DIABETIC EYE DISEASE s NOVEL TREATMENT STRATEGIES FOR DIABETIC EYE DISEASE Next-generation anti–VEGF-A drugs and combination agents show potential.
BY PRAVIN U. DUGEL, MD
here is no doubt that anti–VEGF-A trials of this agent for the treatment ANGIOPOIETIN COMBINATION DRUGS monotherapy has revolutionized of DME may begin in the near future. Angiopoietin, a part of the family the treatment of diabetic macu- The drug has already shown promise of growth factors, plays an important lar edema (DME). However, for treatment of age-related macular role in angiogenesis. Several drugs studies looking at data from the degeneration, including reductions that affect the action of angiopoietin CentersT for Medicare and Medicaid in central retinal thickness on optical are in development. It is important Services and from prospective ran- coherence tomography (OCT) with a to understand the mechanism of domized studies have shown that greater durability, in the HAWK and action for this drug class. In health, some patients have resistant or per- HARRIER clinical trials.1 angiopoietin-1 (Ang-1) is crucial for sistent disease that does not respond vessel development. It maintains to this form of therapy. The unmet Abicipar Pegol healthy vasculature by activating need presented by these patients This drug belongs in the class of the Tie2 receptor. In disease states, forms the impetus for developing genetically engineered antibody Ang-2 is upregulated. This cytokine new options for the treatment of mimetic proteins called designed is an antagonist of Ang-1, which DME. In this article, I discuss some of ankyrin repeat proteins (DARPins). It attracts proangiogenic and inflam- the agents now in the pipeline. is small in size and has high-potency matory cytokines. Its activation is stability and solubility. Results from often coupled with upregulation of NEXT-GENERATION ANTI–VEGF-A DRUGS the phase 2 PALM study showed that VEGF-A, causing increased vascular Agents that inhibit the activity of abicipar pegol, injected every 8 or permeability. VEGF-A have been used for years, but 12 weeks in patients with DME, offered Two products in this category scientists have been working on new, functional and anatomic effects simi- are notable in the DME pipeline: or next-generation, options. There lar to those of ranibizumab injected RG7716 (Genentech/Roche) and are three that I would like to high- monthly.2 Patients receiving 2 mg of a combination of the Ang-2 anti- light: brolucizumab (RTH258; Alcon/ the drug required fewer injections body nesvascumab plus aflibercept Novartis), abicipar pegol (Allergan), than those treated with ranibizumab (Regeneron/Bayer). and conbercept (KH902; Chengdu over a 28-week period. Kanghong Biological Science & RG7716 Technology). Conbercept This bispecific molecule can simul- Clinical studies of this recombinant taneously inhibit Ang-2 and VEGF-A. Brolucizumab human VEGF receptor-Fc fusion Those are two important targets. Brolucizumab is a humanized protein, which inhibits VEGF-A, VEGF-B, The phase 2 BOULEVARD study is single-chain antibody fragment. It is and placental growth factor (PlGF) investigating the safety and efficacy the smallest active unit of VEGF-A have been conducted. The FRONTIER of RG7716 in patients with DME, and antibody, and it allows concentrated and SAILING studies showed improve- results are expected early this year.5 molar dosing at 22 times the dose of ments in visual acuity and concomitant ranibizumab (Lucentis; Genentech) decreases in retinal thickness on OCT in Nesvacumab and Aflibercept and more than 11 times that of patients with DME.3,4 Additional trials This is a co-formulation agent, aflibercept (Eylea; Regeneron). Clinical in DME are being planned. as opposed to a bispecific agent,
