Treatment Approaches for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema

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ABSTRACT

Neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) can cause substantial disease burden for patients. Several organizations have published clinical guidelines on appropriate diagnosis and treatment recommendations to alleviate this burden. Treatment approaches include both nonpharmacologic methods and pharmacologic therapies, with anti-vascular endothelial growth factor (VEGF) therapy being the standard of care. Anti-VEGF therapy is an effective treatment option for both nAMD and DME; however, long-term patient compliance may be reduced due to the burden of costs, monthly intravitreal injections, and repeat clinic visits to assess clinical response parameters. Emerging treatments and dosing strategies aim to decrease treatment burden and increase patient safety. Retina specialists can play a key role in improving the management of both nAMD and DME by incorporating patient-specific treatment strategies tailored to improve clinical outcomes. Enhanced knowledge of retinal disease therapies will allow clinicians to optimize evidence-based treatment strategies to improve clinical outcomes for their patients.

Am J Manag Care. 2023;29(suppl 6):S81-S89. https://doi.org/10.37765/ajmc.2023.89386

The substantial disease burden of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) has led various national and international organizations to publish clinical practice guidelines regarding appropriate diagnosis and treatment recommendations.^1-5 Risk factors associated with nAMD include age, ethnicity, smoking, and comorbidities, such as hypertension and hyperlipidemia.^3,6 Early diagnosis can ensure that patients receive the appropriate treatment, which increases the likelihood of improved long-term visual outcomes. Prevention of DME begins with the management of systemic disease; treatment of comorbidities such as hyperglycemia, hyperlipidemia, and hypertension can delay the onset and progression of diabetic retinal diseases.^2,7,8 The American Academy of Ophthalmology (AAO) recommends all patients with diabetes have a comprehensive ophthalmic eye evaluation at the time of diagnosis to establish baseline criteria for the assessment of potential development of retinal disease. Patients newly diagnosed should be referred to either an ophthalmologist or optometrist for a dilated fundus exam and, if warranted, baseline retinal imaging. Teleophthalmology screening using advanced imaging modalities can also aid in obtaining baseline fundus status.^6,9

Patients with type 1 diabetes should be screened annually starting 5 years after onset of diabetes, and patients with type 2 diabetes should be screened upon diagnosis and then at least annually thereafter. For patients with early-stage AMD or who have a family history of AMD, the AAO recommends patients assess their own visual acuity (VA) by using monocular vision testing (ie, Amsler grid or electronic home monitoring) and have regularly scheduled dilated eye exams.¹⁰ Effective screening practices can help determine which patients need to be referred for treatment.

Current Treatment Options

Patients with DME should be considered for prompt treatment, especially when the center of the macula is already involved or if there is evidence of retinal thickening or hard exudates that are close to the center of vision.⁶ DME can be present in various stages of diabetic retinopathy and is classified as either center-involved (CI-DME) or noncenter-involved DME (NCI-DME).^1,6 The Diabetic Clinical Research Network (now the DRCR Retina Network) is an influential collaborative network that has contributed to multiple advances in the management and treatment of diabetic retinopathy, DME, and associated conditions.¹¹ Since 2002, the DRCR Retina Network has completed over 30 multicenter studies that have helped establish treatment algorithms for diabetic eye care, which include both pharmacologic and nonpharmacologic treatment modalities. Current options for management of DME include close clinical observation, pharmacotherapies, laser treatment, or a combination of these options.¹

Onset of AMD can be rapid or gradual, and it is important to ensure quick diagnosis and treatment for individuals at the earliest stages of disease.3 With nAMD, the most common treatment option is anti-VEGF therapy, and anti-VEGF treatment is considered the gold standard^2,5,8; other treatment options for specific cases include observation, vitamin and mineral supplements, photodynamic therapy, and laser photocoagulation surgery.¹⁰

Nonpharmacologic Treatment Options

One nonpharmacologic option for DME is laser photocoagulation.^2,5 In recent years, the use of laser photocoagulation has been recommended for use in DME without central involvement. Laser photocoagulation has not shown a significant benefit in VA outcomes in patients with CI-DME. In general, the Early Treatment Diabetes Retinopathy Study (ETDRS) letter scoring system for VA is often considered the gold standard for use in ophthalmic clinical trials.¹²

It is important to note that some patients with CI-DME and good VA may be observed without treatment. In the DRCR Network Protocol V study, 702 eyes with a baseline VA of 20/25 or better were randomized to aflibercept, focal/grid laser photocoagulation, or observation to compare vision loss at 2 years. Aflibercept was required for eyes in the laser and observation groups that had decreased VA from baseline by at least 10 letters at any visit or by 5 to 9 letters at 2 consecutive visits.¹³ Only a small percentage of eyes in each group lost 5 or more letters at follow-up (aflibercept, 16%; laser photocoagulation, 17%; observation, 19%). This study demonstrated that eyes with CI-DME and a VA score of at least 20/25 or better may be managed with observation and treated only if their VA worsens.¹⁴

In patients with nAMD, nonpharmacologic therapies that have been studied include photocoagulation laser therapy and various surgical procedures including vitrectomy, photodynamic therapy, and radiation therapy.^4,10 These treatments have been used in rare and specific cases; however, the standard of care is still anti-VEGF treatment.

