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PentaVision

Retinal Physician

Article

Sustained-release Tyrosine Kinase Inhibitors for the Treatment of nAMD

New therapies could improve vision and reduce burden.

By: Arshad M. Khanani, MD, MA, FASRS, Carl D. Regillo, MD, FACS, Charles C. Wykoff, MD, PhD, Andrew A. Moshfeghi, MD, Christina Y. Weng, MD, MBA, Sophie J. Bakri, MD, MBA, Peter K. Kaiser, MD
Retinal Physician October 1, 2022 Vol 19, Issue October 2022 Page(s): 23-25, 30-32

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The current standard of care for patients with neovascular AMD (nAMD) and other retinal vascular diseases are intravitreal anti–vascular endothelial growth factor (VEGF) drugs administered at regular intervals. Patients usually maintain, and in about one-third of cases gain, visual function with proper and frequent treatment.1,2 The advent of anti-VEGF injections has revolutionized AMD treatment. However, there are still significant challenges to overcome: (1) the relatively rapid vitreous clearance of VEGF inhibitors requires injections every 1 to 4 months with worse visual outcomes when not maintaining a high enough injection frequency in real-world studies3,4; (2) adverse events are reported by >10% of subjects during 1 to 2 years of anti-VEGF treatment, including rare but vision-threatening complications, such as endophthalmitis, retinal occlusive vasculitis, and retinal detachment5; (3) treatment is associated with a physical and psychological burden for patients and their caregivers6,7; (4) reasons such as affordability (41.1%), lack of vision improvement (28.4%), and social factors can negatively impact adherence to treatment protocols.8 In one study, 22.2% of patients with nAMD were lost to follow-up within 12 months after starting anti-VEGF injections.9 Moreover, there is a considerable societal cost for the burden of care associated with anti-VEGF therapy on health care systems.10

Extending the durability of anti-VEGF therapy can be accomplished by different strategies. One is to develop sustained-release implants and depots, which are degradable polymers loaded with drug and injected into the eye to release the drug over a long period.11 Due to the fragility of biologic drugs, this approach is difficult and, to date, has not been tested in the clinic. Another is to use refillable reservoirs, which are nonbiodegradable ports surgically fixed to the sclera with an intraocular reservoir that can be refilled in the office at regular intervals.12 The Port Delivery System (PDS) with ranibizumab (Susvimo; Genentech) received FDA approval based on the phase 3 Archway trial, in which the primary endpoint of noninferior best corrected visual acuity (BCVA) in patients with PDS compared to monthly intravitreal ranibizumab injections.13 However, 2.0% of patients receiving an implant developed endophthalmitis during the trial, which represents a rate 3-fold higher than patients in the group treated with monthly intravitreal injections of ranibizumab.14 For context, the incidence of endophthalmitis after intravitreal anti-VEGF in large studies is approximately 0.03% to 0.05%.15 Finally, gene therapies, which use viral vectors to deliver anti-VEGF transgenes to target cells that results in continuous anti-VEGF production after a single administration, are being studied in clinical trials in phases 1 to 3.16

The pathophysiology of nAMD is a complex process requiring attention to other pathologic mechanisms than simply extracellular VEGF inhibition.11 Some patients still have poor clinical outcomes despite receiving regular anti-VEGF injections. For those, a new class of drugs with a novel mechanism of action that targets other complementary mediators involved in angiogenesis could potentially improve clinical efficacy.

TYROSINE KINASE INHIBITORS: A NOVEL MECHANISM OF ACTION

Nearly 60 different tyrosine kinase receptors (TKRs) regulate various aspects of cell biology. VEGF and platelet-derived growth factor (PDGF) receptors (VEGFR and PDGFR) are 2 types of TKRs that play an essential role in angiogenesis.17 Although current anti-VEGF drugs bind different isoforms of VEGF in the extracellular space, tyrosine kinase inhibitors (TKIs) bind to the intracellular domains of VEGFR, PDGFR, and other tyrosine kinase receptors, inhibiting downstream activation pathways irrespective of what is in the extracellular space (Figure 1).18 Given the vast number of TKRs in the body, selective TKIs are preferred, because they cause less off-target effects, potentially improving tolerability and theoretically maximizing efficacy.19 TKIs with higher affinity may also be preferred since they enable a similar clinical effect to be achieved with a lower drug dose, which may facilitate smaller or fewer implants and for a longer period of time.

