We Need a Multipronged Strategy for nAMD

Neovascular age-related macular degeneration (nAMD) accounts for 90 percent of vision loss attributed to AMD. The most recently published data (2019) estimates that 19.8 million Americans aged 40 and older (12.6%) were living with AMD; of these, 1.49 million had vision-threatening disease (1). Although enormous strides have been made in our ability to treat and manage the disease in the past two decades thanks to the development and approval of drugs primarily inhibiting vascular endothelial growth factor A (VEGF-A), therapeutic strategies still fall short in two major ways for many patients.

Shortcomings with current strategies
 

First, current therapeutic strategies place a large burden on patients, physicians, staff, and the healthcare system as a whole – thanks to repeated clinic visits and treatment injections, as well as regular optical coherence tomography (OCT) imaging to monitor disease activity. A recent mixed-methods, prospective, observational time-and-motion study that sought to characterize this burden found that, on average, a patient’s visit for nAMD was 90 minutes (2). According to the study, patients spend an average of 16 minutes in pre-appointment preparation, 66 minutes traveling, 37 minutes waiting, and 43 minutes in treatment. To provide transportation to appointments, 22 percent of patients’ caregivers took time away from work and 28 percent took time away from personal activities.

Second, many patients do not achieve optimal visual outcomes, often due to a lack of compliance or undertreatment. In one study, about 50 percent of patients missed clinic appointments while more than 20 percent had gaps of over 100 days between clinic appointments (3). Another study found that about one in five patients were lost to follow-up, and this was linked to associated vision loss (4,5). Even patients who do adhere to their injection schedule – and all other lifestyle recommendations – may have some limitation in their final vision. Visual acuity outcomes are largely dependent on patients’ baseline visual acuity; therefore, those with worse vision at the start of treatment may have a greater slope of improvement, but their total visual acuity is worse (6). Earlier detection and initiation of therapy to achieve better initial vision outcomes is urgently needed.

In short, real-world outcomes do not match what has been shown in pivotal clinical trials. In trials, visual acuity can be maintained with regular dosing regimens with ≥ 95 percent of patients losing ≤ 15 letters in best corrected visual acuity from baseline after two years of standard-of-care anti-VEGF-A injections (7). However, often these vision gains were not maintained, and vision preservation in the real-world indicates that patients receive fewer anti-VEGF injections and less frequent monitoring than recommended (8, 9, 10, 11, 12). Medicare Part B data from 2012 to 2016 indicate that patients received approximately 4.2 injections annually, fewer than most anti-VEGF regimens require (13).

Toward better outcomes
 

An important first step toward early detection and treatment must include efforts aimed at enhancing awareness. In the US, Australia, and Canada, 20–30 percent of respondents to a recent survey indicated that they were “very familiar” or “somewhat familiar” with AMD (14, 15, 16). Better education and awareness can lead to older people participating in regular eye exams or screening programs. Moreover, enhanced disease understanding may encourage at-risk populations to modify their lifestyles. Elderly populations also need to be aware of AMD symptoms so they can seek care.

Mobile technology offers a variety of unique opportunities for earlier detection and treatment of patients with AMD along with increasingly sophisticated visual function testing, such as hyperacuity testing, in elderly populations with macular disease (17). The challenge confronting retina specialists is to build on and implement these advances in an effective and widespread manner.

Of course, it also makes sense to look at the role of current therapies in achieving optimal visual outcomes. Largely, standard-of-care monotherapy including ranibizumab, aflibercept, brolucizumab, and off-label bevacizumab are aimed at blocking VEGF-A (18,19). Despite their well-studied benefits, these drugs have limitations. For example, 20 percent of patients lose vision despite treatment, and half never achieve 20/40 visual acuity (20,21). There are more biological processes at work in the disease than just the activity of VEGF-A, and it makes sense to turn our attention to other therapeutic targets.

