of patients improved by two lines of acuity with faricimab compared with aflibercept.25

CASE STUDY 1: nAMD

A 72-year-old man with nAMD in his left eye, had persistent fluctuating subretinal fluid associated with pigment epithelial detachment. The patient’s vision deteriorated with the treat and extend regime with aflibercept, and the injection interval could not be extended beyond monthly treatment for a few years.

Serial optical coherence tomography (OCT) scans showed the subretinal fluid and pigment epithelial detachment settled swiftly after swapping over to faricimab treatment and the injection interval has been extended to eight weeks. The central subfield chart clearly demonstrates the constant fluctuation in thickness prior to the swap.

Case Study 1: nAMD

Diabetic Macular Oedema

The longest real-world recruitment study published to date is a single-centre retrospective series of 51 ‘aflibercept-resistant’ eyes switched to treat and extend faricimab for 12 months.17 While a small proportion of patients maintained an injection frequency of four weeks (21.6%), almost 40% achieved an eight week interval with a dry macula on OCT at 12 months. Significant macular thickness and visual acuity improvements were noted, particularly with vision continuously improving at both four- and 12-month analyses. No adverse events were reported.

Other retrospective analyses have been reported. Of 18 eyes with DMO that had a suboptimal response to other agents switched to PRN faricimab, a significantly prolonged interval to the recurrence of exudation was demonstrated.9 More than three-quarters of patients could extend their injection interval and almost half (44.4%) could achieve more than 12 weeks between treatments. In this cohort, visual acuity and macular thickness on OCT were not statistically different from baseline, however, this was maintained with fewer injections. Of note, a small proportion of patients remained unable to extend beyond four weekly intervals (16.7%), with disorganisation of retinal inner layers (DRIL) or previous treatment with triamcinolone reported as risk factors.9

Another retrospective study of both naïve and switch patients, comprising 21 consecutive eyes over 5.5 months, were treated with PRN faricimab. Over the study duration, an average of 1.6 injections were administered, and more than half of patients were maintained with a single injection. They demonstrated an improvement in macular exudation with stable visual acuity.26 Safety of faricimab was again demonstrated, however a case of anterior uveitis was reported.

CASE STUDY 2: DMO

A 33-year-old man with symptomatic diabetic macular oedema in his left eye, had persistent intraretinal cystoid fluid. His vision deteriorated with the treat and extend regime with aflibercept, and macular oedema returned. The injection interval could not be extended beyond monthly treatment for a few years. The patient’s treatment was switched to faricimab and the injection interval has been extended to eight weeks. Serial OCT scans (Figure 2) demonstrated the resolution of the macular oedema with the central subfield plot clearly demonstrating the stabilisation of macular oedema after the swap.

Case Study 2: DMO

THE FUTURE IS BRIGHT

Overall, the real-world data published to date shows that intravitreal faricimab treatments provide sustained anatomic improvement in macular exudation for both naïve and switch patients, with an injection interval of up to 16 weeks in treatment naïve patients. Most studies have also shown a visual acuity benefit accompanying the structural resolution. These benefits are maintained even in switch eyes previously deemed suboptimal responders to conventional treatments.

Intraocular inflammation and occlusive retinal vasculitis rates in the reported literature are similar to aflibercept. In March 2024, Roche Australia informed the community of an update to the product safety information for faricimab, acknowledging that cases of retinal vasculitis and/or retinal occlusive vasculitis have been reported with the use of faricimab in the post-marketing setting. According to the Roche Internal Safety Report, the rate of occlusive retinal vasculitis was estimated to be one in 166,700 injections and retinal vasculitis with or without occlusion was estimated to occur in one in 58,800 injections.

At present, there is one known published case of occlusive retinal vasculitis following intravitreal faricimab in Australia.27 While the true nature of this association is under investigation, it must be balanced against a possible relative reduction in other more common injection-related complications such as exogenous endophthalmitis, due to the extended durability of faricimab.

There are many additional studies underway to enhance our understanding of the real-world performance and safety of faricimab in nAMD and DMO, including: TRUCKEE, TAHOE, VOYAGER, INSITE, FURGGHORN, FARETINA-AMD, FARWIDE-nAMD, FARETINA-DME, and FARWIDE-DME. Preliminary reporting of these trials at conferences includes data for more than 25,000 eyes, an order of magnitude more than the real-world data currently published. Though the studies are ongoing, these preliminary reports consistently demonstrate a favourable safety profile in addition to robust visual and anatomic outcomes for treatment naïve eyes and extended treatment durability for previously treated eyes.4 This real-world evidence is highly anticipated to determine whether the outcomes in treatment naïve patients seen in the Phase 3 clinical trials are reproducible in day-to-day clinical practice.

