New Developments in Retina: 2022 Pharmaceutical Updates

The new year brings emerging drugs to treat age-related macular degeneration (AMD) on the treatment landscape.

Since their advent, intravitreal injections have revolutionized the management of many retinal diseases and have rapidly become the most performed procedure in ophthalmology. Although many trials are showing vascular endothelial growth factor (VEGF) antagonists as beneficial, there are various times the real-world application of these medications falls short of those in prior published randomized clinical trials. Some factors that may contribute to this include poor compliance and undertreatment.^1,2,3,4 As such, interest remains in targeting longer-lasting medications to improve patient compliance and treatment rates.

New treatments targeting existing and new molecular targets involved in the angiogenic process, such as pipeline therapies, biosimilar alternatives, novel intravitreal agents, and sustained drug delivery systems will receive significant attention in the next year.

Biosimilars

Since the patents for ranibizumab and aflibercept will soon lapse in the US, attempts to create biosimilar medications as an alternative treatment to decrease the financial demands of injections are an area of interest.⁵ Unlike generic medications, biosimilar medications attempt to replicate the therapeutic endpoint of existing medications rather than copy their molecular structure.⁶

Interestingly when a biosimilar is approved, if one indication is approved, automatic approval is then granted for all indications of the reference product. SB-11 (Samsung Bioepsis, Incheon, South Korea) is the first ophthalmology biosimilar approved in the United States. In a phase III randomized controlled clinical trial in the treatment of neovascular AMD at 4 and 8 weeks, it met the primary endpoint of non-inferiority to monthly ranibizumab, with similar safety.⁷

Pipeline AMD targets

Advances in bioengineering have led to ankyrin repeat proteins (DARPins), designed to have high specificity and affinity to a selected target. Unlike the antibodies that constitute traditional VEGF antagonists, these agents are smaller than antibodies and may show better tissue penetration with higher binding affinity.⁸ This stability may enable them to be active at lower concentrations, and their effect may be longer lasting. Like ranibizumab, abicipar pegol (Abicipar, Allergan. Dublin, Ireland) is a DARPin directed to bind all VEGF-A isoforms.

Studies have shown that it has a higher affinity and a longer intraocular half-life than ranibizumab (>13 days vs. 7.2 days, respectively).⁸ A phase II multicenter randomized controlled trial forpatients with neovascular AMD (REACH study) showed that best-corrected visual acuity (BCVA) and central retinal thickness (CRT) improvements were similar in both abicipar groups to those with ranibizumab and were maintained for 3 months following the third injection.⁹ At this time, the US Food and Drug Administration is evaluating safety questions in its recent Complete Response Letter.¹⁰

Pipeline combination VEGF and Tie-2 receptor therapies

Multiple drugs targeting the Tie-2 pathway are also being developed. Tie-2 tyrosine kinase receptor is expressed on vascular endothelial cells, allowing for decreased vascular permeability, inflammation, and angiogenesis. Angiopoietin-1 (Ang-1) binds to the Tie-2 receptor to decrease vascular leakage, while angiopoietin-2 (Ang-2) is a competitive antagonist to Ang-1, regulating angiogenic sprouting and vascular regression.

Faricimab (Roche/Genentech, San Francisco, CA) is a bispecific antibody that targets both VEGF-A isoforms, and Ang-2.^11,12 In phase III, randomized, triple-masked trial with 640 patients diagnosed with neovascular AMD (LUCERENE trial), faricimab was shown to be non-inferior and well-tolerated to aflibercept dosed every eight weeks.^13,14

AXT-107 (AsclepiX Therapeutics, Jersey City, New Jersey) is another agent that inhibits both VEGF and growth factor signaling via receptor tyrosine kinase interactions. Currently, it remains in clinical testing and has been shown in preclinical cohorts to decrease blood vessel leakage in neovascular AMD.¹⁵

Sustained treatments

Another novel opportunity for treatment includes sustained drug delivery systems. Ranibizumab port delivery system (PDS) (Genentech, San Francisco, CA) is a permanent, surgically implanted intraocular device that allows for clinic-based refills instead of another surgical procedure.¹⁶ LADDER, a phase II trial, showed comparable visual outcomes in patients treated with the 100 mg/ml treatment arm and the monthly injection arm.¹⁷ Being a more invasive procedure, 16 of 179 implant eyes experienced ocular adverse events, the most common of which were vitreous hemorrhage, occurring in 7 (3.9%) of eyes.¹⁷

Additionally, 98% of patients were able to last 6 months without refills on medication.^16,18 PDS was recently granted FDA approval under the trade name Susvimo.

