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NOVEL TREATMENT STRATEGIES for DIABETIC EYE DISEASE Next-Generation Anti–VEGF-A Drugs and Combination Agents Show Potential

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NOVEL TREATMENT STRATEGIES for DIABETIC EYE DISEASE Next-Generation Anti–VEGF-A Drugs and Combination Agents Show Potential 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, MARCH 2018 | RETINA TODAY 53 s DIABETIC EYE DISEASE The Future of Treatment for Diabetic Eye Disease? NEXT-GENERATION COMBINATION SUPRACHOROIDAL SUBCUTANEOUS ANTI–VEGF-A DRUGS DRUGS CORTICOSTEROID TIE2 ACTIVATOR ALG-1001, KVD001, CLS-TA AKB-9778 abicipar pegol, nesvacumab + aflibercept, brolucizumab, OPT-302, RG7716 conbercept as described above. A phase 1 OPT-302 (0.3 mg, 1.0 mg, and 2.0 mg) KVD001 dose-escalation study of this co- in combination with aflibercept. This KVD001 (KalVista Pharmaceuticals) formulation showed signals of will be followed by a phase 2a ran- is a protease inhibitor that targets increased efficacy and durability. domized, controlled dose expansion plasma kallikrein, a VEGF-independent The phase 2 RUBY study evaluated trial with patients allocated in a 2:1 mediator of DME. Levels of this two different doses of nesvacumab ratio to treatment with either OPT- enzyme are elevated in the vitreous in combination with aflibercept, 302 in combination with aflibercept of patients with DME. According to both of which were administered or to aflibercept monotherapy. the company, plasma kallikrein inhibi- together as a single intravitreal injec- tion targets a pathway independent tion. These were compared with ALG-1001 of VEGF and may therefore serve as an aflibercept monotherapy. Results ALG-1001 (Luminate; Allegro) addition to existing DME treatment did not provide sufficient differen- is a first-in-class integrin peptide options. A phase 1 open-label study tiation between the combined and therapy; the molecule binds to in patients resistant to anti–VEGF-A monotherapy treatments to warrant specific integrin receptor sites monotherapy showed improvement phase 3 development.6 and affects multiple angiogenic with a single injection of KVD001.9 A pathways and inflammation. The phase 2 study will begin enrolling soon. OTHER COMBINATION AGENTS phase 2b DEL MAR study evaluated Other mechanisms of action are also ALG-1001 in combination or as SUPRACHOROIDAL CORTICOSTEROID being explored in combination with sequential therapy with anti-VEGF The injection of a proprietary suspen- anti-VEGF therapy. therapy in patients previously treat- sion formulation of the corticosteroid ed with an anti-VEGF agent, looking triamcinolone acetonide (CLS-TA; OPT-302 for signs of increased durability and Clearside Biomedical) into the supra- This “trap” molecule binds and efficacy with the investigational choroidal space is a novel approach to neutralizes the activity of VEGF-C drug. The patients who did best the treatment of patients with DME. and VEGF-D by blocking and bind- with this therapy were those treated The phase 1/2 exploratory HULK clinical ing to the receptors VEGFR-2 and sequentially, with an anti-VEGF trial examined suprachoroidal CLS-TA VEGFR-3. It is thought that combin- agent followed by ALG-1001.7,8 with and without intravitreal aflibercept ing OPT-302 (Opthea) with currently Most impressive, the patients who and showed signs of increased efficacy available anti–VEGF-A therapies may really drove the study were those and durability with the investigational achieve true VEGF inhibition. Patients who were previously resistant to drug.10 The ongoing phase 2 TYBEE are being enrolled in a multicenter anti–VEGF-A monotherapy, suggest- study is comparing suprachoroidal phase1b/2a clinical trial. The first part ing that such patients may benefit CLS-TA plus intravitreal aflibercept with will be a dose-escalation evaluation of from this treatment with this drug.6,7 intravitreal aflibercept alone.11 54 RETINA TODAY | MARCH 2018 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
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