Looking beyond faricimab, further studies with conventional monophasic anti-VEGF agents are underway. A sustained release ranibizumab port delivery system (PDS) has shown robust functional and anatomical results compared with monthly ranibizumab injections over two years in the treatment of nAMD.28 These benefits were maintained with two refill exchanges per year. Although there were more ocular adverse events in the PDS arm of the ARCHWAY trial (NCT03677934), the results of the extension study: PORTAL (NCT03683251) and 36-week refill regimen: VELODROME (NCT04657289) are anticipated to assess long-term safety and performance data. For patients with diabetic eye disease, the Phase 3 PAGODA (NCT04108156) and PAVILION (NCT04503551) trials are underway. The PDS has been recently redesigned following voluntary recall due to concerns regarding septum dislodgement. However, the redesigned port is anticipated to reduce PDS-related ocular adverse events, which are under continual analysis to optimise patient outcomes.29,30 High-dose aflibercept is also currently under investigation for patients with nAMD and DMO.31,32 The PULSAR (NCT04423718) and PHOTON (NCT04429503) clinical trials demonstrated safety and extension of treatment intervals compared with bi-monthly fixed-dose Eylea.33,34 This high concentration of aflibercept has been approved in the USA, the UK, and European Union based on positive results from the PULSAR clinical trial in nAMD and the PHOTON trial in DMO. This agent is not approved in Australia yet.

Multiple next-generation therapeutics are under investigation. The following examples highlight the multitude of administration routes, drug formulations, and therapeutic targets that make retinal pharmacotherapy such a vibrant area of ongoing research. KSI-301 is an anti-VEGF antibody-biopolymer conjugate (ABC), which combines a humanised anti-VEGF antibody with an ultra-high molecular weight polymer to extend the injection frequency; Phase 3 trials were underway.3 These have been halted, however, due to recent safety and efficacy concerns regarding this agent. Targeting the intracellular domain by way of tyrosine kinase inhibitors (TKI), which exhibit selectivity to VEGF receptors, has also been demonstrated. PAN-90806, a TKI that is formulated as a topical eyedrop suspension, showed favourable results in a Phase 1/2 trial, however receptor specificity with systemic absorption must be balanced against adherence benefits.3,35 Multiple non-antioedematous therapeutics, which are not directed at the effects of VEGF, are also under investigation.

Gene therapy offers another possible avenue to provide sustained suppression of pro-angiogenic factors or potentiation of anti-angiogenic factors.5 Two notable examples include ADVM-022 and RGX-314.3,36 ADVM-022 consists of codon-optimised cDNA expressing an aflibercept-like protein packaged in an adeno-associated viral (AAV) vector. Administered via a single intravitreal injection, it has been used to treat nAMD and DMO in Phase 3 clinical trials. RGX-314 is packaged via AAV vector (AAV8) whereby transfection induces production of a ranibizumab-like monoclonal antibody fragment and is currently under investigation for use in both the subretinal and suprachoroidal spaces.36

Dr Alexander Newman MD (Distinction) MMED (OphthalSci) BAppSci (Optom)Hons FRANZCO is a consultant ophthalmologist. He holds an academic title of Lecturer at Griffith University and is the current Professorial Fellow at the Sydney Eye Hospital. He is a sub-investigator for the INSITE, FURGGHORN, POYANG, PULSAR, and QUASAR clinical trials.

Associate Professor Anthony Kwan MBChB MD (London) FRCOphth FRANZCO is a retinal specialist based in Brisbane. He was trained in the UK and spent over 10 years at Moorfields Eye Hospital in London. He is the Director of Vitreoretinal Services at the Queensland Eye Institute (QEI) and a senior staff specialist at the Mater Health Service. He holds the academic title of Associate Professor at the University of Queensland and is currently the Chair of the Research Committee for Macular Disease Foundation Australia (MDFA). He is a sub-investigator for several clinical trials regarding geographic atrophy, nAMD, and DMO at QEI.

