Diabetic Macular Oedema: Current and Emerging Treatments

In addition to the current global COVID-19 pandemic, a diabetes epidemic is also ongoing. In 2021, it was estimated that 531 million people worldwide had diabetes and this number is expected to increase to 643 million people by 2030 and to 783 million by 2045.¹ Unfortunately, many will remain undiagnosed or poorly controlled, increasing the risk of developing complications.

Patients with vision threatening diabetic retinopathy may not have any visual symptoms, which is why it is important that patients with diabetes undergo regular screening

Diabetic retinopathy is the commonest cause of vision loss among working aged people in the community, with DMO being the most common cause of visual impairment² and proliferative diabetic retinopathy being the most common cause of blindness. DMO is characterised by retinal thickening in the macular region, which may include hard exudates. A recent systematic review and meta-analysis of the global prevalence of diabetic retinopathy³ estimated that 4% of people with diagnosed diabetes had DMO and 6% had vision threatening diabetic retinopathy.

Hyperglycaemia is the primary modifiable risk factor for the development of diabetic retinopathy. The Diabetes Control and Complications Trial Research Group found that intense blood glucose lowering delayed the onset and slowed the advancement of diabetic retinopathy.⁴ Hyperglycaemia and oxidative stress cause upregulation of vascular endothelia derived growth factor (VEGF) leading to an increase in vascular permeability and angiogenesis. Inflammatory mediators also contribute to vascular permeability.

Vision threatening diabetic retinopathy is defined as the presence of severe non proliferative or proliferative diabetic and/ or any diabetic macular oedema. Patients with vision threatening diabetic retinopathy may not have any visual symptoms, which is why it is important that patients with diabetes undergo regular screening.

The Royal Australian and New Zealand College of Ophthalmologists (RANZCO) has released a screening and referral pathway for patients with diabetes (Figure 1). Even if no diabetic retinopathy is present, all patients with diabetes should be screened for diabetic retinopathy at least every two years, and those with risk factors which increase their risk of vision threatening retinopathy should be screened at least yearly.

When screening for diabetic retinopathy, it is important to obtain the best quality fundus photos possible, which may mean having to dilate the pupils. Patients should be encouraged to return to the same practice so that images can be compared from one visit to the next. I prefer to use widefield imaging of the fundus paired with optical coherence tomography (OCT) scans of the macula as it can be easy to miss peripheral new vessels and early DMO otherwise.

It is possible to zoom in on widefield images – new vessels on the disc in Figure 2 are easier to see in a more magnified view (Figure 3).

The new vessels are even easier to visualise using fundus fluorescein angiography, as shown by the leak of dye from the new vessels on the discs and elsewhere in Figure 4. Also, note large areas of hypofluorescence, illustrating areas of noncapillary perfusion with leakage from the veins which pass through those areas.

OCT-angiography (OCT-A) may be useful in assessing for macular ischaemia to help gauge the visual potential of a patient, however OCT-A can be difficult to assess in the presence of macular oedema or lens opacity as there can be degradation of the image quality. Most commercially available OCT-A units do not offer widefield images, limiting their ability to assess for peripheral ischaemia. Swept source OCT-A is able to scan larger areas including the periphery. Figure 5 is an example of a montaged image of a patient’s fundus with proliferative diabetic retinopathy. There is a large frond of new vessels superiorly.

CURRENT MANAGEMENT OF PATIENTS WITH DIABETIC MACULAR OEDEMA

The management of DMO has evolved considerably since I trained as an ophthalmology registrar. At that time, the management of DMO was based on the Early Treatment Diabetic Retinopathy Study (ETDRS) guidelines from the 1980s.⁴ Macular grid and/or focal laser was performed in eyes with DMO to reduce the risk of moderate vision loss. However, vision was gained in only a small minority and, despite setting the laser to a low power and using a small spot, laser burns tended to spread over time. Figure 6 fundus photos are from a patient of mine who had undergone laser pan retinal photocoagulation and macular grid laser more than ten years prior to her being under my care. As you can see, the laser burns have expanded and coalesced.

Because of this risk, and the reduced possibility of improvement in vision, I generally reserve macular grid laser for eyes with non-centre involved DMO, being careful to apply laser burns well away from the foveal centre.