Pharmacologic Treatment Options

There are variations in the underlying causes of nAMD and DME, but they do share similar pathophysiology, such as VEGF signaling pathways.¹⁵ Clinical practice guidelines for both nAMD and DME recommend the use of anti-VEGF therapy as first-line treatment.^1,16 Numerous clinical trials have shown that anti-VEGF therapy is superior to focal laser treatment in improving vision in patients with CI-DME.⁶ The most frequently used anti-VEGF therapies are aflibercept, ranibizumab, and bevacizumab; bevacizumab is additionally FDA approved for the treatment of colorectal and other cancers but is used off-label for nAMD and DME.⁸ Other newer FDA-approved VEGF inhibitors include brolucizumab, faricimab (which also has angiopoietin-2 inhibition), and an intraocular ranibizumab port delivery system (PDS).^8,17

Table 1^{1,2,4,6,10,16,18} summarizes guideline treatment recommendations from various organizations for the clinical management of nAMD and DME. Aside from VEGF inhibitors, intravitreal corticosteroid injections may also be considered in the treatment of DME; they are generally considered second-line agents due to their adverse effect (AE) profile, which includes elevated intraocular pressure and cataract progression.⁶ Per international guidelines, evidence does not currently support the use of corticosteroid injections in nAMD.³

A summary of VEGF inhibitors that are currently used for nAMD and DME can be found in Table 2.^19-26 In addition to the information presented, there are various treatment regimens for intravitreal injections that are used by retina specialists; these include the as-needed (PRN) approach, treat-and-extend (T&E), and monthly dosing.^27-29 Current clinical trial data demonstrate that anti-VEGF therapy is more effective for CI-DME than monotherapy with focal laser therapy. Common AEs for intravitreal VEGF inhibitors include eye pain, blurred vision, cataract, conjunctival hemorrhage, vitreous floaters, and increased intraocular pressure.^{19,21-23,25,26}

It is important to note that there are limited direct randomized comparative trials with anti-VEGF agents for the treatment of nAMD and DME, and it is difficult to estimate differences in safety and efficacy between regimens.^30,31 Indirect comparisons between trials may also have various confounding factors, such as variation in baseline patient characteristics. The National Institutes of Health-sponsored DRCR Protocol T study was a landmark trial that compared bevacizumab, ranibizumab, and aflibercept in the treatment of DME.⁶ All 3 agents were effective with comparable safety profiles in patients with CI-DME, and there was no difference among agents in patients with baseline VA of 20/32 to 20/40. At 1 year, aflibercept had superior VA outcomes among eyes with baseline VA of 20/50 to 20/320; at 2 years, aflibercept remained superior to bevacizumab and ranibizumab when evaluating post hoc area under the curve analyses for those with a baseline VA of 20/50 to 20/320.³² Therapeutic regimens should be discussed between provider and patient and ultimately individually tailored to allow for optimal clinical outcomes.

Treatment Approaches Aiming to Reduce Patient Burden

Anti-VEGF therapy is an effective treatment option for both nAMD and DME; however, long-term patient compliance may be reduced due to costs and overall treatment burden.²⁷ There is currently no standard regimen for injection frequency, and to optimize compliance and reduce costs, there are various flexible dosing strategies that are used in clinical practice. In the PRN approach, the retina specialist only administers intravitreal injections when disease activity is noted on ophthalmologic exam or optical coherence tomography (OCT) results. On the contrary, the T&E regimen involves fixed treatment intervals followed by a stepwise increase or decrease in the treatment interval based on the presence or absence of continued disease activity.^27-29

In 2014, a consensus panel of international retina specialists developed a preferred T&E algorithm with anti-VEGF agents for retinal diseases.²⁷ The consensus panel concluded that monthly injections of anti-VEGF agents should continue until observation of maximum response, identified by complete resolution of subretinal fluid and intraretinal fluid without new retinal hemorrhage or no further reduction of intraretinal fluid or subretinal fluid on OCT for a minimum of 2 consecutive assessments in the absence of new retinal hemorrhage. Once maximum response of monthly injections is reached, the consensus panel agreed that treatment intervals could be extended by up to 2 weeks at a time if the patient’s disease activity remains stable. The maximum extension period the panel considered was 12 weeks, though the extension period also depended on various factors including the type of disease being treated, monocular patients, risk of hemorrhage, and medication being used.²⁷

Published studies comparing T&E with PRN approaches in nAMD have shown greater improvement in both visual and anatomical outcomes using T&E regimens.²⁷ Importantly, PRN regimens require frequent monitoring visits in order to sustain VA gains; this has shown to be impractical in real-world settings compared with clinical trial settings.²⁹ Retreatment criteria reported in clinical trials for PRN regimens are also varied, which can result in practice variations. Conversely, T&E regimens present a more individualized approach. A recent systematic review and meta-analysis also found low-certainty evidence that implied T&E regimens preserve VA similar to fixed-dosing schedules but with significantly fewer injections.²⁸

In patients with nAMD, recent trials, including the TREX-AMD trial, CANTREAT study, and TREND trial, have compared ranibizumab T&E regimens with monthly fixed-dosing regimens.²⁸ The TREX-AMD trial was conducted in 2 US centers (N = 60) where treatment-naïve patients with nAMD (best-corrected visual acuity [BCVA] of 20/32 to 20/500) were randomized to either a ranibizumab 0.5 mg monthly cohort (n = 20) or a T&E regimen cohort (n = 40) with administration no less frequently than every 12 weeks; patients were followed for up to 2 years.³³ Results of the study showed that visual and anatomic improvements were comparable between cohorts, and patients were able to maintain a consistent extension interval. The mean maximum tolerated extension interval was 8.5 weeks over the course of 24 months.

The CANTREAT study was a 2-year, open-label, noninferiority trial of patients (N = 580) who were randomized to receive ranibizumab 0.5 mg in either a monthly (n = 293) or T&E dosing regimen (n = 287).³⁴ The study findings suggested that a T&E regimen compared with a monthly regimen of ranibizumab did not result in a worse change in vision. A T&E regimen can provide clinically meaningful BCVA improvements while using fewer injections. The T&E cohort received an average of 17.6 injections compared with 23.5 injections for the monthly cohort.