 

Figure 1. Comparison between the mechanism of action of monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). mAbs interact with extracellular domains of tyrosinase kinase receptors or the ligand itself (eg, anti-VEGFs), whereas TKIs bind to intracellular domains of multiple tyrosine kinase receptors. The signaling transduction cascade is not started, inhibiting downstream pathways, and resulting cellular activities. Adapted from: Kim K, Khang D. Past, present, and future of anticancer nanomedicine. Int J Nanomedicine. 2020;15:5719-5743.18
Figure 1. Comparison between the mechanism of action of monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). mAbs interact with extracellular domains of tyrosinase kinase receptors or the ligand itself (eg, anti-VEGFs), whereas TKIs bind to intracellular domains of multiple tyrosine kinase receptors. The signaling transduction cascade is not started, inhibiting downstream pathways, and resulting cellular activities. Adapted from: Kim K, Khang D. Past, present, and future of anticancer nanomedicine. Int J Nanomedicine. 2020;15:5719-5743.18

 

There are several TKIs in clinical development for the treatment of nAMD (Table 1). Sunitinib (GB-102; Graybug Vision) is a TKI that also targets VEGFR (1, 2, and 3) and PDGFR (α and β).17 It has been approved for the treatment of advanced renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST), and pancreatic neuroendocrine tumors (NETs). Vorolanib (EYP-1901; Eyepoint Pharmaceuticals) was developed on the same chemical scaffolding as sunitinib, also targeting all VEGFRs and PDGFRs.20 It is currently being investigated in patients with advanced solid tumors, such as RCC and lung cancer. When vorolanib was administered orally in a phase 2 trial for patients with nAMD, 36% of participants discontinued the study due to nonocular adverse events (AEs), mainly elevations in liver enzymes and gastrointestinal symptoms. Although the trial demonstrated clinical activity of oral vorolanib, the study was suspended due to systemic toxicity.21 Axitinib (OTX-TKI; Ocular Therapeutix and CLS-AX; Clearside Biomedical) is a selective inhibitor of VEGFR (1, 2, and 3) and PDGFR (α and β)22 approved for treating patients with advanced RCC.23 Of the TKIs being evaluated for retinal diseases, axitinib has the highest affinity for VEGFRs. The half maximal inhibitory concentration (IC50) for VEGFR2/KDR is 0.2 nM for axitinib, which is lower (higher affinity) than that for sunitinib (43 nM) or vorolanib (52 nM).24,25

Table 1. Sustained-release Tyrosinase Kinase Inhibitors in Clinical-stage Development for nAMD
  GB-10217,23,45 1 mg EYP-190124,24,46,47 0.44-3.09 mg OTX-TKI22,23,29 0.2-0.6 mg CLS-AX38 0.03-1 mg
Drug Sunitinib Vorolanib Axitinib Axitinib
VEGFR affinity (IC50 in nM)a VEGFR2/KDR: 43 VEGFR2/KDR: 42 VEGFR2/KDR: 0.2 VEGFR2/KDR: 0.2
Delivery methodb 27-gauge intravitreal 22-gauge intravitreal 27-gauge intravitreal 30-gauge suprachoroidal
Polymer mPEG-PLGA microspheres PVA/drug matrix plus a PVA-only coating Cross-linked PEG hydrogel implant Micronized suspension (no polymer)
Degradation by-products lactic acid, glycolic acid, and PEG Erosion (solubilization, not degradable) Water-soluble low-molecular-weight PEG N/A
Number of implantsb N/A 1-3 1 N/A
aA lower number means higher agonist activity.bCurrent state of development.
Abbreviations: IC50, half maximal inhibitory concentration; KDR, kinase insert domain receptor; mPEG, methoxy-polyethylene glycol; nAMD, neovascular age-related macular degeneration; nM, nanomolar; PLGA, polylactic-co-glycolic acid; PVA, polyvinyl alcohol; PEG, polyethylene glycol; VEGFR2, vascular endothelial growth factor receptor 2.

