Despite the success of anti-VEGF in improving and maintaining vision in patients who suffer vision loss due to neovascular age-related macular degeneration (nAMD), anti-VEGF treatment can be tedious. Due to the increased frequency of clinic visits and the discomfort associated with intraocular injections, it is no surprise that patients will only complete on average 3.7 years of regular scheduled injections before dropping out of anti-VEGF therapy completely.¹ On average, 7.9 injections are needed in order to improve one’s vision by 15 letters, and at least 5.1 injections within the first year of starting treatment are necessary to maintain such vision.² Moreover, studies such as AURA demonstrated that anti-VEGF allows for maintenance of good vision; however, lower treatment frequencies can lead to decreases in best-corrected visual acuity (BCVA) over time.²

Given the success with current anti-VEGF options, the goals for future drug development include creating medications with longer durations of action. This will require fewer overall injections and follow-up visits to ensure better patient compliance. Targeting different physiological processes throughout the neovascular cascade is also of importance, given the ocular and systemic side effects of current anti-VEGF therapy. Recent advancements have the potential to decrease the frequency of injections. These alternatives aim to deliver anti-VEGF with sustained durability and have been subdivided into office-based treatments, including, new types of anti-VEGF therapies, anti-VEGF biconjugates, depot formulations, and adeno-associated virus gene therapies. Other alternatives require surgery and include port delivery systems and gene therapy. Herein, we summarize the newest alternatives to monthly anti-VEGF treatment.

FARICIMAB

Faricimab (Genentech) is the first bispecific antibody, targeting both angiopoietin-2 (Ang2) and VEGF-A.^3,4 This single molecule has dual inhibition of both Ang2 and VEGF targets in nAMD. The Ang2 fab target enhances vessel stabilization and the modified Fc component greatly reduces the risk of systemic exposure and potential inflammation. The bispecific component of this antibody targets many specific receptor sites to prevent progression of the inflammatory cascade. Rather than monthly dosing, as is the standard of care for bevacizumab and ranibizumab, faricimab dosing ranges from 12 weeks to 16 weeks, suggesting that bispecific antibodies many be more effective than traditional anti-VEGF options.

The AVENUE and STAIRWAY trials found faricimab to be noninferior to ranibizumab for treatment of nAMD. AVENUE was a head-to-head trial of 273 patients comparing ranibizumab every 4 weeks to 1.6 mg or 6 mg faricimab given every 4 or 8 weeks in the treatment of nAMD. Over 36 weeks, this study found BCVA,⁵ central macular thickness (CMT) fluctuations, and choroidal neovascular (CNV) lesion sizes to be comparable. The STAIRWAY study spanned 40 weeks and compared 6.0 mg faricimab to 0.5 mg ranibizumab given every 4, 12, or 16 weeks. At week 24, no active disease was found in the faricimab groups.⁶ Moreover, BCVA gains were meaningful and fully maintained up to 52 weeks.⁶ Given the noninferiority of faricimab compared to ranibizumab, phase 3 TENAYA/LUCERENE trials are ongoing.

ABICIPAR

Abicipar pegol (abicipar; Allergan) is a designed ankyrin repeat protein or DARPin that mimics anti-VEGF, blocking all isoforms of VEGF-A (Figure 1).⁷ Abicipar has already completed phase 3 SEQUOIA (NCT02462486) and CEDAR (NCT02462928) trials for nAMD. These 96-week trials each examined visual outcomes of 2 mg abicipar given every 8 or 12 weeks and found that both BCVA and CMT were comparable to ranibizumab 0.5 mg given every 4 weeks.

In total, only 10 injections of abicipar were given compared to 25 injections of ranibizumab in order to maintain the same BCVA and CMT. An extended study of 2 years showed that abicipar given every 8 to 12 weeks was noninferior to ranibizumab. At the end of 96 weeks, both abicipar groups demonstrated a 15% risk of ocular inflammation, which decreased to 8.9% in the MAPLE safety study due to a new manufacturing process.⁸

BROLUCIZUMAB

The smallest anti-VEGF created so far is brolucizumab (Beovu; Novartis), which received FDA approval in October 2019. It is a 26kDa IgG single-chain antibody fragment that delivers 11 times more anti-VEGF per injection than aflibercept. The 2 major studies of brolucizumab for nAMD, HAWK and HARRIER, proved brolucizumab to be noninferior to aflibercept when delivered at either 12-week or 8-week increments over a period of 96 weeks.⁹ HAWK utilized brolucizumab 3-mg and 6-mg dosing every 12 weeks and HARRIER used 6-mg dosing.