The TREND trial was a 12-month, multicenter, noninferiority study of treatment-naïve patients with nAMD (N = 650) who were randomized to receive either a ranibizumab 0.5 mg monthly (n = 327) or T&E regimen (n = 323).³⁵ The T&E cohort was found to be noninferior to the monthly cohort as assessed by mean change in BCVA from baseline (P <.001). Most BCVA improvements also occurred within the first 6 months of the study and were maintained through the duration of the study in both groups. The T&E cohort also required fewer injections (average, 8.7) compared with the monthly cohort (average, 11.1).

Studies have also evaluated aflibercept T&E protocols in nAMD. ARIES was a multicenter trial that compared an early-start T&E regimen (2-week interval adjustments) with a late-start T&E regimen (8-week interval adjustments until week 48 then 2-week interval adjustments).²⁸ All patients received intravitreal aflibercept (2 mg) at weeks 0, 4, 8, and 16, and then were randomized into their respective treatment groups. Outcomes between the early-start T&E regimen and late-start T&E regimen were similar after initial dosing, and the early-start intravitreal aflibercept T&E regimen was found to be noninferior to late-start T&E in terms of the primary outcome of mean change in BCVA.³⁶

In DME, a growing body of evidence also suggests similar visual results and decreased treatment burden of T&E regimens compared with fixed-dosing schedules.²⁹ A meta-analysis evaluated T&E regimens compared with alternative dosing strategies (eg, PRN, fixed) in patients with CI-DME. The analysis included 22 studies (8 randomized controlled trials, 7 prospective studies, and 7 retrospective studies) of ranibizumab, aflibercept, and faricimab. There were 7 studies that looked at T&E compared with fixed monthly regimens, and the meta-analysis did not find a significant difference in VA at 12 months between the regimens. In the 3 studies that had 24-month results, there was no significant difference between the groups. T&E regimens compared with PRN regimens were evaluated in 4 studies, results of which showed no significant difference in VA at 12 months; 2 studies reported on 24-month outcomes and found no significant difference between groups.

In terms of anatomic outcomes, no significant difference was found between fixed and T&E regimens for central subfoveal thickness or central retinal thickness at 12 or 24 months.²⁹ There were limited anatomic outcomes data on T&E compared with PRN regimens, although no significant difference was found for central retinal thickness at 12 months. In addition, there was no significant difference in the total number of injections between T&E and fixed regimens at 12 months; however, PRN regimens had fewer total injections compared with T&E. Most clinical trials comparing T&E with fixed and PRN dosing regimens report outcomes at 12 and 24 months. More evidence is needed to provide visual and functional outcomes data beyond 24 months.

It is important to note that the reported efficacy of PRN regimens in controlled trial settings is often not observed in real-world assessments.²⁸ There can be differences in patient compliance between controlled settings and clinical practice, and monthly assessments may not be feasible.^28,37 Post hoc analyses of randomized controlled trials, such as Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), HARBOR, and IVAN, have shown patients with poorer visual outcomes and greater fluctuations in retinal thickness following VEGF inhibitor treatment. PRN regimens involve retreatment upon presence of disease activity, and reactive dosing schedules like the PRN regimen may predispose patients to greater fluctuations in retinal thickness. PRN treatment strategies and monthly monitoring also leave patients open to the risk of disease resurgence.³⁷ The ideal patient treatment regimen should be individualized, effective, and proactive, and this can lead to a reduced treatment burden and improved clinical outcomes.

Recent Updates in Treatment Approaches for nAMD and DME

Anti-VEGF agents have been utilized as the gold standard for nAMD and DME treatment for several years, and there have been numerous clinical studies supporting the benefits of these agents in retinal diseases. Real-world evidence and treatment strategies for nAMD and DME are also constantly evolving and improving. Emerging therapy options are using novel delivery systems and mechanisms of action to decrease treatment burden and increase patient safety.³⁸

Novel Formulations and Delivery Mechanisms

Ranibizumab Port Delivery System

A promising therapeutic system that can reduce the frequency of anti-VEGF drug administration is an implantable ocular PDS. The PDS is designed to allow the controlled release of medications that can neutralize VEGF and decrease treatment burden. A PDS with ranibizumab implant was approved by the US FDA in 2021 and is indicated for patients with nAMD who have previously responded to at least 2 intravitreal injections of a VEGF inhibitor.²⁵ The PDS delivers a serum concentration of ranibizumab within the same maximum and minimum range experienced with monthly intravitreal injections of 0.5 mg ranibizumab. The recommended dose of the ranibizumab PDS is 2 mg, which is continuously delivered via the PDS; refill exchange for the implant is performed every 24 weeks.

The safety and efficacy of ranibizumab PDS was evaluated in the phase 3, multicenter, open-label Archway trial.³⁹ Study eligibility criteria included patients with nAMD diagnosed within 9 months of study screening and who had at least 3 prior anti-VEGF intravitreal injections within 6 months of study screening. Patients were randomized to either ranibizumab 100 mg/mL PDS with 24-week refill exchanges (n = 248) or ranibizumab 0.5 mg intravitreal injections every 4 weeks (n = 167). Participants in the ranibizumab PDS arm were eligible for ancillary treatment with intravitreal ranibizumab 0.5 mg injections at study visits that preceded each refill-exchange procedure if they met certain criteria. All patients were monitored monthly through trial completion. The primary efficacy outcome was change in mean BCVA score from baseline to weeks 36 and 40. Safety outcomes included ocular and nonocular AEs. The PDS group was reported to be noninferior and equivalent to the monthly injection group based on adjusted mean change in BCVA score from baseline to the average of weeks 36 and 40: +0.2 letters (standard error [SE], 0.5 letters) in the PDS group and +0.5 letters (SE, 0.6 letters) in the monthly injection group (difference, –0.3 letters; 95% CI, –1.7 to 1.1 letters). Most patients (98.4%) in the PDS group did not receive supplemental ranibizumab injection treatment prior to the first refill exchange at 24 weeks. Ocular AEs were reported in both the PDS (n = 47) and monthly ranibizumab groups (n = 10) and included vitreous hemorrhages, conjunctival retractions, and conjunctival erosions.