MANAGING EYES WITH CENTRE INVOLVED DIABETIC MACULAR OEDEMA

Diabetic Macular Oedema and Good Vision 

I monitor eyes with diabetic macular oedema and good vision. There is still no reliable evidence that initial treatment of eyes with centre involved DMO without visual impairment is beneficial. The best corrected visual acuity (BCVA) included in the landmark intravitreal DMO trials was 78 letters (equivalent to 20/32). This is acknowledged by the Australian Pharmaceutical Benefits Scheme (PBS),⁵ which only subsidises intravitreal treatment in eyes with DMO and visual impairment.

The DRCRnet is an American based collaborative network that facilitates multicentre clinical research on diabetic retinopathy and DMO. It was formed in 2002 and sponsored by the National Eye Institute and National Institute of Diabetes and Digestive and Kidney Diseases. Clinical trials have been designed by the DRCRnet to answer questions about specific DMO scenarios. They examined the management of eyes with centre involved DMO and good vision in their Protocol V study.⁶ Eyes in this study were randomised to receive initial treatment with the antiVEGF agent (intravitreal aflibercept), initial treatment with macular laser, or initial observation. If the BCVA dropped one line on two consecutive visits or two lines at one visit, they were switched to treatment with aflibercept. The authors concluded that in eyes with centre involved DMO and good vision, there was no difference in vision loss at two years, whether the eyes were treated with aflibercept, laser photocoagulation, or observation, and that it was therefore safe to monitor these eyes and treat only when they developed visual impairment. We have reported similar findings in two real-world studies.^7,8 

Diabetic Macular Oedema and Visual Impairment 

For eyes with visual impairment due to centre involved DMO, intravitreal injection of anti-VEGF agents has become the first line treatment. We are fortunate in Australia to have two licensed anti-VEGF agents (ranibizumab and aflibercept), which are subsidised by the Pharmaceutical Benefits Scheme for treating eyes with visual impairment due to DMO. They have been proven effective in improving and maintaining visual acuity in their landmark clinical trials.^9,10 Due to its much lower cost, another anti-VEGF medication called bevacizumab is used off label when patients are unable to obtain subsidised approved anti-VEGF agents. The DRCRnet designed a clinical trial to examine whether one anti-VEGF agent was better than another in managing eyes with DMO. The Protocol T study compared ranibizumab to aflibercept to bevacizumab.¹¹ For eyes with BCVA 20/32 to 20/40, there was no difference in the performance of these three agents. However, for eyes with worse vision (BCVA 20/50 to 20/320), aflibercept was associated with better visual gains than either ranibizumab or bevacizumab at one year. This result has again been supported by real-world studies. The Fight Retinal Blindness! (FRB!) Registry study reported that both ranibizumab and aflibercept were beneficial for managing eyes with DMO. However, larger visual gains were observed with aflibercept treatment when the initial visual acuity was 20/50 or worse.¹²

Diabetic Macular Oedema in Pseudophakic Eyes 

Intravitreal corticosteroids, (such as the dexamethasone implant, Ozurdex [Allergan] or off label use of intravitreal triamcinolone acetonide), are generally reserved as second line agents in the management of DMO due to their associated risk of cataract and ocular hypertension. However, they can be considered first line therapy in pseudophakic eyes with close monitoring for increase in intraocular pressure. There was no difference in visual gain in pseudophakic eyes treated with an anti-VEGF medication (ranibizumab) or a steroid (triamcinolone acetonide) in the DRCRnet Protocol I study.¹³ Similarly, we found no difference in visual acuity gains among pseudophakic eyes in the BEVORDEX study, which compared intravitreal dexamethasone implant to intravitreal anti-VEGF (bevacizumab).¹⁴ It is also reasonable to consider the use of intravitreal steroid at the time of cataract surgery or in the perioperative period as exacerbation of DMO is thought to be secondary to inflammation associated with the surgery. An Australian study found that triamcinolone, given at the time of cataract surgery in eyes with current DMO or recent DMO, led to a more sustained improvement in macular thickness with less need for repeated treatment in the six months after surgery compared to bevacizumab.¹⁵ We have also reported that hard exudates resolve more rapidly in eyes treated with the dexamethasone implant compared with bevacizumab.¹⁶ 

LIMITATIONS OF CURRENT ANTI-VEGF THERAPY

Although anti-VEGF agents can be very effective in treating DMO, they must be administered often, especially in the first year, to achieve optimal results.