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11 AKB-9778 SUBCUTANEOUS TIE2 ACTIVATOR The ongoing phase 2 TYBEE2 phase ongoing The 10 KVD001 (KalVista Pharmaceuticals) (KalVista KVD001 The injection of a proprietary suspen proprietary a of injection The KVD001 targetsthat inhibitor protease a is VEGF-independenta kallikrein, plasma this of Levels DME. of mediator vitreous the in elevated are enzyme to According DME. with patients of inhibi kallikrein plasma company, the independent pathway a targets tion of anas serve therefore may and VEGF treatmentDME existing to addition studyopen-label 1 phase A options. anti–VEGF-Ato resistant patients in improvementshowed monotherapy KVD001. of injection single a with 1/2 exploratory HULK clinical The phase 1/2 exploratory HULK clinical CLS-TAsuprachoroidal examined trial afliberceptintravitreal without and with efficacyincreased of signs showed and investigationalthe with durability and drug. suprachoroidalcomparing is study withaflibercept intravitreal plus CLS-TA alone. aflibercept intravitreal phase 2 study will begin enrolling soon. enrolling begin will study 2 phase SUPRACHOROIDAL CORTICOSTEROID corticosteroid the of formulation sion (CLS-TA;acetonide triamcinolone supra the into Biomedical) Clearside toapproach novel a is space choroidal DME.with patients of treatment the - - 6,7 - CLS-TA 7,8 CORTICOSTEROID SUPRACHOROIDAL mg, and 2.0 mg) 2.0 and mg,
2b DEL MAR study evaluated evaluated study MAR DEL 2b Most impressive, the patients who who patients the impressive, Most ALG-1001 (Luminate; Allegro) Allegro) (Luminate; ALG-1001 ing that such patients may benefit benefit may patients such that ing drug. this with treatment this from sequential therapy with anti-VEGF anti-VEGF with therapy sequential treat previously patients in therapy looking agent, anti-VEGF an with ed and durability increased of signs for investigational the with efficacy best did who patients The drug. treated those were therapy this with anti-VEGF an with sequentially, ALG-1001. by followed agent those were study the drove really to resistant previously were who suggest monotherapy, anti–VEGF-A ratio to treatment with either OPT- either with treatment to ratio aflibercept with combination in 302 monotherapy. aflibercept to or ALG-1001 peptide integrin first-in-class a is to binds molecule the therapy; sites receptor integrin specific angiogenic multiple affects and The inflammation. and pathways phase as or combination in ALG-1001 OPT-302 (0.3 mg, 1.0 mg, (0.3 OPT-302 This aflibercept. with combination in ran 2a phase a by followed be will expansion dose controlled domized, 2:1 a in allocated patients with trial DRUGS OPT-302, RG7716 ALG-1001, KVD001, COMBINATION - nesvacumab + aflibercept, - - -
6 2018 conbercept brolucizumab, abicipar pegol, MARCH
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NEXT-GENERATION ANTI–VEGF-A DRUGS The Future of Treatment for Diabetic Eye Disease? of Treatment The Future This “trap” molecule binds and binds molecule “trap” This Other mechanisms of action are alsoare action of mechanisms Other ing OPT-302 (Opthea) with currently with (Opthea) OPT-302 ing may therapies anti–VEGF-A available Patients inhibition. VEGF true achieve multicenter a in enrolled being are part first The trial. clinical phase1b/2a of evaluation dose-escalation a be will OPT-302 OPT-302 VEGF-C of activity the neutralizes bind and blocking by VEGF-D and and VEGFR-2 receptors the to ing combin that thought is It VEGFR-3. phase 3 development. 3 phase OTHER COMBINATION AGENTS with combination in explored being therapy. anti-VEGF together as a single intravitreal injec intravitreal single a as together with compared were These tion. Results monotherapy. aflibercept differen sufficient provide not did and combined the between tiation warrant to treatments monotherapy formulation showed signals of of signals showed formulation durability. and efficacy increased evaluated study RUBY 2 phase The nesvacumab of doses different two aflibercept, with combination in administered were which of both as described above. A phase 1 1 phase A describedabove. as co- thisof study dose-escalation RETINA TODAY
54 DIABETIC EYE DISEASE s DIABETIC EYE DISEASE s