An extension study (Portal trial; NCT03683251) of the ranibizumab PDS in patients with nAMD is currently ongoing.⁴⁰ It is a multicenter, open-label study that enrolled patients who had completed a previous trial with the PDS implant, including the phase 2 Ladder study, phase 3 Archway study, and phase 3b Velodrome study. Once patients were moved to the Portal trial, they received ranibizumab 100 mg/mL PDS with refill exchanges every 24 weeks. An interim analysis of the Portal extension trial was presented at the 2022 Association for Research in Vision and Ophthalmology conference.⁴¹ The interim analysis assessed efficacy outcomes for patients who transitioned from the Ladder study where they were previously treated with either PDS 100 mg/mL or monthly ranibizumab injections. The analysis evaluated long-term safety data from all patients who received a ranibizumab PDS implant in the Ladder, Archway, or Portal studies. Ranibizumab PDS showed stable BCVA and center point thickness from baseline to 48 months from PDS implant insertion; 95% of patients did not need a supplement ranibizumab injection prior to each refill-exchange procedure. The long-term safety profile of the ranibizumab PDS was reported to be manageable and similar to results observed in the Archway trial. However, the manufacturer of ranibizumab PDS initiated a voluntary recall of the ocular implant and insertion tool assembly in October 2022 after septum dislodgement cases were reviewed in the trial. To date, no cases of septum dislodgement have been reported outside of the clinical trials.⁴²

Faricimab Dual Target Therapy

Faricimab-svoa is a novel monoclonal antibody that inhibits VEGF-A and angiopoietin-2, both of which have a significant pathological role in the destabilization of retinal vasculature. Faricimab was FDA approved in 2022 for the treatment of nAMD and DME.22 The recommended dosing in nAMD is 6 mg by intravitreal injection every 4 weeks and in DME it is either 6 mg every 4 weeks followed by modification of the dosing interval (based on ophthalmic evaluations) or 6 mg every 4 weeks for 6 doses, then 6 mg every 8 weeks.

The clinical efficacy and safety of faricimab for FDA approval in nAMD was evaluated in the noninferiority, randomized, controlled TENAYA and LUCERNE trials.²² Both TENAYA and LUCERNE were identically designed, active-comparator, 2-year trials that were conducted at various sites worldwide (TENAYA, n = 149 sites; LUCERNE, n = 122 sites). Across both trials, a total of 1329 treatment-naïve patients with nAMD were randomized to intravitreal faricimab 6 mg up to every 16 weeks or aflibercept 2 mg every 8 weeks.43 The primary efficacy outcome was mean change in BCVA from baseline to primary end point visits (averaged over weeks 40, 44, and 48). Safety outcomes included incidence and severity of ocular and nonocular AEs. Both TENAYA and LUCERNE met the primary outcome of noninferiority in mean change in BCVA with faricimab compared with aflibercept. In the intention-to-treat population analyses, the adjusted mean gains in BCVA in TENAYA were 5.8 letters (95% CI, 4.6-7.1) in the faricimab group and 5.1 letters (95% CI, 3.9-6.4) in the aflibercept group (treatment difference, 0.7 letters; 95% CI, –1.1 to 2.5). In LUCERNE, the adjusted mean gains in BCVA in the faricimab group were 6.6 letters (95% CI, 5.3-7.8) and 6.6 letters in the aflibercept group (95% CI, 5.3-7.8) (treatment difference, 0.0 letters; 95% CI, –1.7 to 1.8). At week 48, approximately 80% of patients on faricimab in both trials were on a 12-week or 16-week dosing schedule. Rates of ocular AEs leading to study treatment discontinuation were low in both trials (TENAYA, n = 6; LUCERNE, n = 9). Common ocular AEs seen in both trials were consistent with those expected in patients receiving intravitreal treatment and occurred at similar rates between the faricimab and aflibercept groups.

The clinical efficacy and safety of faricimab for FDA approval in DME was evaluated in the noninferiority, randomized, controlled YOSEMITE and RHINE trials.²² YOSEMITE and RHINE were identically designed, active-comparator trials conducted at various sites worldwide (YOSEMITE, n = 179 sites; RHINE, n = 174 sites).⁴⁴ Patients with CI-DME were eligible for inclusion; patients were permitted to be either previously treated with anti-VEGF therapy or treatment naïve. Across both trials, a total of 1891 patients were randomized to intravitreal faricimab 6 mg every 8 weeks, faricimab 6 mg per personalized treatment interval (PTI), or aflibercept 2 mg every 8 weeks. The primary efficacy outcome was mean change in BCVA from baseline to primary end point visits (averaged over weeks 48, 52, and 56). Safety outcomes included incidence and severity of ocular and nonocular AEs. Both YOSEMITE and RHINE met the primary outcome of noninferiority in mean change in BCVA with faricimab (every 8 weeks and PTI) compared with aflibercept every 8 weeks. In the intent-to-treat analyses for YOSEMITE, the adjusted mean BCVA change was 10.7 letters (97.52% CI, 9.4-12.0) in the faricimab every-8-weeks group, 11.6 letters (97.52% CI, 10.3-12.9) in the faricimab PTI group, and 10.9 letters (97.52% CI, 9.6-12.2) in the aflibercept group. In RHINE, the adjusted mean BCVA change was 11.8 letters (97.52% CI, 10.6-13.0) in the faricimab every-8-weeks group, 10.8 letters (97.52% CI, 9.6-11.9) in the faricimab PTI group, and 10.3 letters (97.52% CI, 9.1-11.4) in the aflibercept group. Many patients in both YOSEMITE and RHINE achieved every-12-week or every-16-week dosing at week 52 (YOSEMITE, n = 194 [68%]; RHINE, n = 198 [64%]). Incidence of ocular AEs was comparable among all 3 treatment groups. Overall, faricimab was well tolerated. Most events reported in both trials were mild or moderate in severity and balanced among all 3 groups.