The visual acuity gains seen in clinical trials of DMO are higher than those reported from real world observational studies.12 Some of these differences may be due to exclusion of eyes with poorer visual prognosis from clinical trials. For example, the potential for visual improvement can be limited due to the presence of coexistent macular ischaemia or other ocular disease. Patients with major comorbidities, which can affect adherence to the trial’s treatment plan, are also excluded from most large randomised clinical studies. Patients with DMO have a greater risk of other diabetic complications and often require visits to other healthcare professionals. As many of these patients are of working age, this may require them to take significant time off work. Often a carer is also required to drive them to and from their ophthalmic appointments due to the need for dilating drops and/or treatment with intravitreal therapies. They may also need time to recover from the injections themselves. This competing demand for their time and the related costs of treatment can lead to significant under treatment and, as a result, poorer outcomes. Thus, longer lasting and more effective treatments for DMO could improve real world outcomes.

EMERGING THERAPIES FOR DIABETIC MACULAR OEDEMA

In discussing emerging therapies for DMO, I will focus on agents that are the most advanced in terms of clinical trial results and have the potential to become an approved treatment for DMO in the near future.

Brolucizumab 

Brolucizumab (Beovu, Novartis) is a humanised monoclonal single-chain antibody fragment that binds and inhibits VEGFA. Because it lacks the Fc region of the antibody, it has a smaller molecular weight than other anti-VEGF agents. For example, the molecular weight of brolucizumab is 26kda, whereas the molecular weight of ranibizumab is 48kda. The smaller size allows for a greater molar amount with greater tissue penetration, potentially leading to longer durability. Brolucizumab was found to be non-inferior to aflibercept despite being given less often in eyes with neovascular age related macular degeneration (n-AMD) in the HAWK and HARRIER trials. It was approved in Australia in 2020 by the Therapeutic Goods Administration (TGA) for eyes with n-AMD. However, increased incidence of intraocular inflammation, including development of retinal vasculitis and retinal vascular occlusion, became more apparent in post-marketing surveillance in the United States. This led to the PBS only subsidising brolucizumab in eyes with active n-AMD, despite at least six months of ranibizumab or aflibercept treatment. Novartis also released a statement recommending against treatment of patients with brolucizumab at intervals less than eight-weekly, following the loading doses, due to increased risk of inflammation.¹⁷ 

The KITE and KESTREL studies¹⁸ are two phase 3, two-year randomised controlled trials comparing brolucizumab (6mg and 3mg doses) to aflibercept 2mg in eyes with DMO. In the KITE study, patients were randomised 1:1 to brolucizumab 6mg or aflibercept 2mg. Those in the brolucizumab arm received five loading doses every six weeks, followed by extension to eight to 12 weeks, depending on disease activity. Those in the aflibercept arm received five loading doses of aflibercept 2mg four-weekly, followed by extension to eight-weekly. In the KESTREL study, patients were randomised 1:1:1 to receive brolucizumab 3mg, 6mg or aflibercept 2mg. Those in the brolucizumab arms received five loading doses of brolucizumab followed by extension to eight to 12 weeks, depending on disease activity. Those in the aflibercept arm received five loading doses of 2mg aflibercept every four weeks followed by extension to eight-weekly. The primary endpoint was the mean BCVA change from baseline to week 52. Secondary outcomes included presence of fluid and proportion of eyes with central foveal thickness (CSFT) < 280μm at week 52.

The studies met their primary endpoint with non-inferiority of brolucizumab 6mg to aflibercept 2mg in regard to change in BCVA, despite it being given less frequently. More than half the patients receiving brolucizumab 6mg were maintained on 12-weekly intervals. There were fewer subjects with retinal fluid in the brolucizumab arms compared with the aflibercept arms at 52 weeks. The proportion of eyes with CSFT < 280μm was higher in the brolucizumab arms than the aflibercept arm in each study.

However, similarly to the HAWK and HARRIER studies, higher rates of intraocular inflammation were seen in brolucizumab treated eyes, with 17/190 eyes (8.9%) in the brolucizumab 3mg group, 13/368 (3.5%) in the brolucizumab 6mg group and 5/187 (2.7%) in the aflibercept 2mg group. Although most events of intraocular inflammation were mild or moderate, four eyes randomised to brolucizumab developed vasculitis and three developed retinal vascular occlusions (with none occurring in the aflibercept treated eyes).

