Anti-VEGF drugs have revolutionized the treatment of neovascular age-related macular degeneration (AMD), but recent studies have demonstrated substantially worse VA results in the real world than were achieved in earlier prospective clinical trials.1-3 This discrepancy seems to stem from the relatively high treatment burden associated with current anti-VEGF strategies.4 Many patients require intravitreal injections every 4 to 8 weeks to adequately combat ongoing disease activity over many years. Some will probably require lifelong treatment. Many patients are unable to maintain such frequent injection cycles; as a result, a large share of our real-world patients are, essentially, undertreated.
AT A GLANCE
• Real-world results with anti-VEGF therapies often do not match the results of prospective clinical trials, possibly because the high burden of treatment results in relative undertreatment.
• Several emerging therapies are making headway in addressing the unmet need of more durable suppression of disease activity.
• Approaches under investigation include new anti-VEGF molecules, a refillable implant, molecules targeting other factors, and gene therapy.
On the other hand, evidence is mounting that most patients would benefit from sustained long-term anti-VEGF suppression. Early concerns that frequent anti-VEGF injections might be linked to geographic atrophy seem to have been overstated.5 Data indicate that long-term, frequent injections are safe and associated with excellent preservation of VA.6
Several emerging therapies are making headway in addressing the unmet need of more durable suppression of disease activity. In this article, we review some promising treatment options and the emerging data from their respective clinical trials.
Brolucizumab, also known as RTH258 (Novartis), is a novel small (26 kDa) humanized single-chain antibody fragment that is a potent inhibitor of VEGF-A. The small size of the molecule, relative to other anti-VEGF agents, allows higher dosing per volume, which may result in a longer-lasting effect (Figure 1).
Two large phase 3 studies, HAWK and HARRIER, investigated the efficacy and safety of brolucizumab 3 mg (HAWK only) and brolucizumab 6 mg (HAWK and HARRIER) with a dosing frequency of up to every 12 weeks, in comparison with aflibercept 2 mg (Eylea, Regeneron) every 8 weeks. Both brolucizumab arms had an initial loading phase of injections at day 1, week 4, and week 8. The results demonstrated noninferiority of brolucizumab 3 mg and 6 mg to aflibercept 2 mg in BCVA at week 48, the primary endpoint of the studies.
Moreover, brolucizumab-treated patients showed greater reduction in subretinal and intraretinal fluid on average, indicating that it may be a better drying agent than the comparator drug. In terms of durability, in the brolucizumab arm, 49% to 56% of patients were maintained on a 12-weekly injection regimen until week 48, and most of these patients were maintained on that interval up to week 96.7
MERLIN is an ongoing phase 3 trial comparing brolucizumab 6 mg every 4 weeks with aflibercept 2 mg every 4 weeks in patients with persistent subretinal or intraretinal fluid despite frequent treatment.8 The study began in October 2018, and no results have been posted to date.
Novartis submitted a biologics license application to the US FDA for brolucizumab in April with a request for expedited review. If the drug is approved, the company anticipates launching it by the end of this year.
It will be interesting to see how availability of this drug might change the management of our patients with neovascular AMD. Research results to date suggest that this drug could reduce the burden of neovascular AMD treatment to a quarterly dosing regimen for a substantial number of patients, which would be a welcome change.
Port Delivery System
Another method of extending the duration of VEGF suppression is by use of an indwelling depot. Genentech is developing a surgically implanted drug delivery system, the Port Delivery System (PDS) for use with ranibizumab (Lucentis, Genentech). (Editors’ Note: The article “Use of the Port Delivery System in AMD” in this issue contains images of the PDS.)
A phase 3 clinical trial, ARCHWAY, is evaluating the efficacy, safety, and pharmacokinetics of the PDS implant, filled with 100 mg/mL of ranibizumab at a 24-weekly interval, in comparison with monthly intravitreal ranibizumab injections for the treatment of neovascular AMD.9
The phase 2 LADDER trial compared the efficacy, safety, and pharmacokinetics of three doses (10 mg/mL, 40 mg/mL, and 100 mg/mL) of ranibizumab delivered via the PDS. In that trial, 79.8% of patients who received the highest dose did not require refills for at least 6 months.10 There were concerns about the frequent occurrence of vitreous hemorrhage in the early phase of the trial, but this may have been addressed by modification of the surgical technique.
The ARCHWAY trial is rapidly enrolling patients and we look forward to learning about what the availability of this implant might bring to the field. If the PDS is found to be adequately safe, it may introduce a whole new treatment paradigm, moving away from the peak-and-trough phenomenon seen with intravitreal injections.
Faricimab (Genentech; Figure 2) is a bispecific antibody for both VEGF-A and angiopoietin 2 (Ang-2). Ang-2 is a cytokine associated with vascular destabilization and microvascular inflammation. It is hoped that dual blockade of VEGF and Ang-2 may bring synergistic effects in the treatment of neovascular AMD.