References

1. Keel, S., Xie, J., Dirani, M., et al., Prevalence of age-related macular degeneration in Australia: The Australian National Eye Health Survey. JAMA Ophthalmol 2017;135(11):1242–1249. DOI: 10.1001/jamaophthalmol.2017.4182.
2. Tapp, R.J., Shaw, J.E., Harper, C.A., et al., The prevalence of and factors associated with diabetic retinopathy in the Australian population. Diabetes Care 2003;26(6):1731–7. DOI: 10.2337/diacare.26.6.1731.
3. Martinez-Alejo, J.M., Baiza-Duran, L.M., Quintana-Hau, J.D., Novel therapies for proliferative retinopathies. Ther Adv Chronic Dis 2022;13:20406223221140395. DOI: 10.1177/20406223221140395.
4. Penha, F.M., Masud, M., Khanani, Z.A., et al., Review of real-world evidence of dual inhibition of VEGF-A and ANG-2 with faricimab in nAMD and DME. International Journal of Retina and Vitreous 2024;10(1). DOI: 10.1186/s40942-024-00525-9.
5. Guimaraes, T.A.C., Georgiou, M., Bainbridge, J.W.B., Michaelides, M., Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. Br J Ophthalmol 2021;105(2):151-157. DOI: 10.1136/bjophthalmol-2020-316195.
6. Rofagha, S., Bhisitkul, R.B., Zhang, K., et al., Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology 2013;120(11):2292–9. DOI: 10.1016/j.ophtha.2013.03.046.
7. Kim, L.N., Mehta, H., Gillies, M.C., Metaanalysis of real-world outcomes of intravitreal ranibizumab for the treatment of neovascular age-related macular degeneration. Retina 2016;36(8):1418–31. DOI: 10.1097/iae.0000000000001142.
8. Bressler, S.B., Ayala, A.R., Bressler, N.M., et al., Persistent macular thickening after ranibizumab treatment for diabetic macular edema with vision impairment. JAMA Ophthalmol 2016;134(3):278–85. DOI: 10.1001/jamaophthalmol.2015.5346.
9. Ohara, H., Harada, Y., Kiuchi, Y., Faricimab for diabetic macular edema in patients refractory to ranibizumab or aflibercept. Medicina 2023;59(6):1125. DOI: 10.3390/medicina59061125.
10. Hussain, R.M., Hariprasad, S.M., Ciulla, T.A., Treatment burden in neovascular AMD:Visual acuity outcomes are associated with anti-VEGF injection frequency. Ophthalmic Surg Lasers Imaging Retina 2017;48(10):780–784. DOI: 10.3928/23258160-20170928-01.
11. Wykoff, C.C., Ou, W.C., Brown, D.M., et al. Randomized trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: 2-year results of the TREX-AMD Study. Ophthalmol Retina 2017;1(4):314–321. DOI: 10.1016/j.oret.2016.12.004.
12. Heier, J.S., Khanani, A.M., Quezada Ruiz, C., et al., Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet 2022;399(10326):729–740. DOI: 10.1016/s0140-6736(22)00010-1.
13. Wykoff, C.C., Abreu, F., Adamis, A.P., et al., 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. Lancet 2022;399(10326):741–755. DOI: 10.1016/s0140-6736(22)00018-6.
14. Wong, T.Y., Haskova, Z., Asik, K., et al., Faricimab treat-and-extend for diabetic macular edema: 2-year results from the randomized phase 3 YOSEMITE and RHINE trials. Ophthalmology 2023. DOI: 10.1016/j.ophtha.2023.12.026.
15. Khanani, A.M., Kotecha, A., Chang, A., et al., TENAYA and LUCERNE: 2-year results from the phase 3 nAMD trials of faricimab with treat-and-extend dosing in year 2. Ophthalmology 2024. DOI: 10.1016/j.ophtha.2024.02.014.
16. Ricci, F., Bandello, F., Zarbin, M., et al., Neovascular age-related macular degeneration: therapeutic management and new-upcoming approaches. International Journal of Molecular Sciences 2020;21(21):8242. DOI: 10.3390/ijms21218242.
17. Rush, R.B., One year results of faricimab for aflibercept-resistant diabetic macular edema. Clinical Ophthalmology 2023;Vol 17:2397–2403. DOI: 10.2147/opth.s424314.
18. Khanani, A.M., Aziz, A.A., Khan, H., et al. The real-world efficacy and safety of faricimab in neovascular age-related macular degeneration: the TRUCKEE study – 6 month results. Eye 2023;37(17):3574–3581. DOI: 10.1038/s41433-023-02553-5.
