The Future Looks Bright: The Therapeutics Pipeline for Diabetic Retinopathy New agents, new modalities, different dosages, all now in clinical trials. BY JOHN HINKLE, MD, AND JASON HSU, MD lreatments for diabetic retinopathy (DR) and diabetic every 4 weeks for 16 weeks, then every 8 weeks thereafter. All macular edema (DME) have made tremendous study arms will be continued for 100 weeks. advances in recent decades, but modalities with better Primary outcome data for RHINE and YOSEMITE are efficacy and longer durability are still needed. Many expected at the end of 2020. ongoing trials are aiming to validate new treatment options.T These range from new drugs to advances in dosing Brolucizumab or administration of established pharmaceuticals to entirely Positive results in the HAWK and HARRIER trials in new modalities. In this article, we provide an overview of patients with AMD led to the FDA approval of brolucizum- some phase 2 and 3 studies (Table) that, if successful, may ab-dbll (Beovu, Novartis) for that indication. revolutionize the treatment of DR and DME. The safety and efficacy of brolucizumab for treatment of DME is now being investigated in three phase 3 trials PHASE 3 STUDIES (NCT03481634). The potential benefits of brolucizumab Faricimab stem from the low molecular weight of the drug, allowing RHINE (NCT03622593) and YOSEMITE (NCT03622580) the injection of a much higher molar dose compared with are two phase 3 clinical trials designed to evaluate the effica- currently available therapeutics. cy of intravitreal injections of faricimab (Roche) for the treat- KESTREL (NCT03481634) is a randomized, double-masked, ment of DME in more than 900 participants each. Faricimab noninferiority study including participants with type 1 or is a humanized immunoglobulin G antibody against two type 2 diabetes with VA of 20/32 to 20/320 and abnormally targets: VEGF-A and angiopoietin-2 (Ang-2). VEGF upregu- increased CST on OCT. Individuals who have previously lates Ang-2, which further destabilizes retinal vasculature and undergone any treatment for DME or have proliferative increases inflammation. disease are excluded. The experimental arms of the studies Patients with type 1 or type 2 diabetes, abnormally increased central subfoveal thickness (CST), and VA of 20/40 to 20/320 at baseline are eligible for inclusion. The trials AT A GLANCE exclude patients who have high-risk proliferative DR (PDR) or have received anti-VEGF treatment within the preceding s Multiple trials are under way with the promise of 3 months. The primary endpoint for both studies is change advancing treatment for diabetic eye disease. in BCVA from baseline to 1 year. s In two arms of each trial, participants receive injections In addition to novel therapeutics, some trials are of faricimab. Both experimental arms begin treatment with assessing alternative treatment schedules, delivery 6.0 mg injections dosed every 4 weeks for 20 weeks. Thereafter, systems, and dosages. one arm is treated every 8 weeks and a second experimental s arm is treated every 12 weeks as long as the patient’s CST Gene therapy and photobiomodulation are also being does not increase and require more frequent treatment. The investigated. comparison arm is 2.0 mg aflibercept (Eylea, Regeneron) dosed 38 RETINA TODAY | NOVEMBER/DECEMBER 2020 WHAT’S IN THE RETINA PIPELINE? s compare 3.0 mg and 6.0 mg doses of for ocular disease are excluded. The Importantly, patients with DME are brolucizumab given every 6 weeks for primary outcome is change in BCVA excluded from this trial. The primary five injections followed by maintenance from baseline to 12 months. endpoint is the percentage of par- injections every 8 or 12 weeks until Data from the full enrollment ticipants with an improvement of the end of the study. The comparator of 521 patients in KINGFISHER are greater than 2 steps from baseline for noninferiority is 2.0 mg aflibercept expected in 2021. on the ETDRS Diabetic Retinopathy dosed every 4 weeks for five injections Severity Scale at 1 year. Participants and then every 8 weeks as maintenance Ranibizumab via PDS will receive two intravitreal 0.5 mg until completion of the study. Two ongoing phase 3 studies are ranibizumab injections before PDS s investigating the safety and efficacy of a insertion, and then the PDS will be WATCH IT NOW new, higher concentration (100 mg/mL) refilled with 100 mg/mL ranibizumab of ranibizumab (Hoffman-La Roche) as every 36 weeks. A comparator arm will delivered via the Port Delivery System undergo regular examinations every (PDS) in DME (PAGODA) and DR 4 weeks until crossing over to receive (PAVILION). The PDS is an intraocular the PDS implant. implant, surgically placed in the pars PAVILION is actively recruiting, plana, that provides continuous delivery aiming for 160 patients. of a medication into the vitreous. The implant can be refilled as needed in an Aflibercept The PDS With Ranibizumab Enters Phase 3 Trials. in-office procedure. Building on the