5. A phase 2 study of RO6867461 in participants with center-involving diabetic macular edema (CI-DME) (BOULEVARD). SUBCUTANEOUS TIE2 ACTIVATOR https://clinicaltrials.gov/ct2/show/NCT02699450. AKB-9778 (Aerpio Pharmaceuticals) is a Tie2 activa- 6. Regeneron provides update on EYLEA (aflibercept) injection and nesvacumab (Ang2 antibody) combination program [press release]. Regeneron Pharmaceuticals. November 27, 2017. https://www.prnewswire.com/news-releases/regener- tor that takes a different approach, aiming to prevent the on-provides-update-on-eylea-aflibercept-injection-and-nesvacumab-ang2-antibody-combination-program-300561643. development of DME rather than treat existing disease. html. Accessed February 8, 2018. 7. Kaiser PK. Topline results from prospective, double-masked, placebo controlled phase 2b clinical study evaluating AKB-9778 is self-administered subcutaneously. In the phase Luminate in patients with diabetic macular edema. Paper presented at: Association for Research in Vision and Ophthalmol- 2a proof-of-concept TIME-2 study, AKB-9778 monotherapy ogy Annual Meeting; May 8, 2017; Washington, DC. 8. Boyer DS. Human phase 2 clinical studies update. DEL MAR Phase 2B. Paper presented at: Angiogenesis 2017; February showed the ability to improve underlying diabetic retinop- 11, 2017; Miami, FL. athy by 2 or more steps in both eyes of 10% of patients.12 9. A phase I single ascending dose study of the intravitreal plasma kallikrein inhibitor KVD001 in subjects with DME. https://clinicaltrials.gov/ct2/show/NCT02193113. The company is now recruiting patients with moderate to 10. Wykoff CC. Suprachoroidal triamcinolone acetonide with and without intravitreal aflibercept for diabetic macular severe nonproliferative diabetic retinopathy for a phase 2b edema: Phase 1/2 HULK study. Paper presented at American Academy of Ophthalmology Retina Subspecialty Day; November 10-11, 2017; New Orleans, LA. study (TIME-2b) studying AKB-9778 administered once or 11. Suprachoroidal CLS-TA with intravitreal aflibercept versus aflibercept alone in subject with diabetic macular edema twice daily versus placebo. (TYBEE). https://clinicaltrials.gov/ct2/show/NCT03126786. 12. Campochiaro PA, Khanani A, Singer M, et al; TIME-2 Study Group. Enhanced benefit in diabetic macular edema from AKB-9778 tie2 activation combined with vascular endothelial growth factor suppression. Ophthalmology. THE FRONTIER IN DME TREATMENT 2016;123(8):1722-1730. Although anti–VEGF-A drugs have revolutionized the treatment of DME, a large unmet need remains. There is great opportunity to change the treatment paradigm for this PRAVIN U. DUGEL, MD chronic disease with the next generation anti–VEGF-A drugs n Managing Partner, Retinal Consultants of Arizona, Phoenix, Arizona; Clinical and combination drugs currently in development. n Professor, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California; Physician Executive Director, 1. Novartis brolucizumab (RTH258) demonstrates superiority versus aflibercept in key secondary endpoint measures of Banner Eye Institute, Phoenix, Arizona; and Member of the Retina Today editorial disease activity in nAMD, a leading cause of blindness [press release]. Novartis. November 10, 2017. https://www.novartis. com/news/media-releases/novartis-brolucizumab-rth258-demonstrates-superiority-versus-aflibercept-key. Accessed advisory board February 8, 2018. n [email protected] 2. Hassan TS. A multicenter, double masked phase 2 clinical trial evaluating abicipar pegol for diabetic macular edema. Paper presented at: American Academy of Ophthalmology Annual Meeting; October 14-18, 2016; Chicago, IL. n Financial disclosure: Consultant (Bausch + Lomb, Genentech, Alcon, Novartis, 3. Safety and efficacy by multiple injection of KH902 in patients with diabetic macular edema (DME) (Frontier-1). https:// Regeneron, Ophthotech, Acucela, Aerpio, Graybug Vision); Minor Stockholder (Aerpio, clinicaltrials.gov/ct2/show/NCT01324869. 4. Safety and efficacy study of conbercept in diabetic macular edema (DME) (Sailing). https://clinicaltrials.gov/ct2/show/ Ophthotech); Scientific Advisory Board (Genentech, Novartis, Graybug Vision) NCT02194634.