Additionally, a recent retrospective case-controlled series evaluated the efficacy of faricimab in patients with treatment-resistant nAMD.⁴⁵ A total of 55 patients who had been actively receiving intravitreal aflibercept prior to study initiation were included (intravitreal faricimab group, n = 28; aflibercept [control] group, n = 27). A T&E protocol was used during this study; all patients were given monthly injections until observable intraretinal and/or subretinal fluid was resolved on OCT. After this point, dosing was extended in 1- to 2-week intervals until recurrence of fluid was observed, at which point the treatment interval was adjusted accordingly. The primary outcome was the proportion of patients who achieved a central macular thickness of less than 300 μm without observable fluid on OCT at 4 months. Secondary outcomes included proportion of patients who gained 2 or more lines of BCVA at 4 months. The primary outcome was achieved by 11 patients (39.3%) in the faricimab group and 2 patients (7.4%) in the aflibercept group (P = .004). The secondary outcome was achieved by 10 patients (35.7%) in the faricimab group and 2 patients (7.4%) in the aflibercept group (P = 0.008). The results demonstrate that intravitreal faricimab can improve visual and anatomic outcomes in patients with treatment-resistant nAMD who were previously treated with aflibercept. Longer follow-up is needed to determine how outcomes would compare in longer-duration T&E protocols.

Real-world evidence for faricimab is beginning to emerge. A retrospective review compared dosing intervals of patients with nAMD who had previously received a different anti-VEGF agent with dosing intervals after switching to faricimab within its first 6 months after FDA approval.46 In previously treated patients prior to switching to faricimab therapy, mean injection intervals were 4.68 ± 1.6 weeks for patients receiving bevacizumab, 5.16 ± 2.0 weeks for ranibizumab, 5.57 ± 3.6 weeks for aflibercept, and 6.18 ± 2.6 weeks for brolucizumab. Patients were initiated on monthly (5.16 ± 2.8 weeks) faricimab dosing, which continued for the first 3 injections after which point dosing intervals were increased by approximately 2 weeks based on presence of minimal or no fluid assessed on OCT and physician’s determination. At 35 weeks of follow-up, the mean dosing interval for faricimab was extended to 7.64 ± 6.2 weeks; 14 patients were able to extend dosing to 12 weeks or longer and 5 patients extended dosing interval to 16 weeks or longer.⁴⁶ Clinical and anatomic outcomes found VA and central subfoveal thickness were improved in both treatment-naive and treatment-experienced eyes receiving faricimab.

Another retrospective review (FARETINA-AMD) using the IRIS Registry sought to document initial practice patterns, treatment response, and injection frequency of faricimab in either previously treated or treatment-naive patients with nAMD.⁴⁷ In patients receiving prior anti-VEGF therapy, mean injection frequency was approximately 6 weeks. After switch to or initiation of faricimab, the majority of previously treated (53%) and treatment-naïve eyes (55.7%) were able to extend dosing interval to longer than 6 weeks after 1 or 2 injections. Over the course of treatment, treatment-naive eyes experienced steady improvements in VA. At 6 months of follow-up, VA remained stable in eyes with prior anti-VEGF therapy.⁴⁷ The FARETINA-DME study also utilized data from the IRIS Registry to examine injection frequency and clinical outcomes after initiating faricimab in patients with DME.⁴⁸ The majority of treatment-naive (60.7%) and treatment-experienced eyes (63.5%) achieved at least 1 extended injection interval (up to 6 weeks) within the initial 4 injections per the FDA-approved labeling. After 4 injections, the mean change in BCVA for previously treated eyes was 1.0 letter and for treatment-naive eyes was 4.6 letters.⁴⁸

OPT-302

OPT-302 is a novel intravitreal injection that targets and inhibits VEGF-C and VEGF-D in patients with nAMD and DME.⁴⁹ It is a soluble fusion protein that binds to VEGF-C and VEGF-D, thereby preventing each growth factor from binding to receptors VEGFR-2 and VEGFR-3. Both VEGF-C and VEGF-D promote blood vessel and lymphatic vessel development, which contributes to destabilization of the retinal vasculature. In clinical trials, OPT-302 has been sequentially administered following anti–VEGF-A therapy because the agent is targeting an incomplete response to VEGF-A inhibition. By utilizing the combination of a VEGF-A inhibitor and OPT-302, improved VA and reduced retinal swelling may be achieved due to a more complete blockade of important signaling pathways that contribute to nAMD and DME.

