Next Frontiers in the Management of Neovascular
Age-related Macular Degeneration

Report from the American Academy of Ophthalmology (AAO) Annual Meeting

Las Vegas, Nevada  |  November 14-17, 2015

By Jason Noble, MD, FRCSC

 

Over the past decade, anti-vascular endothelial growth factor (VEGF) therapy has revolutionized the management of many retinal conditions, and has emerged as the gold standard for the treatment of neovascular age-related macular degeneration (AMD). Although these agents have permitted unparalleled vision gains for patients previously destined for severe vision loss, there remains a need to optimize therapeutic approaches in order to further improve visual outcomes, reduce the inconvenience of the need for frequent injections, and improve safety. This issue of Ophthalmology Scientific Update reviews some of the most promising emerging therapies discussed at the 2015 Annual Meeting of the American Academy of Ophthalmology and the potential impact that they might have on Canadian daily ophthalmology practice.

 

Vascular Endothelial Growth Factor (VEGF) Inhibition: Where Do We Stand?

In recent years, significant strides have been made in understanding the pathophysiological processes that lead to the development and progression of age-related macular degeneration (AMD). Although the pathogenesis remains incompletely understood, it has been shown that inflammatory, immune, hypoxic, and oxidative processes alter the natural balance between angiogenic and antiangiogenic factors, resulting in the upregulation of VEGF and other molecules, triggering the development of choroidal neovascularization (CNV).[1,2]

 

To date, targeted inhibition of native VEGF with intravitreal delivery of pharmaceutical agents remains the cornerstone therapy for neovascular AMD. Well-designed, randomized, controlled clinical trials have repeatedly demonstrated the efficacy of fixed-interval (ie, monthly) dosing regimens of anti-VEGFs in the treatment of AMD.[3-5] However, in an effort to reduce the significant inconveniences and costs that monthly injections impose on patients and the healthcare system as a whole, less rigid treatment schedules – including as-needed (PRN) or treat-and-extend (TREX) strategies – have become increasingly used. Despite favourable outcomes in studies such as TREX-AMD (+10.5 letters at 1 year with TREX ranibizumab versus +9.2 letters on monthly dosing),[6] Dr. Michael Larsen (Copenhagen, Denmark) suggested that extended treatment schedules may leave some patients undertreated with suboptimal longer-term outcomes. In his presentation entitled “Long term Anti-VEGF Monotherapy: Do Patients Improve?” Dr. Larsen indicated that with a less frequent injection schedule, many patients on anti-VEGF monotherapy experience improvement only in the first year and best-corrected visual acuity (BCVA) frequently returns to baseline after 2–4 years and continues to decline afterwards.[7] This has been suggested by other studies that have demonstrated that in real-life clinical practices suboptimal visual outcomes are observed, purportedly due to undertreatment.[8] Formal evaluation of the long-term efficacy of TREX strategies is ongoing.

 

Although intravitreal anti-VEGF injections are generally considered very safe modalities of treatment, potential deleterious consequences of long-term VEGF blockade have been debated, such as whether
anti-VEGF therapy is associated with the development of macular atrophy.[9,10] It is presently understood that multiple factors may contribute to the development of atrophy in treated neovascular AMD,[10] and that such eyes generally have worse vision outcomes despite anti-VEGF treatment. Dr. Brandon Busbee (Nashville, Tennessee) presented a subanalysis of the HARBOR trial indicating that eyes with baseline or concurrent subretinal fluid have lower rates of atrophy (hazard ratio 0.50; 95% confidence interval 0.33–0.74).[11] After 24 months of ranibizumab treatment, atrophy was present in fewer eyes with subretinal fluid at baseline (23.6% versus 52.6%) or subretinal fluid at Month 24 (8.1% versus 32.9%). Although this may suggest that aggressive deturgescence of subretinal fluid in eyes with neovascular AMD can result in macular atrophy, the results must be interpreted with caution as they represent subgroup ­analysis, and previously published reports have indicated that eyes with macular fluid tend to have worse vision outcomes.[8,12] Further study is required to more clearly elucidate the relationship of VEGF blockade with macular atrophy.