The two-year results of the KITE and KESTREL studies were released by Novartis in December 2021.¹⁹ These were consistent with the results seen at year one. They reported maintenance of BCVA and sustained reduction in CSFT. Patients randomised to brolucizumab were less likely to have fluid than those randomised to aflibercept. More than 40% of patients randomised to brolucizumab were maintained on 12-weekly injections. However, brolucizumab was associated with increased rates of intraocular inflammation compared to aflibercept treated eyes.

Faricimab 

Faricimab (Vabysmo, Roche) is a bispecific antibody. Its one molecule independently binds and blocks both angiopoietin-2 (Ang-2) and VEGF-A. In healthy vessels, Ang-1/ Tie signalling on vascular endothelial cells maintains vascular stability. Under pathologic conditions, such as in eyes with DMO, increased Ang-2 levels prevent Tie2 activation by Ang-1, weakening the integrity of endothelial cell junctions and contributing to vascular instability. Thus, blocking Ang-2 in addition to VEGF may lead to greater efficacy and durability. Faricimab was approved by the United States Food and Drug Administration (FDA) for eyes with n-AMD and eyes with DMO in January 2022. It has not yet been approved by the TGA in Australia.

The BOULEVARD trial²⁰ is a randomised controlled, phase 2 study which compared the safety and efficacy of faricimab to ranibizumab in patients with DMO. Both naïve and previously treated eyes were included. Naïve patients were randomised 1:1:1 to receive faricimab 6mg, or faricimab 1.5mg, or ranibizumab 0.3mg. Previously treated patients received either faricimab 6mg or ranibizumab 0.3mg. All patients received six loading doses given fourweekly then were observed until week 36. The primary endpoint was the mean BCVA change from baseline to week 24. Naive eyes randomised to faricimab had superior vision gains compared to ranibizumab at week 24, whereas in previously treated eyes, there was no significant difference in BCVA gains for either treatment.

The YOSEMITE and RHINE²¹ studies are two identical phase 3, randomised controlled trials. Patients were randomised 1:1:1 to receive faricimab 6mg eight-weekly, faricimab 6mg four to 16-weekly (depending on disease activity) or aflibercept eight-weekly. Both faricimab groups met the primary endpoint of non-inferior BCVA gains compared to aflibercept. More than 70% of patients were extended to 12 or more weeks and 50% extended to 16 weeks. More patients randomised to faricimab achieved resolution of DMO (defined as CSFT less than 325μm) than those randomised to aflibercept.

The two-year results of YOSEMITE and RHINE were consistent with the results seen at one year. More than three quarters of patients were on 12-weekly or longer intervals and more than 60% on 16-week intervals. There were no cases of retinal vasculitis or occlusive retinitis.²² 

The ongoing Rhone X extension study will generate four-year results.

Port Delivery System 

The port delivery system (PDS) (Susvimo, Genentech) is an implantable, non-biodegradable reservoir inserted transsclerally via a pars plana incision in the operating theatre. It is preloaded with 100mg/ml ranibizumab (customised formulation) and can be refilled in the clinic. The drug moves by passive diffusion into the vitreous cavity so that a slow release of drug occurs over a longer time frame.²³

The ARCHWAY²⁴ phase 3 trial compared the safety and efficacy of the PDS refilled every 24 weeks to monthly ranibizumab for the treatment of n-AMD. It met its primary endpoint of non-inferior BCVA. However, 1.6% of eyes in the PDS arm developed endophthalmitis compared to 0.6% in the monthly ranibizumab arm. Vitreous haemorrhage occurred in 5% of the PDS treated eyes and 4% developed conjunctival erosions or retractions. Although it is approved by the FDA in the United States for patients with n-AMD who have responded to two or more anti-VEGF injections, it comes with a warning of a three-fold-higher incidence of endophthalmitis.

The PAGODA²⁵ trial is a randomised, noninferiority study with the main objective to evaluate the PDS’ efficacy, safety and pharmacokinetics in patients with DMO. More than 500 patients have been randomised to receive treatment with the PDS refilled six monthly, or ranibizumab 0.5mg monthly intravitreal injections. The estimated completion date is late 2024.