The clinical efficacy and safety of OPT-302 in nAMD was evaluated in a phase 2b sham-controlled study.⁵⁰ Treatment-naïve patients with wet AMD (N = 366) were randomized to receive OPT-302 (0.5 mg) plus ranibizumab 0.5 mg, OPT-302 (2 mg) plus ranibizumab 0.5 mg, or ranibizumab 0.5 mg plus sham injection. The OPT-302 (2 mg) combination therapy demonstrated superiority over ranibizumab 0.5 mg monotherapy at week 24. The 2-mg dose also demonstrated anatomic improvements including reductions in central subfield thickness, subretinal/intraretinal fluid, and greater decreases in total lesion area and choroidal neovascularization, as well as favorable safety outcomes. SHORE and COAST are 2 concurrent, phase 3, sham-controlled clinical trials in patients with nAMD that are currently ongoing and enrolling treatment-naïve participants to assess the efficacy and safety of OPT-302 (2 mg) combination therapy with an anti–VEGF-A agent.51 SHORE will evaluate 2 mg OPT-302 plus ranibizumab 0.5 mg and COAST will evaluate 2 mg OPT-302 plus aflibercept 2 mg. The primary outcomes for both trials will be the mean change in VA from baseline to week 52.

In DME, OPT-302 has been evaluated in a phase 1b dose escalation trial and a phase 2a dose expansion trial.⁵² The phase 2a trial enrolled patients with persistent CI-DME despite prior VEGF-A inhibitor monotherapy. Participants (N = 115) received 2 mg OPT-302 combination therapy with aflibercept 2 mg. The primary efficacy outcome of clinical response rate (≥5 letter gain VA at week 12 compared with baseline) was achieved in 52.8% of patients treated with the OPT-302 combination therapy. Currently, no plans for phase 3 clinical trials of OPT-302 in DME have been announced. If OPT-302 gains FDA approval, it will represent an expansion of treatment options in both nAMD and DME to target VEGF subtypes beyond VEGF-A isoforms.

ONS-05010: Intravitreal Bevacizumab

ONS-05010 (bevacizumab-vikg) is an intravitreal injection formulation of bevacizumab dosed monthly for the treatment of nAMD and other retinal diseases.⁵³ The FDA accepted the Biologics License Application for bevacizumab-vikg to treat nAMD in October 2022, and the Prescription Drug User Fee Act (PDUFA) goal date is set at August 29, 2023.⁵⁴ Completed clinical trials evaluating bevacizumab-vikg include NORSE 1, NORSE 2, and NORSE 3. The first registered clinical trial, NORSE 1, reported positive proof-of-concept data for safety and efficacy of bevacizumab-vikg. NORSE 2 was a phase 3 trial that enrolled 228 patients in the United States; bevacizumab-vikg achieved a statistically significant primary outcome (gain of ≥15 letters in BCVA at 11 months) compared with ranibizumab, and safety outcomes were favorable. NORSE 3 was an open-label safety study that included 197 patients in the United States and reported no incidences of ocular inflammation. The drug manufacturer states that future trials evaluating bevacizumab-vikg for branch retinal vein occlusion and DME are being assessed.

Anti-VEGF Biosimilars

For ophthalmic biosimilars, a comparative clinical trial is required for approval because systemic pharmacokinetics are not predictive of efficacy or safety.⁵⁵ Currently, the only FDA-approved biosimilars for intravitreal use are for ranibizumab, and ranibizumab-eqrn is an interchangeable biosimilar. Also, additional biosimilars are in development for the treatment of nAMD and DME.^24,54,55 The AAO recognizes the value of ophthalmic biosimilars for improving patient care and supports the notion that selection of biosimilar agents should occur through a discussion between the provider and patient.⁵⁵

Conclusions

Both nAMD and DME pose substantial burdens for patients that has warranted national and international organizations to publish clinical practice guidelines on appropriate management recommendations to optimize clinical outcomes. Intravitreal anti-VEGF agents continue to be the standard of care for both nAMD and DME, and numerous clinical trials have shown anti-VEGF therapy to be efficacious in improving vision along with having favorable safety profiles. There are novel and emerging therapies aimed to improve clinical and visual outcomes and patient adherence through new mechanisms of action, innovative drug delivery systems, and development of biosimilar agents. Retina specialists and managed care professionals play a key role in improving the management of both nAMD and DME. Enhanced knowledge of retinal disease therapies will allow clinicians to increase the evidence-based use of these agents and optimize patient outcomes.

Author affiliation: Arghavan Almony, MD, is senior retina partner and vice president, Carolina Eye Associates, PA, in Southern Pines, NC; and an adjunct assistant professor at Campbell University School of Medicine, Lillington, NC.

Funding source: This activity is supported by an educational grant from Genentech, a member of the Roche Group.

Author disclosure: Dr Almony has the following relevant financial relationship with a commercial interest to disclose: Consultant: Cardinal Health.

Authorship information: Critical revision of the manuscript for important intellectual content; supervision; and administrative, technical, or logistic support.