The completed phase 2 STAIRWAY trial compared two extended dosing regimens of faricimab 6.0 mg, given every 12 and every 16 weeks, to ranibizumab 0.5 mg given every 4 weeks. Results of the study showed noninferior BCVA and anatomic outcomes with these regimens compared with monthly ranibizumab, and the drug was well tolerated with no concerning safety signals.11
TENAYA and LUCERNE are two identically designed phase 3 clinical trials commenced in early 2019 by Roche and Genentech to evaluate the safety, efficacy, and durability of faricimab given every 16 weeks, with an option to decrease the treatment interval to every 12 or 8 weeks based on clinical indications, compared with aflibercept given every 8 weeks.12,13 The primary outcome of the studies will be BCVA at 48 weeks.
With its dual blockage mechanism, faricimab may allow longer dosing intervals. We anticipate learning more about the rollout of the phase 3 trials.
Abicipar pegol (Allergan) is a designed ankyrin repeat protein, or DARPin, a 34-kDa molecule that inhibits both VEGF and platelet-derived growth factor. Two parallel 52-week phase 3 clinical trials, CEDAR and SEQUIOA, evaluated abicipar pegol 2.0 mg, injected either every 8 weeks (after three initial monthly injections) or every 12 weeks (after injections at day 1, week 4 and week 12) in comparison with monthly ranibizumab.14,15
In those trials, abicipar was found to be noninferior to ranibizumab in VA results, even in the quarterly treatment arms. However, an ocular adverse event rate of 15.0% was reported, mostly in the form of intraocular inflammation, compared with 0.3% in the ranibizumab arm.16 It is possible that Allergan may be able to address these issues, but for now we are concerned that these inflammatory reactions may significantly limit clinical use in a field full of potent and safe competitors.
Conbercept (Chengdu Kang Hong Biotech) is an anti-VEGF–receptor fusion protein that blocks isoforms of VEGF-A, VEGF-B, VEGF-C, and platelet-derived growth factor. It was approved for the treatment of neovascular AMD in China in 2013 based on the PHOENIX trial, which reported effectiveness of conbercept with three initial monthly injections followed by quarterly injections.17 In the United States, the PANDA-1 trial is a recently launched phase 3 clinical trial comparing the efficacy and safety of intravitreal injection of 0.5 mg conbercept, 1.0 mg conbercept, and 2.0 mg aflibercept.18 Patients in each arm will receive injections at day 1, week 4, and week 8, followed by injections every 8 weeks (conbercept 0.5 mg, aflibercept 2.0 mg) or every 12 weeks (conbercept 1.0 mg) for a total of 96 weeks.
In the more distant future, there may be even greater promise for patients with neovascular AMD through one or more of the gene therapies that are now being explored in phase 1 and 2 clinical trials.
The OPTIC trial is a phase 1 study that is investigating the safety of the ADVM-022, also known as AAV.7m8-aflibercept (Adverum Biotechnologies), a gene therapy product designed to express aflibercept protein within retinal cells after a one-time intravitreal injection.19 The OPTIC trial will evaluate three doses in a small number of patients under active treatment who have already demonstrated a meaningful response to anti-VEGF therapy. With improved gene vector efficiency, this therapy has the potential to achieve long-term sustained anti-VEGF suppression with a single administration.
HMR59 (AAVCAGsCD59; Hemera Biosciences) is an adeno-associated virus 2 gene therapy that produces a soluble form of CD59, which blocks complement activity at the membrane attack complex. This gene therapy is being tested in phase 1 clinical trials for both wet and dry AMD. In the phase 1 HMR-1002 trial, treatment-naïve patients will receive an intravitreal anti-VEGF injection at day 1 and a single injection of HMR59 injection at day 7, followed by anti-VEGF treatment on an as-needed basis.20
RGX-314 (RegenxBio) is a recombinant adeno-associated virus gene therapy vector carrying a coding sequence for a soluble monoclonal antibody fragment that binds to and neutralizes VEGF.21 A phase 1/2a clinical trial is evaluating the safety of subretinal injection of RGX-314 in patients with previously treated neovascular AMD.21 The study is designed to assess whether a single dose of RGX-314 will allow expression of a therapeutic level of anti-VEGF proteins by retinal cells.
It will be intriguing to see how this product, which is being delivered surgically by subretinal injection, will pan out in this well-designed clinical trial.
QUESTIONS TO BE ANSWERED
There are a number of questions about the pipeline of AMD treatments. Regarding conbercept, will the promise of the PHOENIX trial hold up in the PANDA-1 trial? Will Allergan be able to adjust for the inflammatory reactions seen after administration of abicipar pegol in CEDAR and SEQUIOA? Will the phase 3 studies of faricimab show that longer dosing intervals can become a reality for patients? How will brolucizumab and the PDS, if they are approved, change the ways we treat patients?
There is a significant unmet need of undertreatment due to the relatively high treatment burden of AMD therapy, and we are looking forward to seeing if the newer treatment options discussed here may really help further our field.
1. 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(2):220-226.