Both studies showed less residual intraretinal, subretinal, and sub-RPE fluid when compared to every-8-week dosing of aflibercept at timepoints of 16, 48, and 96 weeks (Figure 2).^10,11 Of these patients, 56% of patients in HAWK and 51% of patients in HARRIER remained on every-12-week scheduling until week 48. In addition, 45% of patients in HAWK and 39% of patients in HARRIER remained on 12-week dosing from weeks 48 to 96. Brolucizumab has potential for extended dosing with comparable efficacy compared to monthly dosing.¹¹ In terms of anatomy, at week 16, patients on brolucizumab had less disease activity than those receiving aflibercept at 16 weeks.¹²

Intraocular inflammation was seen in 4% of brolucizumab patients, and retinal artery occlusion was seen in 1% of patients in both the HAWK and HARRIER studies. In February 2020, the American Society of Retina Specialists notified its membership that since FDA approval of Beovu, 14 cases of vasculitis were discovered following Beovu administration, of which 11 were identified as occlusive retinal vasculitis. Novartis stated that investigation into these reported cases is ongoing, and that clinicians’ reports suggest that these events can occur as early as the first or second injection of Beovu. Patients affected often reported changes in vision, such as significant increase in floaters or blurry vision, within 1 to 2 weeks of treatment.

PORT DELIVERY SYSTEM

The Port Delivery System (Genentech) is a sustained-release device that delivers ranibizumab through an implanted pump (Figure 3).¹³ In the phase 2 LADDER study, 80% of patients did not need another injection for at least 6 months and the median time to refill in highest dose was 15 months. The phase 3 ARCHWAY and PORTAL studies are ongoing.

KSI-301 ANTIBODY BIOPOLYMER CONJUGATE

KSI-301 (Kodiak Sciences) is an antibody biopolymer conjugate (ABC) and contains binding sites similar to ranibizumab, brolucizumab, and aflibercept.¹⁴ Antibody biopolymer conjugates allow for increased bioavailability, and improvements in BCVA are noticed within 1 week of delivery. What makes KSI-301 different than other ABCs is that BCVA last up to 12 weeks with a single dose, and all VEGF-A isoforms are blocked with a single dose. Preliminary data from the phase 1b study of KSI-301 showed an increase in BCVA of 4.3 letters, which was maintained for at least 12 weeks after 3 monthly loading doses (Figure 4).

OPT-302 TRAP MOLECULE

OPT-302 (Opthea), a VEGF-C/D trap molecule, has been devised to be used in conjunction with existing standard-of-care anti-VEGF-A therapies.¹⁶ This pan-VEGF blocker completed a phase 1/2a study, which found OPT-302 to be noninferior as both a monotherapy and in combination with ranibizumab. Its phase 2b study found OPT-302 (0.5 mg and 2.0 mg) in combination with ranibizumab 0.5 mg to show a statistically significant improvement in visual improvement compared to ranibizumab alone in a 24-week trial of 366 nAMD patients (Figure 5).^17,18 Similar visual gains and visual stability were found in patients with polypoidal choroidal vasculopathy.¹⁶

RGX-314 GENE THERAPY

RGX-314 (Regenxbio) is an adeno-associated virus that codes for an anti-VEGF fab protein. Its delivery system is more novel and complex, requiring a small-gauge vitrectomy. It is delivered via a 250-µL bleb surrounding the supratemporal arcades by a subretinal canula. Following its insertion, an air/fluid exchange and subconjunctival steroids are performed. The patient does not require any positioning postoperatively. It contains a gene that encodes for an anti-VEGF fab protein. A phase 1 study (NCT03066258) found that in most cases, no significant safety issues were associated with the drug. In cohort 5, 75% of patients did not need rescue therapy.¹⁹

ADVM-022 GENE THERAPY

ADVM-022 (Adverum Biotechnologies) is another adeno-associated virus-based therapy being developed for nAMD. ADVM-022 is optimized for intravitreal administration and uses the AV2.7m8 capsid, which was engineered from the AAV2 vector and screened for highly efficient retinal transduction following intravitreal administration²⁰ and which carries a strong, ubiquitous expression cassette encoding a codon-optimized complementary DNA of aflibercept. In the phase 1 study (NCT03748784), which included patients previously treated with anti-VEGF, no subjects needed rescue injections during the first 6 months. Treatment was associated with intraocular inflammation; however, all cases were managed using steroid eye drops.²¹

CONCLUSION

Although anti-VEGF medications made significant improvements in the treatment of nAMD, the high frequency of injections makes treatment difficult to sustain. New anti-VEGF treatments, new delivery systems, and gene therapy are exciting potential developments to help combat the treatment burden associated with current therapy. These could help maintain the initial visual acuity gains patients experience over the longer term. RP