Address correspondence to: almony@gmail.com

Medical writing and editorial support provided by: Faria Munir, PharmD, MS, BCPS

References

1. Bakri SJ, Wolfe JD, Regillo CD, Flynn HW Jr, Wykoff CC. Evidence-based guidelines for management of diabetic macular edema. J VitreoRetin Dis. 2019:1-8. doi:10.1177/2474126419834711
2. ElSayed NA, Aleppo G, Aroda VR, et al. 12. Retinopathy, neuropathy, and foot care: standards of care in diabetes-2023. Diabetes Care. 2023;46(suppl 1):S203-S215. doi:10.2337/dc23-S012
3. Age-related macular degeneration: diagnosis and management. NICE Guideline, No. 82. 6, Risk factors. National Institute for Health and Care Excellence (NICE). Published January 2018. www.ncbi.nlm.nih.gov/books/NBK536467/
4. Schmidt-Erfurth U, Chong V, Loewenstein A, et al; European Society of Retina Specialists. Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). Br J Ophthalmol. 2014;98(9):1144-1167. doi:10.1136/bjophthalmol-2014-305702
5. Wong TY, Sun J, Kawasaki R, et al. Guidelines on diabetic eye care: The International Council of Ophthalmology Recommendations for Screening, Follow-up, Referral, and Treatment Based on Resource Settings. Ophthalmology. 2018;125(10):1608-1622. doi:10.1016/j.ophtha.2018.04.007
6. Flaxel CJ, Adelman RA, Bailey ST, et al. Diabetic retinopathy preferred practice pattern. Ophthalmology. 2020a;127(1):P66-P145. doi:10.1016/j.ophtha.2019.09.02
7. Diabetes and vision loss. Centers for Disease Control and Prevention. Updated December 19, 2022. Accessed January 16, 2023. www.cdc.gov/diabetes/managing/diabetes-vision-loss.html
8. Chauhan MZ, Rather PA, Samarah SM, Elhusseiny AM, Sallam AB. Current and novel therapeutic approaches for treatment of diabetic macular edema. Cells. 2022;11(12):1950. doi:10.3390/cells11121950
9. Kuo KH, Anjum S, Nguyen B, Marx JL, Roh S, Ramsey DJ. Utilization of remote diabetic retinal screening in a suburban healthcare system. Clin Ophthalmol. 2021;15:3865-3875. doi:10.2147/OPTH.S330913
10. Flaxel CJ, Adelman RA, Bailey ST, et al. Age-related macular degeneration preferred practice pattern. Ophthalmology. 2020b;127(1):P1-P65. doi:10.1016/j.ophtha.2019.09.024
11. Sun JK, Jampol LM. The Diabetic Retinopathy Clinical Research Network (DRCR.net) and its contributions to the treatment of diabetic retinopathy. Ophthalmic Res. 2019;62(4):225-230. doi:10.1159/000502779
12. Shaw J. VA variability: Snellen versus ETDRS outcomes. American Academy of Ophthalmology. Published August 31, 2021. Accessed March 26, 2023. www.aao.org/eyenet/article/va-variability-snellen-versus-etdrs-outcomes
13. Baker CW, Glassman AR, Beaulieu WT, et al; 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. doi:10.1001/jama.2019.5790
14. Glassman AR, Baker CW, Beaulieu WT, et al. Assessment of the DRCR Retina Network approach to management with initial observation for eyes with center-involved diabetic macular edema and good visual acuity: a secondary analysis of a randomized clinical trial. JAMA Ophthalmol. 2020;138(4):341-349. doi:10.1001/jamaophthalmol.2019.6035
15. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell. 2019;176(6):1248-1264. doi:10.1016/j.cell.2019.01.021
16. Brown D, Heier JS, Boyer DS, et al. Current best clinical practices—management of neovascular AMD. J VitreoRetin Dis. 2017;1(5):294-297. doi:10.1177/2474126417725946
17. Dunaief J. Anti-VEGF treatments for wet age-related macular degeneration. BrightFocus Foundation. Published November 8, 2022. Accessed January 18, 2023. www.brightfocus.org/macular/article/anti-vegf-treatments-wet-age-related-macular
18. Dexamethasone intravitreal implant for treating diabetic macular oedema. Technology appraisal guidance (TA824). National Institute for Health and Care Excellence (NICE). Published September 2022. Accessed January 18, 2023. www.nice.org.uk/guidance/TA824/chapter/1-Recommendations
19. Eylea. Prescribing information. Regeneron Pharmaceuticals, Inc; 2022. Accessed January 18, 2023. www.regeneron.com/downloads/eylea_fpi.pdf
20. Avastin. Prescribing information. Genentech, Inc; 2022. Accessed January 18, 2023. www.gene.com/download/pdf/avastin_prescribing.pdf
21. Beovu. Prescribing information. Novartis Pharmaceuticals Corporation; 2022. Accessed January 18, 2023. www.novartis.com/us-en/sites/novartis_us/files/beovu.pdf
22. Vabysmo. Prescribing information. Genentech, Inc; 2022. Accessed January 18, 2023. www.gene.com/download/pdf/vabysmo_prescribing.pdf
23. Lucentis. Prescribing information. Genentech, Inc; 2018. Accessed January 18, 2023. www.gene.com/download/pdf/lucentis_prescribing.pdf
24. FDA Purple Book. U.S Food and Drug Administration. Accessed January 22, 2023. purplebooksearch.fda.gov/
25. Suvismo. Prescribing information. Genentech, Inc; 2022. Accessed January 18, 2023. www.gene.com/download/pdf/susvimo_prescribing.pdf
26. Bevacizumab. Lexi-drugs. Hudson, OH: Lexicomp, 2023. Accessed January 19, 2023. online.lexi.com/
27. Freund KB, Korobelnik JF, Devenyi R, et al. Treat-and-extend regimens with anti-VEGF agents in retinal diseases: a literature review and consensus recommendations. Retina. 2015;35(8):1489-1506. doi:10.1097/IAE.0000000000000627
28. Rosenberg D, Deonarain DM, Gould J, et al. Efficacy, safety, and treatment burden of treat-and-extend versus alternative anti-VEGF regimens for nAMD: a systematic review and meta-analysis. Eye (Lond). 2023;37(1):6-16. doi:10.1038/s41433-022-02020-7
29. Sarohia GS, Nanji K, Khan M, et al. Treat-and-extend versus alternate dosing strategies with anti-vascular endothelial growth factor agents to treat center involving diabetic macular edema: a systematic review and meta-analysis of 2,346 eyes. Surv Ophthalmol. 2022;67(5):1346-1363. doi:10.1016/j.survophthal.2022.04.003
