Emerging Treatments for Neovascular AMD

Novel treatment options hold the promise of longer-term VEGF suppression.

BY NATALIE HUANG, MD; AND PATRICK OELLERS, MD

nti-VEGF drugs have revolution- Several emerging therapies are mak- fragment that is a potent inhibitor of ized the treatment of neovascular ing headway in addressing the unmet VEGF-A. The small size of the molecule, age-related macular degenera- need of more durable suppression of relative to other anti-VEGF agents, tion (AMD), but recent studies disease activity. In this article, we review allows higher dosing per volume, which have demonstrated substantially some promising treatment options and may result in a longer-lasting effect Aworse VA results in the real world than the emerging data from their respective (Figure 1). were achieved in earlier prospective clinical trials. Two large phase 3 studies, HAWK clinical trials.1-3 This discrepancy seems and HARRIER, investigated the effi- to stem from the relatively high treat- EMERGING THERAPIES cacy and safety of brolucizumab ment burden associated with current Brolucizumab 3 mg (HAWK only) and broluci- anti-VEGF strategies.4 Many patients Brolucizumab, also known as RTH258 zumab 6 mg (HAWK and HARRIER) require intravitreal injections every 4 to (Novartis), is a novel small (26 kDa) with a dosing frequency of up to 8 weeks to adequately combat ongoing humanized single-chain antibody every 12 weeks, in comparison with disease activity over many years. Some will probably require lifelong treatment. Many patients are unable to maintain such frequent injection cycles; as a AT A GLANCE

result, a large share of our real-world s patients are, essentially, undertreated. Real-world results with anti-VEGF therapies often do not match the results On the other hand, evidence is of prospective clinical trials, possibly because the high burden of treatment mounting that most patients would results in relative undertreatment. benefit from sustained long-term anti- VEGF suppression. Early concerns that s Several emerging therapies are making headway in addressing the unmet frequent anti-VEGF injections might be linked to geographic atrophy seem to need of more durable suppression of disease activity.

have been overstated.5 Data indicate s that long-term, frequent injections Approaches under investigation include new anti-VEGF molecules, a are safe and associated with excellent refillable implant, molecules targeting other factors, and gene therapy. preservation of VA.6

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Drug Unlicensed Bevacizumab Aflibercept Ranibizumab Brolucizumab Format Full antibody (IgG1) VEFGR1/2-Fc Fusion Protein Fab Fragment Single-Chain Antibody Fragment Molecular Structure