The proangiogenic family of VEGF ligands – including VEGF-A, -C, and -D, each of which displays differentiated binding and activation profiles for VEGF receptors 1, 2, and 3 – drives neovascular AMD (18,19). Whereas VEGF-A, -C, and -D all simultaneously bind and activate VEGF receptor 2 (VEGFR-2), which is considered the most validated receptor signaling pathway for choroidal angiogenesis and vascular permeability – VEGF-C and -D – are additionally the only known ligands for another part of the angiogenic disease process: VEGF receptor 3 (VEGFR-3) (19).

The circulating ligands VEGF-A, -C and -D stimulate angiogenesis, while VEGF-C and -A induce vascular leakage and permeability. Clinical specimens from neovascular AMD patients have shown that VEGFR-2 and VEGFR-3 are co-localized with increased levels of VEGF-C in retinal tissue, and circulating plasma concentrations of this ligand are elevated. In addition, VEGF-A suppression upregulates the release of VEGF-C and -D. These mediators of angiogenesis may contribute to the suboptimal response of patients treated with anti-VEGF-A monotherapy (22, 23, 24, 25, 26). Coupling VEGF-A inhibition with a VEGF-C and -D blocker may provide a more complete approach to nAMD treatment with synergistic effects.

VEGF-C and -D trap
 

An intravitreally administered VEGF-C and -D “trap” inhibitor biologic (OPT-302, Opthea Limited) is being studied in two concurrent phase III clinical trials. In ShORe, OPT-302 is administered in combination with ranibizumab and in COAST the study drug is being combined with aflibercept (27,28). OPT-302 is given once every four or eight weeks following three-monthly loading doses in combination with anti-VEGF-A therapy. ShORe control subjects receive ranibizumab 0.5 mg plus sham every four weeks and COAST control subjects receive aflibercept 2 mg plus sham for three-monthly loading doses and then every eight weeks thereafter. The primary endpoint for both studies is superiority in change in BCVA gains from baseline at 12 months for OPT-302 combination therapy versus anti-VEGF-A monotherapy.

A completed phase IIb study of OPT-302 (2 mg) plus ranibizumab (0.5 mg) in treatment naive patients with nAMD achieved the primary endpoint of a statistically significant mean change in BCVA from baseline to week 24 of +14.2 letters, representing an additional gain of +3.4 letters (P = .0107) over the ranibizumab plus sham control group (+10.8 letters) (29). The OPT-302 combination therapy also showed improvements in secondary anatomic endpoints. Additional phase IIb results informed the design of the phase III trials, as it was demonstrated that OPT-302 combination therapy had a mean additional BCVA gain at 24 weeks of +5.7 letters over the ranibizumab control group (16.1 vs 10.3 letters, P = .0002) in a pre-specified analysis of minimally classic and occult lesions. The endpoints in the ShORe and COAST trials will be analyzed in a hierarchical fashion, starting with the primary endpoint in these two lesion types (high responders) and then followed by the total population (including predominantly classic lesions).

Other approaches
 

Recently approved faricimab (Vabysmo, Genentech) and high-dose (8 mg) aflibercept (Regeneron) have demonstrated extended treatment intervals, rather than improving upon visual gains seen with established standard of care anti-VEGF-A monotherapy. The former molecule is a bispecific antibody targeting two VEGF-A and Ang-2, with the goal of improving durability (30). Two phase III trials (TENAYA and LUCERNE) compared treatment intervals up to 16 weeks against aflibercept dosed at eight-week intervals. Similar functional and anatomic outcomes were shown, along with a low risk of adverse effects with an increased treatment duration.

In the phase III PULSAR trial patients treated with Regeneron’s 8 mg aflibercept met the primary endpoint of non-inferiority in vision gains for both the 12- and 16-week dosing regimens after initial monthly doses at 48 weeks compared with patients treated with standard-of-care 2 mg aflibercept (Eylea) injection eight-week dosing regimen. A majority of patients in the aflibercept 8 mg group in both trials were able to maintain the 12- and 16-week dosing regimens through 48 weeks and the safety profile was similar to that of Eylea.

Therapies that more completely target the angiogenic process, combined with efforts to improve awareness and the expanded use of technology to enable earlier detection, will allow retinal specialists to more successfully address the unmet visual acuity needs of the growing population of nAMD patients.