CONCLUSION

All diabetic patients should be screened for diabetic retinopathy so that those who need treatment can be identified and those who are at high risk of vision loss can be properly monitored. The availability of anti-VEGF therapy has revolutionised the management of DMO. However, many patients with DMO have unsatisfactory visual outcomes as a result of under treatment due to the burden of frequent injections. Ongoing research of new therapies is focused on improved efficacy and durability, although any benefit must be balanced against safety considerations. Treatments that are more effective, safe, and last longer could result in superior visual outcomes, enhancing our patients’ quality of life.

Samantha Fraser-Bell BSc(Med), MBBS, MHA, MPH, PHD, FRANZCO is an Associate Professor in the discipline of Ophthalmology at the University of Sydney. She is a consultant Medical Retina specialist at Sydney Eye Hospital and Medical Retina/Uveitis specialist at Royal North Shore Hospital. She is the Deputy Director of Clinical Trials at the Macula Research Unit, Save Sight institute. Assoc/Prof Fraser-Bell continues to be actively involved in clinical research and has authored more than 100 peer reviewed publications and has been an investigator on more than 50 retinal clinical trials, most as primary investigator. She is Medical Retinal subeditor for the journal, Clinical and Experimental Ophthalmology, a Macula Society member and Australian Vision Research (formally known as Ophthalmic Research Institute of Australia) board member and secretary of their grant review panel.