 

Notwithstanding that anti-VEGF therapy remains the gold standard for wet AMD, novel approaches that have the potential to reduce the injection burden and improve long-term visual outcomes are being explored. These include other anti-VEGF options with longer therapeutic effects and potentially reduced treatment frequency, novel therapeutic targets that can be used alone or in combination with anti-VEGFs, and different modes of drug administration and intravitreal delivery.

 

Other Anti-VEGF Options

Conbercept

Studies of the efficacy and safety of conbercept (KH902), the most recent addition to the anti-VEGF family, were presented. Similar to aflibercept, conbercept is a recombinant fusion protein composed of the second immunoglobulin (Ig) domain of VEGF receptor 1 (VEGFR1) and the third and fourth Ig domains of VEGFR2 to the constant region (Fc) of human IgG1. This agent was developed and is approved in China – it has not received approval for use in Canada or the United States – based on the PHOENIX trial, which was presented by Dr. Xun Xu (Shanghai, China).[13] PHOENIX was a 52-week, randomized, double masked, sham-injection ­controlled trial. Patients were randomized to either a normal or delayed conbercept group. The normal-treatment group received conbercept 0.5 mg per eye monthly for the 3-month core study phase, followed by 2 months of sham injection, a dose of conbercept at Month 5 and every 3 months (ie, Months 8 and 11). The delayed treatment group received sham injections for 3 months, then 0.5 mg per eye monthly for 3 months, and finally 0.5 mg per eye every 3 months (ie, Months 8 and 11). Conbercept significantly improved VA compared to sham: at 3 months, the gains in BCVA were 9.2 letters for the normal treatment group and 2.0 letters for delayed treatment (P<0.001; Figure 1). It was also determined that injections every 3 months were sufficient to maintain the vision acquired during the loading phase.

The efficacy of conbercept in the treatment of patients with polypoidal choroidal vasculopathy (PCV), a subtype of wet AMD[14] that is more common in African-Americans and Asians, was also presented.[15] In the AURORA trial, which tested the 0.5-mg and 2.0-mg doses of conbercept in 122 patients with CNV secondary to AMD, 53 patients were diagnosed with PCV. After 12 months of treatment, complete regression of polyps was observed in 56.5% of patients treated with 0.5 mg and 52.9% of those treated with 2.0 mg. Partial regression was observed in 26.1% and 35.3% of patients treated with 0.5 mg and 2.0  mg, respectively. Duration of benefit was also observed to be longer with conbercept than with currently available anti-VEGFs.

 

Brolucizumab (RTH258) is a humanized single-chain antibody fragment that inhibits all isoforms of VEGF-A. Its significantly smaller molecule (26 kDa) than other current treatment options (50 kDa for ranibizumab, 97 kDa for aflibercept, and 149 kDa for bevacizumab) points to improved tissue penetration and lower systemic exposure. Brolucizumab was shown to be noninferior to aflibercept (2 mg) in a Phase II clinical trial that involved 90 patients with wet AMD.[16,17] Brolucizumab was also associated with a longer duration of action, administered every 3 versus every 2 months for aflibercept. Based on these promising results, combination therapy with brolucizumab and Fovista® are undergoing Phase III clinical trials (Phase III Safety and Efficacy Study of Fovista [E10030] Intravitreous Administration in Combination With Either Avastin or Eylea Compared to Avastin or Eylea Monotherapy [NCT01940887]; Efficacy and Safety of RTH258 Versus Aflibercept [NCT02307682]).

 

Ziv-aflibercept

Off-label compounding of anti-VEGF formulations that have been developed for the treatment of patients with various forms of cancer (ie, bevacizumab) is a commonly accepted practice. This practice is perceived by many physicians as a cost-effective way to treat patients who otherwise would not be able to afford more expensive anti-VEGF therapies. Similar to bevacizumab, aflibercept is also developed and approved for intravenous oncology use and, as such, has the potential to be compounded into smaller aliquots for intravitreal administration (ziv-aflibercept). A presentation by Prof. Dr. Michel Eid Farah (São Paulo, Brazil) suggested that ziv-aflibercept is as effective as intravitreal aflibercept in the treatment of wet AMD.[18] According to Dr. Farah, a 4-mL ziv-aflibercept bottle can provide 30 doses of 0.05 mL at a much lower cost than a single dose of intravitreal aflibercept at the standard dose. Although this might be an appealing option for patients who cannot afford intravitreal aflibercept, compounding procedure issues, such as safe repackaging under aseptic conditions and storage, need to be taken into consideration, as well as off-label use and preparation.

