Several studies have undertaken comparison of anti-VEGF drugs in terms of efficacy in treatment of neovascular age-related macular degeneration (nAMD). The Comparison of AMD Treatments Trials (CATT) trial compared monthly ranibizumab (Lucentis; Genentech) with monthly bevacizumab (Avastin; Genentech) injections, as well as with pro re nata (PRN) regimens.¹ Monthly treatment with bevacizumab and ranibizumab resulted in similar best corrected visual acuity (BCVA) gains (8.0 and 8.5 letters, respectively), whereas PRN ranibizumab was noninferior to monthly treatment, and PRN bevacizumab did not achieve noninferiority to monthly injections. The Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) study similarly found no significant differences in visual function between ranibizumab and bevacizumab or between treatment regimens.²

The VIEW 1 and 2 studies showed noninferiority of aflibercept (Eylea; Regeneron) compared to monthly ranibizumab injections. Notably, all 33 aflibercept regimens studied in the VIEW trials behaved similarly to monthly ranibizumab in terms of anatomic measures and reduction of fluid in the different retinal compartments. During year 2, patients received a “capped” PRN regimen with mandatory dosing at least every 12 weeks, and the proportions of eyes with fluid in all treatment arms exhibited a synchronized increase in intraretinal cystoid fluid, subretinal fluid (SRF), and pigment epithelial detachment for the first 8 weeks and a subsequent reduction in fluid corresponding to the first mandatory treatment. Real-world data from the Fight Retinal Blindness registry reveal similar results: Neither visual acuity nor treatment frequency differed between ranibizumab and aflibercept used for neovascular AMD.³ The RIVAL study reported no significant differences in visual and anatomical outcomes, nor in the rate of development or growth of macular atrophy using a treat-and-extend regimen with ranibizumab and aflibercept.⁴

SAFETY

A recent meta-analysis did not identify large differences in risk of systemic serious adverse events between intravitreal bevacizumab and ranibizumab use for any serious adverse event in general, and arteriothrombotic events specifically.⁵ While there are no significant differences in safety between the agents themselves, the syringe preparation techniques seem to play an important role in determining risk of postinjection endophthalmitis. The use of prefilling by professional pharmacies or the manufacturers significantly reduces this risk.

Bevacizumab, aflibercept, and ranibizumab have positively impacted the management of retinal disease. However, a high burden of injection remains. Most patients do not receive the number of treatments and retreatments necessary to achieve the anatomic and functional result shown in randomized clinical trials.^1,6-8 This has led to frequent undertreatment.⁹ New intravitreal agents have recently been approved for the treatment of nAMD, with the aim to be injected less frequently and which theoretically effect better and longer drying of retinal fluid.

BROLUCIZUMAB

Brolucizumab (Beovu; Novartis) is a humanized single-chain antibody fragment approved in October 2019 by the US Food and Drug Administration (FDA) for the treatment of nAMD.¹⁰ It is considered the smallest subunit of an antibody for treatment in medicine tested for human use, with a molecular weight of ~26 kD. Brolucizumab inhibits VEGF-A binding to VEGF receptors VEGFR1 and VEGFR2.¹¹ Its small molecular size and the absence of the crystallizable fragment provide amplified bioavailability and reduction of immunogenicity, with better tissue penetration, more sustained effect, and less systemic exposure. There is also a potential for fewer adverse effects when using smaller antibodies than full-size antibodies.¹² The molecule can be concentrated in a smaller amount of net liquid volume, allowing for 6 mg of brolucizumab in as little as 50 μL for intravitreal injection; put another way, 11 times more brolucizumab than aflibercept can be concentrated in the same amount of liquid.¹³

Preclinical data have shown higher penetration of the drug into the retina and the retinal pigment epithelium (RPE) compared to ranibizumab, which suggests that brolucizumab provides better control over all retinal layers and decreases fluid in all retinal compartments.¹² The phase 2 OSPREY study showed that brolucizumab was as efficacious as aflibercept at 8-week and 12-week intervals, supporting phase 3 clinical trials.¹⁴

Pivotal Trials

The HAWK and HARRIER clinical trials were 2 similarly designed phase 3 trials comparing brolucizumab with aflibercept in the treatment of nAMD. Both were double-masked, multicenter, active-controlled, randomized trials. After 3 initial monthly injections, the frame interval was modified to every 8 weeks in HAWK and every 12 weeks in HARRIER. HAWK utilized brolucizumab at 3 mg and 6 mg dosing, and HARRIER only at 6 mg dosing. Patients in the aflibercept group received a fixed 2-mg dose at 8-week intervals. Both studies showed good results in the brolucizumab groups, with reduction in intraretinal fluid and SRF compared to aflibercept at 16 weeks, 48 weeks, and 96 weeks.