Molecular Weight = 149 kDa 97-115 kDa = 48 kDa 26 kDa Clinical Dose 1.25 mg 2.00 mg 0.50 mg 6.00 mg Equivalent Molar Dose 0.4-0.5 1.0 0.5-0.6 11.2-13.3 Figure 1. Brolucizumab’s significantly smaller size allows greater molar doses per volume of injection. aflibercept 2 mg (Eylea, Regeneron) every 8 weeks. Both bro- comparison with monthly intravitreal ranibizumab injections lucizumab arms had an initial loading phase of injections at for the treatment of neovascular AMD.9 day 1, week 4, and week 8. The results demonstrated nonin- The phase 2 LADDER trial compared the efficacy, safety, feriority of brolucizumab 3 mg and 6 mg to aflibercept 2 mg and pharmacokinetics of three doses (10 mg/mL, 40 mg/mL, in BCVA at week 48, the primary endpoint of the studies. and 100 mg/mL) of ranibizumab delivered via the PDS. In Moreover, brolucizumab-treated patients showed greater that trial, 79.8% of patients who received the highest dose reduction in subretinal and intraretinal fluid on average, did not require refills for at least 6 months.10 There were indicating that it may be a better drying agent than the concerns about the frequent occurrence of vitreous hemor- comparator drug. In terms of durability, in the brolucizumab rhage in the early phase of the trial, but this may have been arm, 49% to 56% of patients were maintained on a 12-weekly addressed by modification of the surgical technique. injection regimen until week 48, and most of these patients The ARCHWAY trial is rapidly enrolling patients and we were maintained on that interval up to week 96.7 look forward to learning about what the availability of this MERLIN is an ongoing phase 3 trial comparing brolu- implant might bring to the field. If the PDS is found to be cizumab 6 mg every 4 weeks with aflibercept 2 mg every adequately safe, it may introduce a whole new treatment 4 weeks in patients with persistent subretinal or intrareti- paradigm, moving away from the peak-and-trough phenom- nal fluid despite frequent treatment.8 The study began in enon seen with intravitreal injections. October 2018, and no results have been posted to date. Novartis submitted a biologics license application to the Faricimab US FDA for brolucizumab in April with a request for expedit- Faricimab (Genentech; Figure 2) is a bispecific antibody for ed review. If the drug is approved, the company anticipates both VEGF-A and angiopoietin 2 (Ang-2). Ang-2 is a cyto- launching it by the end of this year. kine associated with vascular destabilization and microvas- It will be interesting to see how availability of this drug cular inflammation. It is hoped that dual blockade of VEGF might change the management of our patients with neovas- and Ang-2 may bring synergistic effects in the treatment of cular AMD. Research results to date suggest that this drug neovascular AMD. could reduce the burden of neovascular AMD treatment The completed phase 2 STAIRWAY trial compared two to a quarterly dosing regimen for a substantial number of extended dosing regimens of faricimab 6.0 mg, given every patients, which would be a welcome change. 12 and every 16 weeks, to ranibizumab 0.5 mg given every 4 weeks. Results of the study showed noninferior BCVA and Port Delivery System anatomic outcomes with these regimens compared with Another method of extending the duration of VEGF monthly ranibizumab, and the drug was well tolerated with suppression is by use of an indwelling depot. Genentech no concerning safety signals.11 is developing a surgically implanted drug delivery system, TENAYA and LUCERNE are two identically designed the Port Delivery System (PDS) for use with ranibizumab phase 3 clinical trials commenced in early 2019 by Roche (Lucentis, Genentech). (Editors’ Note: The article “Use of the and Genentech to evaluate the safety, efficacy, and durabil- Port Delivery System in AMD” on page 34 in this issue con- ity of faricimab given every 16 weeks, with an option to tains images of the PDS.) decrease the treatment interval to every 12 or 8 weeks based A phase 3 clinical trial, ARCHWAY, is evaluating the effi- on clinical indications, compared with aflibercept given cacy, safety, and pharmacokinetics of the PDS implant, filled every 8 weeks.12,13 The primary outcome of the studies will with 100 mg/mL of ranibizumab at a 24-weekly interval, in be BCVA at 48 weeks.

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- 19 - The study isstudy The 21 (Continued on page (Continued

20 A phase 1/2a clinical trial is evaluatingis trial clinical 1/2a phase A 21

HMR59 (AAVCAGsCD59; Hemera Biosciences) is anis Biosciences) Hemera (AAVCAGsCD59; HMR59 adeno-associatedrecombinant a is (RegenxBio) RGX-314 In the more distant future, there may be even greatereven be may there future, distant more the In investi is that study 1 phase a is trial OPTIC The There are a number of questions about the pipeline ofpipeline the about questions of number a are There It will be intriguing to see how this product, which is beingis which product, this how see to intriguing be will It ADVM-022 HMR59 HMR59 RGX-314 solu a produces that therapy gene 2 virus adeno-associated theat activity complement blocks which CD59, of form ble testedbeing is therapy gene This complex. attack membrane theIn AMD. dry and wet both for trials clinical 1 phase in receivewill patients treatment-naïve trial, HMR-1002 1 phase injec single a and 1 day at injection anti-VEGF intravitreal an anti-VEGF by followed 7, day at injection HMR59 of tion basis. as-needed an on treatment afor sequence coding a carrying vector therapy gene virus andto binds that fragment antibody monoclonal soluble VEGF. neutralizes GENE THERAPY GENE THERAPY orone through AMD neovascular with patients for promise inexplored being now are that therapies gene the of more trials. clinical 2 and 1 phase asknown also ADVM-022, the of safety the gating genea Biotechnologies), (Adverum AAV.7m8-aflibercept proteinaflibercept express to designed product therapy injection. intravitreal one-time a after cells retinal within numbersmall a in doses three evaluate will trial OPTIC The dem already have who treatment active under patients of Withtherapy. anti-VEGF to response meaningful a onstrated poten the has therapy this efficiency, vector gene improved suppression anti-VEGF sustained long-term achieve to tial administration. single a with QUESTIONS TO BE ANSWERED QUESTIONS TO BE ANSWERED promisethe will conbercept, Regarding treatments. AMD Willtrial? PANDA-1 the in up hold trial PHOENIX the of reactionsinflammatory the for adjust to able be Allergan and CEDAR in pegol abicipar of administration after seen thatshow faricimab of studies 3 phase the Will SEQUIOA? patients?for reality a become can intervals dosing longer the safety of subretinal injection of RGX-314 in patientsin RGX-314 of injection subretinal of safety the AMD. neovascular treated previously with will RGX-314 of dose single a whether assess to designed proteins anti-VEGF of level therapeutic a of expression allow cells.retinal by inout pan will injection, subretinal by surgically delivered trial. clinical well-designed this - - In 17 It is possibleis It 16 Patients in each arm will arm each in Patients 18 14,15 , a 34-kDa molecule that inhibits both VEGFboth inhibits that molecule 34-kDa a , DARPin | MAY/JUNE 2019 | MAY/JUNE