 

New Therapeutic Targets

Designed ankyrin repeat proteins (DARPins)

DARPins are small, single-domain proteins that can selectively bind to a target protein with high affinity and specificity. Their role in the treatment of wet AMD was discussed during the instructional course entitled “Where Are We Now? The Current State of Intravitreal Drug Delivery.”[19] Abicipar pegol, a recombinant protein previously known as MP0112, was recently compared to ranibizumab in a Phase II trial. A total of 64 patients were randomized to abicipar pegol at doses of 1 mg (n=25) or 2 mg (n=23) or to ranibizumab 0.5 mg (n=16) and were followed for 20 weeks. All patients received treatment at the beginning of the trial and at weeks 4 and 8. Patients in the ranibizumab arm of the study received additional doses at weeks 12 and 16. Although the study was not powered to show statistically significant differences between treatment groups, the data suggest that abicipar pegol 2 mg is at least as effective as monthly ranibizumab, with a longer duration of action.

 

Platelet-derived growth factor (PDGF) antagonists

PDGF is a cytokine involved in the stimulation and maintenance of pericytes, which are cells required for formation and ­stabilization of new blood vessels.[20] By blocking pericyte recruitment, survival, and maturation, PDGF antagonists inhibit the development and maturation of newly formed vessels and render endothelial cells more susceptible to anti-VEGF drugs. Additionally, there is clinical evidence that PDGF is a mediator of fibrosis and subretinal fibrosis is a common late-stage indicator of vision loss in wet AMD. Recent trials have shown superiority of combining anti-VEGF and anti-PDGF therapies versus anti-VEGF monotherapy.[21,22] This might be explained by the fact that chronic anti-VEGF treatment causes PDGF upregulation, leading to pericyte recruitment and neovascular membrane stabilization. This vessel-protective mechanism may be suppressed with the addition of a PDGF antagonist to anti-VEGF treatment.

 

An interesting study presented by Dr. Pravin Dugel (Phoenix, Arizona) demonstrated that pretreatment (as opposed to combination treatment) with Fovista improves visual outcomes in patients with wet AMD who were resistant to anti-VEGF treatment (persistent or recurrent fluid and/or no improvement in vision).[23] In this study, 27 patients were randomized to either combination therapy (Fovista + bevacizumab or aflibercept) or pretreatment with Fovista + combination therapy. Baseline characteristics of participants are presented in Table 1. After 18 months of treatment, pretreated patients gained an average of 20.3 letters compared to 1.6 letters gained by patients receiving combination therapy (Figure 2). Further subanalysis demonstrated that patients who were dry on optical coherence tomo­graphy (OCT) and without leakage on angiography but with some flow on OCT angiography had the best outcomes. This leads to the “Goldilocks principle” of flow, in which some blood vessel functioning may be necessary for the survival of photoreceptor cells during the wound healing process. This observation, according to Dr. Dugel, may challenge the current treatment approach to completely dry the retina of patients with AMD.

Dr. David Boyer (Los Angeles, California) presented a Phase I open-label dose escalation study of REGN2176-3 in patients with neovascular AMD.24 REGN2176-3 is an anti-PDGF-Rb monoclonal antibody coformulated with aflibercept (2 mg) and administered as a single 50-µL intravitreal injection. The study tested 4 dose-escalating cohorts (0.2 mg: 2 mg, 0.5 mg: 2 mg, 1 mg: 2 mg, and 3 mg: 2 mg; 3 patients per cohort). No relationship was found between the dose and incidence of adverse events, there were no reports of intraocular inflammation, and no adverse event was considered as a dose-limiting toxicity. Figure 3 shows mean changes in BCVA from baseline by cohort. A planned Phase II trial will randomize approximately 500 patients to low- and high-dose combination therapy or aflibercept monotherapy.