REFERENCES

1. Boulanger-Scemama E, Querques G, About F, et al. Retrospective chart review and follow-up telephone survey. J Fr Ophtalmol. 2015;38(7):620-627.
2. Holz FG, Tadayoni R, Beatty S, et al. Determinants of visual acuity outcomes in eyes with neovascular AMD treated with anti-VEGF agents: an instrumental variable analysis of the AURA study. Eye (Lond). 2016;30(8):1063-1071.
3. Regula JT, Lundh von Leithner P, Foxton R, et al. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol Med. 2016;8(11):1265-1288.
4. Sahni J, Patel SS, Dugel PU, et al. 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.
5. Dugel PU, Sahni J, Osborne A, et al. Anti-VEGF/anti–angiopoietin-2 bispecific antibody faricimab (RG7716) in neovascular AMD. Paper presented at: The Retina Society 43rd Annual Scientific Meeting; Sept 12-15, 2018; San Francisco, CA.
6. Khanani AM. Simultaneous inhibition of ang-2 and VEGF with faricimab in neovascular AMD: STAIRWAY phase 2 results. Paper presented at: American Academy of Ophthalmology Retina Subspecialty Day; October 26-27, 2018; Chicago, IL.
7. Barakat MR, Dugel PU. New developments for the treatment of exudative and nonexudative AMD. Retin Phys. 2015;12(8):26-27,30,32-36.
8. Allergan and Molecular Partners announce topline safety results from MAPLE study of abicipar pegol. Press release. https://www.molecularpartners.com/allergan-and-molecular-partners-announce-topline-safety-results-from-maple-study-of-abicipar-pegol/ . Accessed March 10, 2020.
9. Dugel PU, Koh A, Ogura Y, et al. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2020;127(1):72-84.
10. Dugel P. Brolucizumab for neovascular AMD: the 2 year HAWK and HARRIER results. Abstract presented at: AAO 2018; November 11-14, 2018; New Orleans, LA.
11. Jaffe G, Koh AHC, Ogura Y, Weichselberger A, Holz FG, Dugel PU. Phase III studies of brolucizumab versus aflibercept in nAMD: 48-week primary and key secondary outcomes from HAWK/HARRIER. Invest Ophthalmol Vis Sci. 2018; ARVO e-Abstract 1624. Paper presented at: the Association for Research in Vision and Ophthalmology (ARVO) 2018 Annual Meeting; April 30, 2018; Honolulu, HI.
12. Yannuzzi NA, Freund KB. Brolucizumab: evidence to date in the treatment of neovascular age-related macular degeneration. Clin Ophthalmol. 2019;23:1323-1329.
13. 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(8);1141-1154.
14. Form S-1 registration statement. Kodiak Sciences Inc. Accessed March 10, 2020. https://www.sec.gov/Archives/edgar/data/1468748/000119312518269221/d516071ds1.htm
15. Kodiak Sciences. 3Q business highlights. Accessed March 16, 2020. https://ir.kodiak.com/static-files/ebde263d-8390-461e-85f2-dd660375013a
16. Opthea. Wet AMD clinical trial. Accessed March 10, 2020. https://www.opthea.com/wet-amd-clinical-trial/
17. Jackson T. A multicenter, randomized, double-masked, sham-controlled clinical trial of intravitreal OPT-302, a novel anti-VEGF C and D drug for the treatment of neovascular age-related macular degeneration. Paper presented at: EURETINA Congress; September 5, 2019; Paris, France.
18. Opthea meets primary endpoint in phase 2b study of OPT-302 in wet AMD. Press release. August 7, 2019. Available at: https://www.opthea.com/wp-content/uploads/2019/08/Opthea-Limited-Opthea-Results-of-Wet-AMD-Clinical-Trial-10001623-070819_V2.pdf
19. Grishanin R, Vuillemenot B, Sharma P, et al. Preclinical evaluation of ADVM-022, a novel gene therapy approach to treating wet age-related macular degeneration. Presented at: 21st Annual Meeting of the American Society of Gene & Cell Therapy; May 17, 2018; Chicago, IL.
20. Dalkara D, Byrne LC, Klimczak RR, et al. In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous. Sci Transl Med. 2013;5(189):189.
21. Kiss S. 24-week results of phase 1 study of intravitreal gene therapy with ADVM-022 for neovascular AMD (OPTIC trial). Presented at AAO 2019; Oct 11-15, 2019; San Francisco, CA.