Emerging therapies for neovascular AMD

Class	Brand name, manufacturer	Target/mechanism	Status
Biosimilars	SB-11 (Samsung Bioepsis, Incheon, South Korea)	Ranibizumab biosimilar	Phase III trial completed
Anti-VEGF	Abicipar pegol (Abicipar; Allergan, Coolock, Dublin)	VEGF-A	Phase III trial completed
Tie-2 receptor	Faricimab (Roche/Genentech, San Francisco, CA)	VEGF-A and Ang-2	Phase II trial completed
	AXT-107 (AsclepiX Therapeutics, Jersey City, New Jersey), inhibits both	VEGFR2	Pre-clinical investigation
Sustained treatments	Ranibizumab PDS (Genentech, San Francisco, CA)	VEGF-A	Phase III completed, FDA approval granted (Susvimo)

Treatments for dry nonexudative AMD

For years, the only proven supplement in nonexudative AMD was the Age-Related Eye Disease Study (AREDS) formulation showing a 25% reduced risk of severe vision loss in subjects with intermediate-sized drusen, at least 1 large druse, noncentral geographic atrophy (GA), or advanced atrophy at 5 years.¹⁹ Currently, there are numerous emerging drugs for thetreatment of nonexudative AMD, some of which focus on the C5 and C3 complement pathways, well regarded as major contributing factors in the development of nonexudative AMD.

Zimura, manufactured by IVERIC bio (Princeton, NJ), is an anti-C5 aptamer.²⁰ The cleavage of C5 leads to a downstream complement cascade that results in the formation of the membrane attack complex (MAC) and the destruction of the cellular membrane.²⁰ The inhibition of the C5 pathway prevents this process and thereby decreases inflammatory cell cascade, potentially affecting the progression of nonexudative AMD.

A phase 2/3, randomized, double-masked, sham-controlled study (GATHER1) studied the change in GA lesion size and VA at month 12 in patients with nonexudative AMD.²¹ At 12 months, compared to the sham arms, Zimura showed a reduction of 27.81% in GA lesion size. There was an increase of 0.38 ETDRS letters in the Zimura 2 mg arm and a decrease of 1.44 ETDRS letters in the 4 mg arm, when compared to the sham arms. Enrollment of patients started for a second confirmatory GATHER2 trial in the second half of 2020.20,21

APL-2, manufactured by Apellis (Waltham, MA), is a C3 inhibitor. Inhibition of C3 stops the activation of multiple complement pathways, including C3a/b and C5a/b, which are vital in the progression of nonexudative AMD.²² A phase 2, randomized, multicentered trial (FILLY) showed the effectiveness of intravitreal APL-2 in nonexudative AMD patients with a significant reduction of 20% in square root GA lesion size from baseline when compared to the pooled sham at 12 months.^23-25 Two future trials include the DERBY (NCT03525613) and OAKS (NCT03525600) also evaluating the effectiveness of intravitreal APL-2 on nonexudative AMD patients (n = 600) with GA.²⁶

Conclusions

AMD has a complex pathogenesis and various emerging treatment options. Traditionally, modalities aimed at the VEGF pathway have stabilized the disease process in neovascular AMD. However, the regimented schedule of injections creates a financial and treatment burden which may lower long-term compliance. Current therapeutic avenues are investigating additional cytokine and complement pathways with the ultimate goal of reducing the frequency of visits and easing the social burdens surrounding the disease.