Table 1: Baseline characteristics of 27 anti-VEGF-resistant patients enrolled in the Fovista® pre-treatment trial[23]

VEGF = vascular endothelial growth factor

Figure 1: Mean change in BCVA achieved with conbercept over 12 months of treatment in the PHOENIX trial[13]

BCVA = best-corrected visual acuity

Figure 2: Change in mean VA in treatment-resistant patients pretreated with Fovista[23]

X-82 oral VEGF/PDGF receptor inhibitor

An orally administered inhibitor of VEGF and PDGF receptors (X-82) for patients with wet AMD is being developed. Dr. Nauman Chaudhry (New London, Connecticut) presented an open-label Phase I trial where
X-82 was given to treatment-naïve patients and to those who were refractory to frequent injections of
anti-VEGF.[25] Doses of 50 mg every other day, 100 mg every other day, 200 mg daily, and 300 mg daily were tested. BCVA and spectral domain OCT were performed every 4 weeks to detect the need for rescue therapy, as indicated by a 5-letter decrease in VA and/or a 50-µm increase in fluid. The 24-week treatment period was completed by 25 of 35 patients; most patients maintained or improved vision and 15 (60%) did not require rescue injections (Figure 4). Of the 10 patients who failed to complete the full 24 weeks, 6 discontinued due to treatment-related adverse events.​

Figure 3: REGN2176-3 – mean change in BCVA from baseline by study cohort[24]

Sphingosine-1-phosphate (S1P) as a therapeutic target

Retinal pigment epithelial (RPE) cells are a major source of S1P in the posterior segment of the eye where S1P is presumed responsible for pathological angiogenesis, vascular permeability, fibrosis, and inflammation.[26] Released S1P also promotes choroidal endothelial cells and pericytes to form new blood vessels, leading to CNV as well as the inflammatory component of wet AMD by directly activating macrophages or indirectly by promoting their survival. Sonepcizumab, a recombinant, humanized IgG1κ monoclonal antibody that binds to S1P, was proven effective in preventing the development of pathologic laser-induced CNV lesions in a mouse model.[27,28] In a Phase I study, intravitreal sonepcizumab was safe and well tolerated in 15 patients with wet AMD at doses up to 1.8 mg/eye.[29]

 

The NEXUS trial, presented by Dr. Thomas Ciulla (Indianapolis, Indiana),[30] is a Phase IIa, multicentre, masked, randomized, comparator-controlled study. The objective of the study is to evaluate ­efficacy, safety, and tolerability of sonepcizumab as either monotherapy or adjunctive therapy to currently available anti-VEGF treatments versus anti-VEGF monotherapy in the treatment of wet AMD. Researchers randomized 160 patients who had poor response to ≥3 anti-VEGF injections and baseline VAs of 20/40 to 20/320 into 4 equal groups: anti-VEGF monotherapy, sonepcizumab monotherapy, and 2 doses of sonepcizumab (0.5 mg and 4.0 mg) in combination with anti-VEGF. Intravitreal injections were administered every 4 weeks. From baseline to Day 120, the anti-VEGF monotherapy group gained an average of 4.2 letters and the sonepcizumab monotherapy group lost an average of 3.0 letters (P=0.0005). Both combination groups gained about 4 letters: 4.3 letters for anti-VEGF + sonepcizumab 0.5 mg and 3.6 letters for anti-VEGF + sonepcizumab 4.0 mg. None of the key VA or anatomical secondary endpoints showed a significant difference in favour of any of the 3 sonepcizumab study groups versus the anti-VEGF monotherapy arm. Thus, 4 monthly injections of sonepcizumab, alone or in combination with anti-VEGF, did not provide additional VA benefit at Day 120 in a patient population with suboptimal response to previous anti-VEGF therapy. However, long-term follow-up data through Month 9 suggest that 4 monthly injections of 4.0 mg sonepcizumab combined with anti-VEGF followed by PRN anti-VEGF monotherapy maintain BCVA gains. The BCVA gain was correlated with reduction in total lesion area.