30. Ye L, Jiaqi Z, Jianchao W, Zhaohui F, Liang Y, Xiaohui Z. Comparative efficacy and safety of anti-vascular endothelial growth factor regimens for neovascular age-related macular degeneration: systematic review and Bayesian network meta-analysis. Ther Adv Chronic Dis. 2020;11:2040622320953349. doi:10.1177/2040622320953349
31. Muston D, Korobelnik JF, Reason T, et al. An efficacy comparison of anti-vascular growth factor agents and laser photocoagulation in diabetic macular edema: a network meta-analysis incorporating individual patient-level data. BMC Ophthalmol. 2018;18(1):340. doi:10.1186/s12886-018-1006-9
32. Cai S, Bressler NM. Aflibercept, bevacizumab or ranibizumab for diabetic macular oedema: recent clinically relevant findings from DRCR.net Protocol T. Curr Opin Ophthalmol. 2017;28(6):636-643. doi:10.1097/ICU.0000000000000424
33. Wykoff CC, Ou WC, Brown DM, 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
34. Kertes PJ, Galic IJ, Greve M, et al. Efficacy of a treat-and-extend regimen with ranibizumab in patients with neovascular age-related macular disease: a randomized clinical trial. JAMA Ophthalmol. 2020;138(3):244-250. doi:10.1001/jamaophthalmol.2019.5540
35. Silva R, Berta A, Larsen M, et al. Treat-and-extend versus monthly regimen in neovascular age-related macular degeneration: results with ranibizumab from the TREND study. Ophthalmology. 2018;125(1):57-65. doi:10.1016/j.ophtha.2017.07.014
36. Mitchell P, Holz FG, Hykin P, et al. Efficacy and safety of intravitreal aflibercept using a treat-and-extend regimen for neovascular age-related macular degeneration: the Aries study: a randomized clinical trial. Retina. 2021;41(9):1911-1920. doi:10.1097/IAE.0000000000003128
37. Lanzetta P, Loewenstein A; Vision Academy Steering Committee. Fundamental principles of an anti-VEGF treatment regimen: optimal application of intravitreal anti-vascular endothelial growth factor therapy of macular diseases. Graefes Arch Clin Exp Ophthalmol. 2017;255(7):1259-1273. doi:10.1007/s00417-017-3647-4
38. Sarkar A, Junnuthula V, Dyawanapelly S. Ocular therapeutics and molecular delivery strategies for neovascular age-related macular degeneration (nAMD). Int J Mol Sci. 2021;22(19):10594. doi:10.3390/ijms221910594
39. Holekamp NM, Campochiaro PA, Chang MA, et al. Archway randomized phase 3 trial of the port delivery system with ranibizumab for neovascular age-related macular degeneration. Ophthalmology. 2022;129(3):295-307. doi:10.1016/j.ophtha.2021.09.016
40. Extension study for the port delivery system with ranibizumab (Portal). ClinicalTrials.gov. ClinicalTrials.gov identifier: NCT03683251. Updated May 10, 2022. Accessed January 27, 2023. clinicaltrials.gov/ct2/show/NCT03683251
41. Haug S, Callaway N, DeGraaf S, et al. Interim analysis of the Portal extension trial evaluating the long-term safety and efficacy of the port delivery system with ranibizumab (PDS) in neovascular age-related macular degeneration (nAMD). Abstract presented at: Association for Research in Vision and Ophthalmology 2022 Congress; May 1-4, 2022; Denver, CO. Accessed January 27, 2023. medically.gene.com/content/dam/pdmahub/restricted/ophthalmology/arvo-2022/ARVO-2022-poster-haug-interim-analysis-of-the-portal-extension-trial-evaluating-the-long-term-safety-and-efficacy.pdf
42. Voluntary recall of the Susvimo ocular implant. Genentech, Inc. October 2022. Accessed February 19, 2023. www.gene.com/download/pdf/Susvimo_DHCP_Important_Prescribing_Information_2022-10-18.pdf
43. Heier JS, Khanani AM, 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
44. Wykoff CC, Abreu F, Adamis AP, 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
45. Rush RB, Rush SW. Intravitreal faricimab for aflibercept-resistant neovascular age-related macular degeneration. Clin Ophthalmol. 2022;16:4041-4046. doi:10.2147/OPTH.S395279
46. Leung Eh, Oh DJ, Alderson SE, 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
47. Borkar D, Tabano D, Garmo V, et al. Poster C0171. Early treatment patterns and outcomes in patients with neovascular age-related macular degeneration initiating faricimab: an IRIS Registry analysis (FARETINA-AMD). Presented at the 2023 Association for Research in Vision and Ophthalmology Annual Meeting; April 2023; New Orleans, LA.
48. Tabano D, Borkar DS, Garmo V, et al. Poster B0521. FARETINA-DME- Early Treatment Patterns and Outcomes in Patients with Diabetic Macular Edema Treated with Faricimab: an IRIS Registry Analysis. Presented at the 2023 Association for Research in Vision and Ophthalmology Annual Meeting; April 2023; New Orleans, LA.
49. Retinal diseases. Opthea. Accessed January 27, 2023. opthea.com/focus/#opt302/
50. Phase 2b wet AMD trial. Opthea. Accessed January 28, 2023. opthea.com/wet-amd-clinical-trial/
51. Phase 3 wet AMD trial. Opthea. Accessed January 28, 2023. opthea.com/wet-amd-trialsphase-3/
52. DME clinical trials. Opthea. Accessed January 28, 2023. opthea.com/dme-clinical-trial/
53. ONS-5010/ Lytenava overview. Outlook Therapeutics. Accessed January 28, 2023. outlooktherapeutics.com/lytenava-overview/
54. ONS-5010 clinical progress. Outlook Therapeutics. Accessed January 28, 2023. outlooktherapeutics.com/lytenava-clinical-progress/
55. The use of biosimilars in ophthalmic practice. American Academy of Ophthalmology. Published January 1, 2022. Accessed January 28, 2023. www.aao.org/clinical-statement/use-of-biosimilars-in-ophthalmic-practice