References

Arevalo JF, Lasave AF, Wu L, et al. Intravitreal bevacizumab for choroidal neovascularization in age related macular degeneration: 5 year results of the pan American collaborative retina study group. Retina. 2016;36:859–67.
Cohen SY, Mimoun G, Oubraham H, et al. Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE study. Retina. 2013;33:474–81.
Mones J, Singh RP, Bandello F, Souied E, Liu X, Gale R. Undertreatment of neovascular age-related macular degeneration after 10 years of anti-vascular endothelial growth factor therapy in the real world: the need for a change of mindset. Ophthalmologica. 2020;243:1–8.
Holz FG, Tadayoni R, Beatty S, et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration. Br J Ophthalmol. 2015;99:220–6.
Sharma A, Kumar N, Bandello F, Loewenstein A, Kuppermann BD. Need of education on biosimilars amongst ophthalmologists: combating the nocebo effect. Eye. 2019;34(6):1006–7.
Sharma A, Kumar N, Kuppermann BD, Bandello F, Loewenstein A. Understanding biosimilars and its regulatory aspects across the globe: an ophthalmology perspective. Br J Ophthalmol. 2020;104:2–7.
A study to compare SB11 (proposed ranibizumab biosimilar) to lucentis in subjects with neovascular age-related macular degeneration (AMD). ClinicalTrials.gov Identifier: NCT03150589. https://clinicaltrials.gov/ct2/show/NCT03150589. Accessed 1 Jan 2020.
Rodrigues GA, Mason M, Christie LA, Hansen C, Hernandez LM, Burke J, et al. Functional characterization of abicipar-pegol, an Anti-VEGF DARPin therapeutic that potently inhibits angiogenesis and vascular permeability. Invest Ophthalmol Vis Sci. 2018;59:5836–46.
Callanan D, Kunimoto D, Maturi RK, Patel SS, Staurenghi G, Wolf S, et al. Double-masked, randomized, phase 2 evaluation of abicipar pegol (an anti-VEGF DARPin Therapeutic) in neovascularage-related macular degeneration. J Ocul Pharmacol Ther. 2018.
Abicipar pegol not approved for treatment of wet AMD. 2020. https://www.healio.com/news/ophthalmology/20200626/abicipar-pegol-not-approved-for-treatment-of-wet-amd. Accessed 20 July 2020.
Al-Khersan H, Hussain RM, Ciulla TA, Dugel PU. Innovative therapies for neovascular age-related macular degeneration. Expert Opin Pharmacother. 2019;20:1879–91.
Hussain RM, Ciulla TA. Emerging vascular endothelial growth factor antagonists to treat neovascular age-related macular degeneration. Expert Opin Emerg Drugs. 2017;22:235–46.
A study to evaluate the efficacy and safety of faricimab in participants with neovascular age-related macular degeneration (TENAYA). https://clinicaltrials.gov/ct2/show/NCT03823287. Accessed 20 June 2020.
A study to evaluate the efficacy and safety of faricimab in participants with neovascular age-related macular degeneration (LUCERNE). https://clinicaltrials.gov/ct2/show/NCT03823300. Accessed 20 June 2002.
AsclepiX Therapeutics. Our pipeline. 2020. https://asclepix.com/pipeline/.
Campochiaro PA, Marcus DM, Awh CC, et al. The port delivery system with ranibizumab for neovascular age-related macular degeneration: results from the randomized phase 2 ladder clinical trial. Ophthalmology. 2019;126:1141–54.
Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118:2041–9.
ASRS 2020: PDS with ranibizumab signals paradigm shift in treatment of neovascular AMD. 2020. https://www.modernretina.com/view/asrs-2020-pds-with-ranibizumab-signals-paradigm-shift-in-treatment-of-neovascular-amd.
Kassoff A, Kassoff J, Buehler J, et al. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001; 119:1417–1436.
IVERIC Bio's Zimura®, a novel complement C5 inhibitor, met its primary endpoint and reached statistical significance in a phase 2b randomized, controlled clinical trial in geographic atrophy secondary to dry age-related macular degeneration.; 2019. https://ivericbio.com/wp-content/uploads/2019/10/Zimura_dry_AMD_Results_102819.pdf.
Zimura in subjects with geographic atrophy secondary to dry agerelated macular degeneration. Clinicaltrials.gov. 2020. https://clinicaltrials.gov/ct2/show/NCT02686658.
Slakter J. Atrophy, presentation: complement C3 inhibition in geographic atrophy. In: EURETINA, Novemeber 22, 2018, Vienna, Austria. https://apellis.com/presentations/2018-complementC3inhibitioningeographicatrophy.pdf.
Glenn J Jaffe, Keith Westby, Karl G Csaky, et al. C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial. Ophthalmology. 2020;S0161-6420:30845–9
Study to compare the efficacy and safety of intravitreal APL-2 therapy with sham injections in patients with geographic atrophy (GA) secondary to age-related macular degeneration - full text view - ClinicalTrials.gov. Clinicaltrials.gov. 2020. https://clinicaltrials.gov/ct2/show/NCT03525600.
Apellis completes enrollment in two phase 3 studies of the targeted C3 therapy, pegcetacoplan, in patients with geographic atrophy (GA). https://investors.apellis.com/news-releases/news-release-details/apellis-completes-enrollment-two-phase-3-studies-targeted-c3.
Study of APL-2 therapy in patients geographic atrophy - full text view - ClinicalTrials.gov. Clinicaltrials.gov. 2020. https://clinicaltrials.gov/ct2/show/NCT02503332.