 

Squalamine lactate eye drops (OHR-102)

Squalamine lactate inhibits new blood vessel formation by a long-lasting intracellular mechanism of action utilizing a unique calmodulin binding site, through which it inhibits multiple growth factors including VEGF, PDGF, and basic fibroblast growth factor.[31,32] The Phase II IMPACT study, presented by Dr. Boyer,[33] evaluated squalamine lactate ophthalmic solution (OHR-102, 0.2%) in combination with PRN ranibizumab in 142 treatment-naïve patients with wet AMD. A gain of ≥3 lines of vision was achieved in 40% of patients with occult CNV <10 mm2 in area treated with the combination of OHR-102 + ranibizumab, compared with 26% of patients receiving ranibizumab monotherapy. Mean gains in VA compared to baseline were +11.0 letters for the OHR-102 + ranibizumab combination and +5.7 letters for ranibizumab monotherapy (Figure 5). The IMPACT study also demonstrated that VA outcomes correlate with the size and composition of lesions: the smaller the occult CNV size, the more pronounced the combination treatment effect on VA, regardless of the presence of classic component. This size effect, however, was not observed in patients treated with ranibizumab monotherapy. This analysis provides an insight into the mechanism of action and optimal patient population for OHR-102 and suggests that occult CNV size is a more important and inclusive classification to predict outcomes of combination therapy.​

Radiation for Wet AMD

The rationale for the use of radiation in wet AMD include the observation that radiation preferentially damages proliferating cells, including fibroblasts, inflammatory cells, and endothelial cells, while mature retinal cells are less sensitive to
radiation.[34] Early radiation of wet AMD was first reported in 1993 by Chakravarthy.[35] Modern AMD radiation involves epimacular brachytherapy (EMB) or stereotactic radio­therapy (SRT).[36] Although initial uncontrolled studies showed positive results with EMB radiation,[37,38] 2 subsequent large, randomized, controlled trials – CABERNET[39,40] and MERLOT[41] – were somewhat disappointing. Dr. Timothy Jackson (London, United Kingdom) discussed the results of SRT in the treatment of wet AMD and the results of the INTREPID study.[42,43] This randomized, double masked, sham-controlled study enrolled 230 participants already receiving anti-VEGF therapy. Patients were randomized to 16 Gray, 24 Gray, or sham SRT. The study met its primary endpoint, showing a one-third reduction in PRN anti-VEGF injections at 1 year; mean injections were 2.64 and 2.43 in the 16 Gray and 24 Gray groups, respectively, compared with 3.74 injections for the control group. Subgroup analysis demonstrated that eyes with lesions <4 mm at enrollment and those with active leakage (defined as a macular volume greater than the median) were the “best responders.” At 1 year, these best responders had significantly better vision (5 letters superior to control) and significantly fewer anti-VEGF injections (55% fewer than control). Based on these encouraging results, another study is planned (Stereotactic Radiotherapy for Age-Related Macular Degeneration [STAR; NCT02243878]). A total of 411 participants will be randomized 2:1 to 16 Gray SRT + PRN ranibizumab or PRN ranibizumab monotherapy. The primary outcome will be number of PRN ranibizumab injections over 2 years.

 

According to Dr. Jackson, a possible reason for differences in clinical response between EMB and SRT is that EMB requires vitrectomy, which reduces the drug half-life approximately 5-fold. The EMB dose reduces exponentially with increasing distance from the probe. Thus, it is important to keep the probe positioned on the retina, and in the area of greatest disease activity, during treatment. This may be difficult to determine in some occult lesions.

 

Although initial results with SRT are promising, a longer follow-up before its incorporation into routine practice is required as radiation damage may occur over time. Patient selection is also important as lesions size within the treatment zone and leakage status at time of treatment seem to impact overall outcomes; however, SRT may never become a routine application.