Figure 2. Faricimab is a bispecific antibody that shows potential for increased antibody that shows potential for increased Figure 2. Faricimab is a bispecific AMD. durability in treatment of neovascular

Conbercept (Chengdu Kang Hong Biotech) is an is Biotech) Hong Kang (Chengdu Conbercept In those trials, abicipar was found to be noninferior tononinferior be to found was abicipar trials, those In Abicipar pegol (Allergan) is a designed ankyrin repeat pro repeat ankyrin designed a is (Allergan) pegol Abicipar With its dual blockage mechanism, faricimab may allow may faricimab mechanism, blockage dual its With bercept, and 2.0 mg aflibercept. mg 2.0 and bercept, followed 8, week and 4, week 1, day at injections receive aflibercept mg, 0.5 (conbercept weeks 8 every injections by total a for mg) 1.0 (conbercept weeks 12 every or mg) 2.0 weeks. 96 of AMD in China in 2013 based on the PHOENIX trial, which trial, PHOENIX the on based 2013 in China in AMD initial three with conbercept of effectiveness reported injections. quarterly by followed injections monthly launched recently a is trial PANDA-1 the States, United the of safety and efficacy the comparing trial clinical 3 phase con mg 1.0 conbercept, mg 0.5 of injection intravitreal safe competitors. safe Conbercept isoforms blocks that protein fusion anti-VEGF–receptor growth platelet-derived and VEGF-C, VEGF-B, VEGF-A, of neovascular of treatment the for approved was It factor. arms. However, an ocular adverse event rate of 15.0% was15.0% of rate event adverse ocular an However, arms. inflammation,intraocular of form the in mostly reported, arm. ranibizumab the in 0.3% with compared forbut issues, these address to able be may Allergan that reactionsinflammatory these that concerned are we now andpotent of full field a in use clinical limit significantly may abicipar pegol 2.0 mg, injected either every 8 weeks (afterweeks 8 every either injected mg, 2.0 pegol abicipar (afterweeks 12 every or injections) monthly initial three withcomparison in 12) week and 4 week 1, day at injections ranibizumab. monthly treatmentquarterly the in even results, VA in ranibizumab the rollout of the phase 3 trials. 3 phase the of rollout the Abicipar or tein, 52-weekparallel Two factor. growth platelet-derived and evaluatedSEQUIOA, and CEDAR trials, clinical 3 phase longer dosing intervals. We anticipate learning more about more learning anticipate We intervals. dosing longer RETINA TODAY