LONGER DURATION OF ACTION WITH SUSTAINED-RELEASE IMPLANTS

Characteristics of the drug, the type of polymer, the shape of the implant or microparticle, and specifics regarding their construction all impact the release rate of the drug. Polymer chemists have most commonly used either microparticles or implants for ocular studies. Implants can be made into different shapes and implanted through 22-gauge to 27-gauge needles or applicators. Microparticles, which range from 1 μm to 1,000 μm in size, can be delivered through even smaller needles but can be more prone to dispersion and migration, especially into the anterior chamber.26 Although solid implants are less likely to migrate, the release kinetics are dependent on polymer factors, including the degradation or erosion mechanism, the surface area of the implant, the solubility and diffusivity of the active agent in the implant matrix, the development of porosity as the matrix degradation proceeds, and implant dimensions.27 The implant size and polymer characteristics limit the amount of drug it can hold. Therefore, large or multiple implants may be needed for some drugs to achieve the release rate and kinetics required for efficacy.28 In the case of EYP-1901, a polyvinyl alcohol (PVA) coating covers the entire surface of the cylinder, aiming to deliver a consistent rate of diffusion of vorolanib out of the insert.28

Drug-release kinetics can also be dissolution-limited or solubility-limited and depend on the drug and polymer properties. Axitinib, in OTX-TKI and CLS-AX, has a lower water solubility than the other TKIs, allowing for dissolution-based controlled drug release.29 Absorbable polymers are temporary and ultimately break down as the drug is released. Biodegradation is a broad term encompassing biological and chemical-based processes that may involve human enzymes, microbial enzymes, and hydrolysis of biodegradable polymers that include hydrolytically and enzymatically susceptible bonds. Synthetic, absorbable polymers used in devices and drug-releasing implants are most commonly chemically (not enzymatically) hydrolyzed. Some implants are composed of bioerodible polymers (eg, PVA) instead, which are physically eroded by solubilization.30

EYP-1901 is a novel bioerodible intravitreal insert containing PVA. Polyvinyl alcohol has been used in FDA-approved commercial products using the Durasert drug delivery technology, including Vitrasert, Retisert, and Yutiq, and its intraocular safety is well established. Retisert contains microcrystalline cellulose, PVA, and magnesium stearate. Vitrasert contains magnesium stearate, PVA, and ethylene vinyl acetate (EVA). Yutiq contains a polyimide tube, PVA, silicone adhesive and water for injection. Neither Vitrasert, Retisert, nor Yutiq are fully erodible intravitreal products, because they contain nonerodable ingredients such as EVA, microcrystalline cellulose, and polyimide, respectively, whereas EYP-1901 contains only erodible components.

Polylactic-co-glycolic acid (PLGA) has been approved for the delivery of drugs in the dexamethasone implant (Ozurdex; Allergan) and bimatoprost implant (Durysta; Allergan). It is important to note that the degradation of polymers like polylactide and PLGA, which is used in GB-102, generates acidic monomers that can decrease the pH, resulting in a local acidic microenvironment that may potentially be harmful to intraocular structures.31 The bimatoprost implant is only approved for a single use. Poly(ethylene-glycol) (PEG) hydrogel is one of the most used polymers for drug delivery due to its water solubility, flexibility, and neutral surface charge. Hemophilia, phenylketonuria, lymphoblastic leukemia, and acromegaly, as well as hepatitis B and C, are just some of the clinical indications for commercially available PEG-based pharmaceutical systems.32 The biodegradation of the PEG hydrogel involves a change in its physical state from a cross-linked polymer hydrogel network, swollen with water, to a water-soluble low-molecular-weight polymer that facilitates clearance from the vitreous.30 The OTX-TKI uses PEG hydrogel. Additional details regarding the current development status of each sustained-release TKI are presented in Table 1.