 

Gene Therapy

Adeno-associated virus vectors

As the eye is a small, isolated, and relatively protected organ, retinal diseases are well suited for treatment with gene-based therapies. AVA-101, the recombinant adeno-associated viral vector containing a gene encoding soluble fms-like tyrosine kinase-1 (sFLT1), has the potential to reduce the effect of VEGF. In a Phase I study, AVA-101 was shown to be well tolerated with no significant drug-related safety concerns and patients who received AVA-101 gained or maintained vision with minimal or no need for rescue treatment at 1 year.[44] Dr. Jeffrey Heier (Boston, Massachusetts) presented results from a Phase IIa controlled trial that assessed the safety and tolerability of AVA-101 in 32 subjects with exudative AMD for a period of 3 years.45 AVA-101 was administered at Day 7, and 2 0.5-mg ranibizumab injections (baseline and 1 month) covered the “ramp up” period for sFLT-1 production. Although the study demonstrated biologic activity of AVA-101 without significant safety signals, evidence of a complete and durable anti-VEGF response was not seen. Numerous factors are being studied in an effort to fully understand the suboptimal response seen in this trial, and additional preclinical studies are underway to provide insight into variables that could improve outcomes with gene therapy in wet AMD.

 

Encapsulated cell technology (ECT)

Dr. Peter Kaiser (Cleveland, Ohio) provided a brief overview of the latest developments involving ECT, which involves biotechnical implants that are able to produce ­continuously recombinant therapeutics.[46] NT-503 ECT implants with human RPE cells with sFLT-1 are surgically placed in the vitreous cavity, where they continuously produce a soluble VEGF receptor protein for at least 2 years, at therapeutic levels effective for the treatment of wet AMD.

 

Conclusion

The presentations highlighted during AAO 2015 underscore the cutting-edge research underway aimed at expanding the therapeutic options available for the treatment of neovascular AMD. Novel agents, gene therapy, combination treatment, and innovative modes of intravitreal delivery are exciting modalities that show great promise to improve outcomes for patients. Although several of these options are in the later stages of clinical development, in particular PDGF inhibitors, these novel therapies are not yet available for clinical use. In the meantime, optimized use of anti-VEGF therapies remains the standard of care in the treatment of neovascular AMD.

 

Dr. Noble is an Assistant Professor, Department of Ophthalmology and Vision Sciences, University of Toronto, and a medical retinal specialist at Markham-Stouffville Hospital and Sunnybrook Health Sciences Centre, Toronto, Ontario.

 

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Figure 4: Mean change in VA in patients treated with X-82 oral VEGFR/PDGFR inhibitor who completed 6 months of treatment without rescue injection (N=15)[25]

PDGFR = platelet-derived growth factor receptor; ETDRS = Early Treatment Diabetic Retinopathy Study; SEM = standard error of the mean

Disclosure Statement: Dr. Noble has acted as a consultant and speaker for Alcon Canada, Bayer Inc, and Novartis Pharmaceuticals Canada. 

SNELL Medical Communication acknowledges that it has received an unrestricted educational grant from Novartis Pharmaceuticals Canada to support the ­distribution of this issue of Ophthalmology ­Scientific Update. Acceptance of this grant was conditional upon the sponsors’ acceptance of the policy established by the ­Department of Ophthalmology and Vision ­Sciences and SNELL Medical Communication guaranteeing the ­educational integrity of the publication. This policy ensures that the author and editor will at all times ­exercise unrestricted, rigorous, ­scientific independence free of interference from any other party. This publication may include discussion of products or product indications that have not been granted approval by Health Canada. This content is intended for medical, scientific, and educational purposes only.

© 2016 Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, which is solely responsible for the contents. Publisher: Snell Medical Communication Inc. in cooperation with the Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto. ™Ophthalmology Scientific Update is a Trade Mark of Snell Medical Communication Inc. All rights reserved. The administration of any therapies discussed or referred to in Ophthalmology Scientific Update should always be consistent with the approved prescribing information in Canada. Snell Medical Communication Inc. is committed to the development of superior Continuing Medical Education.

Figure 5: Mean VA gain in patients treated with OHR-102 in combination with ranibizumab[33]

PRN = as needed