References 

1. diabetesatlas.org/idfawp/resource-files/2021/07/IDF_ Atlas_10th_Edition_2021.pdf accessed 8/5/22. 
2. P. Romero-Aroca. Managing diabetic macular edema: the leading cause of diabetes blindness. World J Diabetes, 2011; 2(6) 98-104. 
3. Teo ZL, Tham YC, Yu M, Chee ML, Rim TH, Cheung N, Bikbov MM, Wang YX, Tang Y, Lu Y, Wong IY, Ting DSW, Tan GSW, Jonas JB, Sabanayagam C, Wong TY, Cheng CY. Global Prevalence of Diabetic Retinopathy and Projection of Burden through 2045: Systematic Review and Metaanalysis. Ophthalmology. 2021;128(11):1580-1591. 
4. Early Treatment Diabetic Retinopathy Study Research Group Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;103:1796–1806. 
5. www.servicesaustralia.gov.au/pb155 accessed 8/5/22. 
6. Baker CW, Glassman AR, Beaulieu WT, Antoszyk AN, Browning DJ, Chalam KV, Grover S, Jampol LM, Jhaveri CD, Melia M, Stockdale CR, Martin DF, Sun JK; DRCR Retina Network. Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial. JAMA. 2019;321(19):1880-1894. 
7. Gabrielle PH, Nguyen V, Bhandari S, Mehta H, Viola F, Arnold J, Fraser-Bell S, Barthelmes D, Creuzot-Garcher C, Gillies M. Initial observation or treatment for diabetic macular oedema with good visual acuity: two-year outcomes comparison in routine clinical practice: data from the Fight Retinal Blindness! Registry. Acta Ophthalmol. 2022;100(3):285-294. 
8. Busch C, Fraser-Bell S, Zur D, Rodríguez-Valdés PJ, Cebeci Z, Lupidi M, Fung AT, Gabrielle PH, Giancipoli E, Chaikitmongkol V, Okada M, Laíns I, Santos AR, Kunavisarut P, Sala-Puigdollers A, Chhablani J, Ozimek M, Hilely A, Unterlauft JD, Loewenstein A, Iglicki M, Rehak M; International Retina Group. Real-world outcomes of observation and treatment in diabetic macular edema with very good visual acuity: the OBTAIN study. Acta Diabetol. 2019;56(7):777-784. 
9. Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, Gibson A, Sy J, Rundle AC, Hopkins JJ, Rubio RG, Ehrlich JS; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801. 
10. Heier JS, Korobelnik JF, Brown DM, Schmidt-Erfurth U, Do DV, Midena E, Boyer DS, Terasaki H, Kaiser PK, Marcus DM, Nguyen QD, Jaffe GJ, Slakter JS, Simader C, Soo Y, Schmelter T, Vitti R, Berliner AJ, Zeitz O, Metzig C, Holz FG. Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID Studies. Ophthalmology. 2016;123(11):2376-2385. 
11. Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, Antoszyk AN, Arnold-Bush B, Baker CW, Bressler NM, Browning DJ, Elman MJ, Ferris FL, Friedman SM, Meila M, Pieramici DJ, Sun JK, Beck RW. Aflibercept, bevacizumab or ranibizumab for diabetic macular oedema. N Engl J Med 2015;372(13):1193-1203. 
12. Bhandari S, Nguyen V, Fraser-Bell S, Mehta H, Viola F, Baudin F, Gabrielle PH, Creuzot-Garcher C, Gillies M, Barthelmes D. Ranibizumab or Aflibercept for Diabetic Macular Edema: Comparison of 1-Year Outcomes from the Fight Retinal Blindness! Registry. Ophthalmology. 2020;127(5):608-615. 
13. Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064–77. 
14. Fraser-Bell S, Lim LL, Campain A, Mehta H, Aroney C, Bryant J, Li J, Quin GJ, McAllister IL, Gillies MC. Bevacizumab or Dexamethasone Implants for DME: 2-year Results (The BEVORDEX Study). Ophthalmology. 2016;123(6):1399-401. 
15. Kandasamy R, Constantinou M, Rogers SL, Sandhu SS< Wickramasinghe S, Al-Qureshi S, Lim LL, Prospective randomised controlled trial of intravitreal bevacizumab versus triamcinolone in eyes with diabetic macular oedema undergoing cataract surgery: 6-month results. Br J Ophthalmol. 2019;103(12):1753-1758. 
16. Mehta H, Fraser-Bell S, Yeung A, Campain A, Lim LL, Quin GJ, McAllister IL, Keane PA, Gillies MC. Efficacy of dexamethasone versus bevacizumab on regression of hard exudates in diabetic maculopathy: data from the BEVORDEX randomised clinical trial. Br J Ophthalmol. 2016 ;100(7):1000-1004. 
17. Novartis reports one year results of Phase III MERLIN study evaluating Beovu every four week dosing and provides update on Beovu clinical program | Novartis accessed 8/5/22. 
18. Brown DM, Emanuelli A, Bandello F, Barranco JJE, Figueira J, Souied E, Wolf S, Gupta V, Ngah NF, Liew G, Tuli R, Tadayoni R, Dhoot D, Wang L, Bouillaud E, Wang Y, Kovacic L, Guerard N, Garweg JG. KESTREL and KITE: 52-Week Results From Two Phase III Pivotal Trials of Brolucizumab for Diabetic Macular Edema. Am J Ophthalmol. 2022;238:157-172. 
19. Novartis announces positive results from year two of the Phase III trial of Beovu in diabetic macular edema | Novartis accessed 8/5/22. 
20. Sahni J, Patel SS, Dugel PU, Khanani AM, Jhaveri CD, Wykoff CC, Hershberger VS, Pauly-Evers M, Sadikhov S, Szczesny P, Schwab D, Nogoceke E, Osborne A, Weikert R, Fauser S. Simultaneous Inhibition of Angiopoietin-2 and Vascular Endothelial Growth Factor-A with Faricimab in Diabetic Macular Edema: BOULEVARD Phase 2 Randomized Trial. Ophthalmology. 2019;126(8):1155-1170 
21. Wykoff CC, Abreu F, Adamis AP, Basu K, Eichenbaum DA, Haskova Z, Lin H, Loewenstein A, Mohan S, Pearce IA, Sakamoto T, Schlottmann PG, Silverman D, Sun JK, Wells JA, Willis JR, Tadayoni R; YOSEMITE and RHINE Investigators. 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. 
22. retinaroundup.com/2022/02/17/angiogenesis- 2022-update-on-the-2-year-data-from-rhine-andyosemite- involving-faricimab-for-the-treatment-of-dme/ accessed 8/5/22. 
23. Campochiaro PA, Marcus DM, Awh CC, Regillo C, Adamis AP, Bantseev V, Chiang Y, Ehrlich JS, Erickson S, Hanley WD, Horvath J, Maass KF, Singh N, Tang F, Barteselli G. The Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration: Results from the Randomized Phase 2 Ladder Clinical Trial. Ophthalmology. 2019;126(8):1141-1154. 
24. Holekamp NM, Campochiaro PA, Chang MA, Miller D, Pieramici D, Adamis AP, Brittain C, Evans E, Kaufman D, Maass KF, Patel S, Ranade S, Singh N, Barteselli G, Regillo C; all Archway Investigators. Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2022;129(3):295-307. 
25. clinicaltrials.gov/ct2/show/NCT04108156 accessed 8/5/22.