19. Stanga, P.E., Valentín-Bravo, F.J., Downes, S.M., Faricimab in neovascular AMD: first report of real-world outcomes in an independent retina clinic. Eye (Lond) 2023;37(15):3282–3289. DOI: 10.1038/s41433-023-02505-z.
20. Mukai, R., Kataoka, K., Tanaka, K., et al., Three-month outcomes of faricimab loading therapy for wet age-related macular degeneration in Japan. Scientific Reports 2023;13(1). DOI: 10.1038/s41598-023-35759-4.
21. Matsumoto, H., Hoshino, J., Akiyama, H., et al.,
Short-term outcomes of intravitreal faricimab for treatment-naïve neovascular age-related macular degeneration. Graefe’s Archive for Clinical and Experimental Ophthalmology 2023;261(10):2945–2952. DOI: 10.1007/s00417-023-06116-y.
22. Ng, B., Kolli, H., Ajith Kumar, N., et al., Real-world data on faricimab switching in treatment-refractory neovascular age-related macular degeneration. Life 2024;14(2):193. DOI: 10.3390/life14020193.
23. Cheng, A.M., Joshi, S., Chalam, K.V., Faricimab effectively resolves intraretinal fluid and preserves vision in refractory, recalcitrant, and nonresponsive neovascular age-related macular degeneration. Cureus 2023. DOI: 10.7759/cureus.40100.
24. Leung, E.H., Oh, D.J., Alderson, S.E., et al., Initial real-world experience with faricimab in treatment-resistant neovascular age-related macular degeneration. Clin Ophthalmol 2023;17:1287–1293. DOI: 10.2147/opth.S409822.
25. Rush, R.B., Rush, S.W., Intravitreal faricimab for aflibercept-resistant neovascular age-related macular degeneration. Clin Ophthalmol 2022;16:4041–4046. DOI: 10.2147/opth.S395279.
26. Kusuhara, S., Kishimoto-Kishi, M., Nakamura, M., Short-term outcomes of intravitreal faricimab injection for diabetic macular edema. Medicina 2023;59(4):665. DOI: 10.3390/medicina59040665.
27. Li, Y., Chong, R., Fung, A.T., Association of occlusive retinal vasculitis with intravitreal faricimab. JAMA Ophthalmol 2024 (In eng). DOI: 10.1001/jamaophthalmol.2024.0928.
28. Regillo, C., Berger, B., Brooks, L., et al., Archway phase 3 trial of the port delivery system with ranibizumab for neovascular age-related macular degeneration 2-year results. Ophthalmology 2023;130(7):735–747. DOI: 10.1016/j.ophtha.2023.02.024.
29. Sharma, A., Khanani, A.M., Kuppermann, B.D., Port delivery system with ranibizumab (Susvimo) recall – What does it mean to the retina specialists? Int J Retina Vitreous 2023;9(1):6. DOI: 10.1186/s40942-023-00446-z.
30. Ranade, S.V., Wieland, M.R., Tam, T., et al., The port delivery system with ranibizumab: a new paradigm for long-acting retinal drug delivery. Drug Deliv 2022;29(1):1326–1334. DOI: 10.1080/10717544.2022.2069301.
31. Nielsen, J.S., Roberts, C.L., Saggau, D.D., Alliman, K.J., High-dose aflibercept for neovascular AMD and DME in suboptimal responders to standard-dose aflibercept. J Vitreoretin Dis 2023;7(2):116–124. DOI: 10.1177/24741264221150345.
32. Wykoff, C.C., Brown, D.M., Reed, K., et al., Effect of high-dose intravitreal aflibercept, 8 mg, in patients with neovascular age-related macular degeneration: The phase 2 CANDELA randomized clinical trial. JAMA Ophthalmol 2023;141(9):834–842. DOI: 10.1001/jamaophthalmol.2023.2421.
33. Brown, D.M., Boyer, D.S., Do, D.V., et al., Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, non-inferiority, phase 2/3 trial. Lancet 2024 DOI: 10.1016/s0140-6736(23)02577-1.
34. Lanzetta, P., Korobelnik, J.F., Heier, J.S., et al., Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial. Lancet 2024 DOI: 10.1016/s0140-6736(24)00063-1.
35. Song, D., Liu, P., Shang, K., Ma, Y., Application and mechanism of anti-VEGF drugs in age-related macular degeneration. Frontiers in Bioengineering and Biotechnology 2022;10. DOI: 10.3389/fbioe.2022.943915.
36. Khanani, A.M., Thomas, M.J., Aziz, A.A., et al., Review of gene therapies for age-related macular degeneration. Eye (Lond) 2022;36(2):303-311. DOI: 10.1038/s41433-021-01842-1.