22 THE FUTURE MACULAR OF AGE-RELATED DEGENERATION s - - - - . n JCI . 2015;122(4):803-808. Ophthalmology Retina Ophthalmology 2017;48(10):780-784. . 2015;99(2):220-226. . 2019;197:156-167. ) . Br J Ophthalmol 22 Am J Ophthalmol Ophthalmic Surg Lasers Imaging Retina. . 2018;62(2):137-143. Ophthalmology . Jpn J Ophthalmol Ophthalmology . 2018;3(10). pii: 120231. There is a significant unmet need of undertreatment dueundertreatment of need unmet significant a is There [email protected] Financial disclosure: None Partner, Retina-Vitreous Surgeons of Central New York, PC; Assistant [email protected] Financial disclosure: Speaker Bureau (Novartis) PGY-1, Preliminary Internal Medicine Resident, State University of New York, PGY-1, Preliminary Internal Medicine Resident, State University of New York, Professor, State University of New York, Upstate Medical Center, Department of Professor, State University of New York, Upstate Medical Center, Department of Ophthalmology and Visual Sciences; both in Syracuse, New York Upstate Medical University, Syracuse, New York     2018;2(7):645-653. M, et al. A 5-year multicenter prospective cohort study on the long-term 3. Akagi-Kurashige Y, Tsujikawa A, Yuzawa the visual outcome in Japanese patients with age-related macular degeneration: visual prognosis and predictive factors for AMD2000 study. Treatment burden in neovascular AMD: visual acuity outcomes are associated 4. Hussain RM, Hariprasad SM, Ciulla TA. with anti-VEGF injection frequency. atrophy in AMD-relevant models. 5. Long D, Kanan Y, Shen J, et al. VEGF/VEGFR2 blockade does not cause retinal n n PATRICK OELLERS, MD n n n 8. Study of safety and efficacy of brolucizumab 6 mg dosed every 4 weeks compared to aflibercept 2 mg dosed every 4 8. Study of safety and efficacy of brolucizumab 6 mg dosed every 4 weeks compared Sponsor: Novartis Pharmaceuticals. weeks in patients with retinal fluid despite frequent anti-VEGF injections (MERLIN). https://clinicaltrials.gov/ct2/show/NCT03710564. Accessed April 30, 2019. compared with monthly ranibizumab 9. A phase III study to evaluate the port delivery system implant with ranibizumab Sponsor: Hoffman-LaRoche. https:// injections in participants with wet age-related macular degeneration (archway). clinicaltrials.gov/ct2/show/NCT03677934. Accessed April 30, 2019. for neovascular age-related 10. Campochiaro PA, Marcus DM, Awh CC, et al. The port delivery system with ranibizumab [published online ahead of print April 1, macular degeneration: results from the randomized phase 2 ladder clinical trial 2019]. Ang-2 and VEGF with faricimab in neo 11. Khanani A, Osborne A, Basu K, Grzeschik S, Lin H. Simultaneous inhibition of of Ophthalmology Retina Subspecialty vascular AMD: STAIRWAY phase 2 results. Paper presented at: American Academy Day; October 26-27, 2018; Chicago, IL. age-related macular degenera 12. A study to evaluate the efficacy and safety of faricimab in participants with neovascular Accessed April 30, 2019. tion (TENAYA). Sponsor: Hoffman-La Roche. https://clinicaltrials.gov/ct2/show/NCT03823287. age-related macular degenera 13. A study to evaluate the efficacy and safety of faricimab in participants with neovascular Accessed April 30, 2019. tion (LUCERNE). Sponsor: Hoffman-LaRoche. https://clinicaltrials.gov/ct2/show/NCT03823300. macular degeneration (CDER). 14. A safety and efficacy study of abicipar pegol in patients with neovascular age-related April 30, 2019. Sponsor: Allergan. https://clinicaltrials.gov/ct2/show/NCT02462928. Accessed macular degeneration. Sponsor: Allergan. 15. Safety and efficacy of abicipar pegol in patients with neovascular age-related https://clinicaltrials.gov/ct2/show/NCT02462486. Accessed April 30, 2019. macular degeneration. Paper 16. Khurana R. Safety and efficacy of abicipar in patients with neovascular age-related 2018; Chicago, IL. presented at: American Academy of Ophthalmology Annual Meeting; October 27, macular degeneration: results of the 17. Liu K, Song Y, Xu G, et al. Conbercept for treatment of neovascular age-related randomized phase 3 PHOENIX study. macular degeneration 18. Efficacy and safety trial of conbercept intravitreal injection for neovascular age-related Accessed April 30, (PANDA-1). Sponsor: Chengdu Kanghong Biotech. https://clinicaltrials.gov/ct2/show/NCT03577899. 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 n (Continued from page from (Continued approved,are they if PDS, the and brolucizumab will How patients? treat we ways the change therapy,AMD of burden treatment high relatively the to treatmentnewer the if seeing to forward looking are we and field. our further help really may here discussed options real-life experience of anti-vascular endothelial growth factor therapy 1. Holz FG, Tadayoni R, Beatty S, et al. Multi-country for wet age-related macular degeneration. DF, Zaveri S, Patel SC. Real-world outcomes of anti-vascular endothelial 2. Ciulla TA, Huang F, Westby K, Williams macular degeneration in the United States. growth factor therapy in neovascular age-related Insight receiving fixed-interval dosing of anti-vas 6. Peden MC, Suner IJ, Hammer ME, Grizzard WS. Long-term outcomes in eyes cular endothelial growth factor agents for wet age-related macular degeneration. and HARRIER: phase 3, multicenter, 7. Dugel PU, Koh A, Ogura Y, et al; HAWK and HARRIER Study Investigators. HAWK macular degeneration [published online randomized, double-masked trials of brolucizumab for neovascular age-related ahead of print April 12, 2019]. | MAY/JUNE 2019 | MAY/JUNE

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