2. Ciulla TA, Huang F, Westby K, Williams DF, Zaveri S, Patel SC. Real-world outcomes of anti-vascular endothelial growth factor therapy in neovascular age-related macular degeneration in the United States. Ophthalmology Retina. 2018;2(7):645-653.
3. Akagi-Kurashige Y, Tsujikawa A, Yuzawa M, et al. A 5-year multicenter prospective cohort study on the long-term visual prognosis and predictive factors for visual outcome in Japanese patients with age-related macular degeneration: the AMD2000 study. Jpn J Ophthalmol. 2018;62(2):137-143.
4. Hussain RM, Hariprasad SM, Ciulla TA. Treatment burden in neovascular AMD: visual acuity outcomes are associated with anti-VEGF injection frequency. Ophthalmic Surg Lasers Imaging Retina. 2017;48(10):780-784.
5. Long D, Kanan Y, Shen J, et al. VEGF/VEGFR2 blockade does not cause retinal atrophy in AMD-relevant models. JCI Insight. 2018;3(10). pii: 120231.
6. Peden MC, Suner IJ, Hammer ME, Grizzard WS. Long-term outcomes in eyes receiving fixed-interval dosing of anti-vascular endothelial growth factor agents for wet age-related macular degeneration. Ophthalmology. 2015;122(4):803-808.
7. Dugel PU, Koh A, Ogura Y, et al; HAWK and HARRIER Study Investigators. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration [published online ahead of print April 12, 2019]. Ophthalmology.
8. Study of safety and efficacy of brolucizumab 6 mg dosed every 4 weeks compared to aflibercept 2 mg dosed every 4 weeks in patients with retinal fluid despite frequent anti-VEGF injections (MERLIN). Sponsor: Novartis Pharmaceuticals. https://clinicaltrials.gov/ct2/show/NCT03710564. Accessed April 30, 2019.
9. A phase III study to evaluate the port delivery system implant with ranibizumab compared with monthly ranibizumab injections in participants with wet age-related macular degeneration (archway). Sponsor: Hoffman-LaRoche. https://clinicaltrials.gov/ct2/show/NCT03677934. Accessed April 30, 2019.
10. 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 [published online ahead of print April 1, 2019]. Ophthalmology.
11. Khanani A, Osborne A, Basu K, Grzeschik S, Lin H. 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.
12. A study to evaluate the efficacy and safety of faricimab in participants with neovascular age-related macular degeneration (TENAYA). Sponsor: Hoffman-La Roche. https://clinicaltrials.gov/ct2/show/NCT03823287. Accessed April 30, 2019.
13. A study to evaluate the efficacy and safety of faricimab in participants with neovascular age-related macular degeneration (LUCERNE). Sponsor: Hoffman-LaRoche. https://clinicaltrials.gov/ct2/show/NCT03823300. Accessed April 30, 2019.
14. A safety and efficacy study of abicipar pegol in patients with neovascular age-related macular degeneration (CDER). Sponsor: Allergan. https://clinicaltrials.gov/ct2/show/NCT02462928. Accessed April 30, 2019.
15. Safety and efficacy of abicipar pegol in patients with neovascular age-related macular degeneration. Sponsor: Allergan. https://clinicaltrials.gov/ct2/show/NCT02462486. Accessed April 30, 2019.
16. Khurana R. Safety and efficacy of abicipar in patients with neovascular age-related macular degeneration. Paper presented at: American Academy of Ophthalmology Annual Meeting; October 27, 2018; Chicago, IL.
17. Liu K, Song Y, Xu G, et al. Conbercept for treatment of neovascular age-related macular degeneration: results of the randomized phase 3 PHOENIX study. Am J Ophthalmol. 2019;197:156-167.
18. Efficacy and safety trial of conbercept intravitreal injection for neovascular age-related macular degeneration (PANDA-1). Sponsor: Chengdu Kanghong Biotech. https://clinicaltrials.gov/ct2/show/NCT03577899. Accessed April 30, 2019.
19. ADVM-022 gene therapy for wet AMD (OPTIC). Sponsor: Adverum Biotechnologies. https://clinicaltrials.gov/ct2/show/NCT03748784. Accessed April 30, 2019.
20. Treatment of advanced dry age related macular degeneration with AAVCAGsCD59. Sponsor: Hemera Biosciences. https://clinicaltrials.gov/ct2/show/NCT03585556. Accessed April 30, 2019.
21. RGX-314 gene therapy for neovascular AMD trial. Regenxbio. https://clinicaltrials.gov/ct2/show/NCT03066258. Accessed April 30, 2019.
Natalie Huang, MD
• PGY-1, Preliminary Internal Medicine Resident, State University of New York, Upstate Medical University, Syracuse, New York
• Financial disclosure: None
Patrick Oellers, MD
• Partner, Retina-Vitreous Surgeons of Central New York, PC; Assistant Professor, State University of New York, Upstate Medical Center, Department of Ophthalmology and Visual Sciences; both in Syracuse, New York
• Financial disclosure: Speaker Bureau (Novartis)