findings of its Protocol BIT.LY/PORT-DELIVERY-SYSTEM PAGODA (NCT04108156) is a non- T, the Diabetic Retinopathy Clinical KESTREL reached full enrollment inferiority trial evaluating PDS with Research Network (DRCR.net) has initi- with 571 patients in March 2020. Study 100 mg/mL ranibizumab compared ated Protocol AC (NCT03321513), a completion is expected in 2021. with intravitreal 0.5 mg ranibizumab phase 3 study to compare initial versus Similarly, KITE (NCT03481660) is an (Lucentis, Genentech) injections in deferred treatment with aflibercept in international, randomized, noninferior- patients with DME. Participants have DME, to look for differences in visual out- ity trial comparing brolucizumab with type 1 or type 2 diabetes, increased comes. In the experimental arm of the aflibercept for DME. This study includes CST, and VA of between 20/32 and study, treatment is initiated with 1.25 mg patients with type 1 or type 2 diabetes 20/320; patients with high-risk PDR are bevacizumab (Avastin, Genentech) and with nonproliferative DR and previ- excluded. One arm of the study begins then patients are changed to 2.0 mg ously untreated DME. Patients in one with four injections of ranibizumab, aflibercept when CST meets the criteria study arm will undergo treatment with administered every 4 weeks. This treat- for switching treatment. In the compara- 6.0 mg doses of brolucizumab given for ment period is followed by insertion of tor arm, 2.0 mg aflibercept is admin- five loading doses followed by mainte- the PDS, which is then refilled every 24 istered from the beginning. The study nance therapy. The comparator is 2 mg weeks with 100 mg/mL ranibizumab. A will evaluate 260 patients with diabetes aflibercept also administered for five second study arm starts with 16 intra- with increased CST and VA of 20/50 loading doses followed by maintenance vitreal injections of 0.5 mg ranibizumab, to 20/320; patients who have recently therapy. The primary outcome is change administered every 4 weeks, followed by received treatments are excluded. The in BCVA from baseline to week 52. insertion of the PDS. Change in BCVA primary outcome is mean change in KITE is still active and has com- from baseline to week 64 is the primary visual acuity at 2 years. pleted enrollment with 361 patients. In endpoint to demonstrate noninferiority, Protocol AC is fully enrolled, and September, Novartis announced that and assessments of the patient experi- completion and outcomes data are preliminary data show the trial met its ence and quality of life are also included. expected at the end of 2021. primary noninferiority endpoint. Recruitment for PAGODA is ongoing, PHOTON (NCT04429503) is a phase KINGFISHER (NCT03917472) is progressing toward a target enrollment 2/3 randomized double-masked study another phase 3 study assessing the of 545 participants, and primary out- designed to investigate the efficacy and effectiveness of brolucizumab in DME. come data are expected in 2021. safety of 8.0 mg aflibercept, referred This trial randomly assigns participants PAVILION (NCT04503551) is to as high-dose (HD) aflibercept, with DME to one of two treatment designed to evaluate the PDS with compared with the current FDA- arms: 6.0 mg of brolucizumab every ranibizumab 100 mg/mL versus approved dose of 2.0 mg aflibercept. 4 weeks or 2 mg of aflibercept every intravitreal 0.5 mg ranibizumab injec- The target population is patients with 4 weeks. Patients with proliferative DR tions in patients with moderately DME, excluding patients with PDR or or prior medical or laser treatment severe or severe nonproliferative DR. recent treatment for DME. In the two NOVEMBER/DECEMBER 2020 | RETINA TODAY 39 s WHAT’S IN THE RETINA PIPELINE? TABLE. AN OVERVIEW OF THE DIABETIC RETINOPATHY PIPELINE Photobiomodulation DRCR.net Protocol AE (NCT03866473) STUDY PHASE TARGET INTERVENTION MECHANISM OF ACTION COMPARATOR DISEASE is assessing the effect of photobiomodu- RHINE/YOSEMITE 3 DME faricimab anti-VEGF and anti-Ang-2 aflibercept lation compared with sham on CST in eyes with center-involved DME and KESTREL 3 DME brolucizumab anti-VEGF aflibercept good vision. In photobiomodulation, KITE 3 DME brolucizumab anti-VEGF aflibercept far red or near infrared light is used KINGFISHER 3 DME brolucizumab anti-VEGF aflibercept to decrease diabetes-induced retinal PAGODA 3 DME PDS (ranibizumab) sustained delivery via ranibizumab IVI inflammation, likely by stimulation of surgical implant mitochondrial cytochrome C oxidase. PAVILION 3 DR PDS (ranibizumab) sustained delivery via ranibizumab IVI In the experimental arm of this study, surgical implant patients will undergo two 90-second Protocol AC 3 DME bevacizumab with anti-VEGF aflibercept sessions each day using a device that deferred aflibercept delivers 670-nm wavelength light, while PHOTON 2/3 DME high-dose aflibercept anti-VEGF aflibercept those in the control arm will receive INFINITY 2 DME ADVM-022 intravitreal anti-VEGF gene aflibercept sham treatment.