Regarding BCVA, brolucizumab showed noninferiority vs. aflibercept. More than 50% of the patients in both trials were able to maintain a 12-week treatment interval with brolucizumab.^15,16

Safety Profile

The intraocular inflammation (IOI) rate was 5.3% and 2.7% with brolucizumab in HAWK and HARRIER, respectively, and the rate was <1% in the aflibercept group. A total of 6/730 patients (0.82%) presented retinal arterial occlusions in the brolucizumab 6 mg group. Post marketing, 11 more cases of occlusive retinal vasculitis were reported.¹⁶ By March 2020, 27 cases were reported by the American Society of Retina Specialists (ASRS) Research and Safety in Therapeutics (ReST) committee in conjunction with brolucizumab-induced inflammation reports by The American Academy of Ophthalmology (AAO).^17,18 Recent publications have raised concerns about these serious adverse events and revealed more detailed information.²² Careful evaluation for inflammation and continued vigilance in monitoring brolucizumab treatment outcomes are advised.¹⁹

FARICIMAB

Faricimab (Vabysmo; Genentech), approved in January 2022 by the FDA for nAMD, is a bispecific antibody and the first of its kind designed for intraocular use. It is a single molecule with a dual mechanism of action blocking angiopoietin-2 (Ang-2) and VEGF-A simultaneously.²⁰ Ang-2 blocking promotes pericyte stabilization, decreased leakage, and inflammation.

Pivotal Trials

The AVENUE trial was a 36-week, multiple dose–regimen (1.5 mg and 6 mg faricimab), double-masked, phase 2 randomized clinical study comparing faricimab to ranibizumab. Although the primary endpoint of superiority of faricimab over ranibizumab in BCVA was not met, overall visual and anatomic gains supported pursuing phase 3 trials.

The STAIRWAY trial was a 52-week, multicenter, randomized, phase 2 study, aiming to assess the durability of faricimab vs ranibizumab for the treatment of nAMD. Seventy-six nAMD patients were enrolled and randomized 2:2:1, to faricimab 6 mg every 12 weeks, 6 mg every 16 weeks (both after 4 monthly initial injections), and ranibizumab 0.5 mg monthly. Both faricimab arms were noninferior to monthly ranibizumab injections in terms of functional and anatomic results.²¹

TENAYA and LUCERNE were phase 3 trials comparing 6-mg faricimab every 16 weeks to aflibercept 2 mg every 8 weeks.^22,23 Best-corrected visual acuity change from baseline with faricimab was noninferior to aflibercept in both trials.²⁴

Faricimab demonstrated extended durability, with about 80% of faricimab-treated patients on extended fixed-dosing intervals of every 12 weeks or more, and nearly 45% of patients on fixed-dosing intervals of every 16 weeks. Visual benefits with faricimab given at up to 16-week intervals demonstrate its potential to extend intervals between treatments with sustained efficacy, thereby reducing treatment burden.

Safety Profile

The STAIRWAY and AVENUE trials showed similar results: Faricimab was well tolerated, and there were no new or unexpected safety events. Rates of ocular adverse events were comparable between faricimab and aflibercept in the TENAYA and LUCERNE studies.

SUSVIMO

Susvimo (Port Delivery System ranibizumab injection; Genentech) 100 mg/mL is a permanent, refillable implant that is surgically inserted through a small incision in the sclera, accessing the vitreous cavity at the level of the pars plana. This system gives the potential to reduce the treatment burden while achieving optimal management, allowing a continuous release of a customized formulation of ranibizumab into the vitreous cavity. There is a self-sealing septum at the outer surface of the implant that allows access to a cavity reservoir, where a replenishment with the drug can be performed without the need to remove it. Once stored in the implant’s reservoir, the drug moves by passive diffusion through a porous metallic element designed for ranibizumab’s molecular structure, hence reaching the vitreous cavity. In this way, an active release of the drug is achieved over a longer time frame.

Susvimo was approved by the FDA in October 2021 for patients with nAMD. The approval is based on positive results from the phase 3 Archway study primary analysis, which showed nAMD patients treated with Susvimo achieved and maintained vision gains equivalent to monthly ranibizumab injections +0.2 and +0.5 letters from baseline, respectively, at weeks 36 and 40 of treatment. Moreover, only 1.6% of Susvimo patients received supplemental ranibizumab treatment before their first refill, and more than 98% could go 6 months before their first refill.²⁵

Susvimo was generally well tolerated, with a favorable benefit–risk profile, but it has been associated with a three-fold higher rate of endophthalmitis than monthly intravitreal injections of ranibizumab. In the Archway study, 1.6% of patients receiving a ranibizumab implant experienced at least 1 episode of endophthalmitis.²⁵ The Portal and Velodrome extension studies are evaluating the long-term safety and efficacy of Susvimo in nAMD.

A NEW ERA OF TREATMENT

Many nAMD patients are undertreated in real-life settings and achieve suboptimal outcomes with anti-VEGF treatment. This is mainly due to the burden of injections. This new era of therapies is characterized by more durable intravitreal effect, lasting many more weeks or even months with faricimab, brolucizumab, and the Port Delivery System than the established treatments. These novel drugs will prevent blindness from the most common cause in elderly patients, ie, nAMD. A large proportion of patients who are in need of monthly anti-VEGF injections might benefit from these new agents with fewer procedures per year and superior effect.

CONCLUSION

The long-lasting drugs discussed here open the door to better nAMD treatments. These new molecules and new device will diversify and therefore improve the current algorithm of treatment in nAMD. In consequence, these treatments might lead to less frequent check-ups and fewer side effects, but more importantly better vision and quality of life due to better treatment compliance. RP

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