CLINICAL TRIALS

All the sustained-release TKI candidates mentioned in this article are currently in clinical testing. As expected for early-stage clinical drugs, they have shown biological activity, minimal safety concerns (albeit the sample size is limited), and sustained concentrations in target tissues above the IC50 in preclinical animal studies.28,33-37 The study design and key baseline characteristics of clinical trials using sustained-release TKIs are summarized in Table 2, and efficacy and safety results are detailed in Table 3. Most are phase 1 trials designed to test mainly for safety and include a relatively small number of patients and, at times, different doses of the study drug. Given the early stage of clinical development and the fact that certain aspects of each study design and baseline characteristics vary, it is difficult to compare results directly. Nevertheless, it is encouraging to see that, overall, the investigational candidates seem well tolerated, and the efficacy results are promising.

Table 2. Study Design and Baseline Characteristics in Clinical Trials for Sustained-release Tyrosinase Kinase Inhibitors for nAMD
  GB-10240,48 1 mg EYP-190128,46,49 0.44-3.09 mg OTX-TKI25,43 0.2-0.6 mg CLS-AX38 0.03-1 mg
Design Phase 2b, examiner-masked, randomized, parallel-arm design study compared with aflibercept Phase 1, open-label, dose-escalating Phase 1a, open-label, dose-escalating Phase 1b, masked, randomized study compared with aflibercept Phase 1, open-label, dose-escalating
Inclusion criteria Diagnosis of nAMD within 18 months; ≥3 prior anti-VEGF injections; last anti-VEGF treatment within the 21 days; demonstrated response to prior anti-VEGF therapy; BCVA 35-88 letters Diagnosis of nAMD within 18 months; ≥3 prior anti-VEGF injections within 6 months; demonstrated response to prior anti-VEGF therapy; BCVA 25-75 letters Phase 1a: Treatment naïve or previously treated nAMD; CST >300 μm; documented response to prior anti-VEGF therapy (if treated); no BCVA criteria Phase 1b: ≥3 anti-VEGF within past year; last anti-VEGF within 1-4 weeks prior to the screening/baseline injection; demonstrated response to prior anti-VEGF; BCVA 24-83 letters Diagnosis of nAMD within 18 months; active MNV; ≥2 prior anti-VEGF injections; BCVA 20-75 letters
Primary endpoint(s) Time to first rescue Ocular and systemic TEAEs Incidence of TEAEs Incidence of TEAEs and SAEs
Rescue criteria BCVA loss: ≥5 letters vs average of last 2 visits; ≥10 letters vs best on-study. increase in CST: ≥75 μm vs average of last 2 visits; ≥100 μm vs lowest on-study. BCVA loss ≥10 letters from baseline; increase in CST >75 μm from baseline; new or worsening vision-threatening hemorrhage Phase 1a; BCVA loss from previous best value: >15 letters; >10 letters on 2 consecutive visits, evidence of >75 µm CST from previous best value Phase 1b; increase in CST >75 μm from best previous AND loss of ≥5 letters from best previous; loss of ≥10 letters from best VA; new or worsening hemorrhage BCVA loss ≥10 letters from best measurement with exudation; increase in CST >75 µm; vision-threatening hemorrhage
Average age 78.5 (SD: 8.44) 77.4 (range: 67-94) 76.2 (SD: 5.3) Cohort 1: 81.8 (range: 66-93); cohort 2: 78.2 (65-90)
Average BCVA at baseline, ETDRS letters 70.5 (SD: 11.52) 69 (range: 38-85) Phase 1a: 51 + 4.7   Cohort 1: 59.0 (29-74); cohort 2: 65.6 (52-75)
Baseline CFT, µm 221.0 (SD: 47.42) 299 (range: 204-441) Phase 1a: 526 + 49   Cohort 1: 231.2 (208-294); cohort 2: 209.4 (184-227)
Number of implants N/A 1-3 1-3 1 N/A
Abbreviations: BCVA, best-corrected visual acuity; CST, central subfield thickness; ETDRS, Early Treatment Diabetic Retinopathy Study; MNV, macular neovascularization; nAMD, neovascular age-related macular degeneration; SAE, serious adverse event; SD, standard deviation; TEAE, treatment-emergent adverse event; VA, visual acuity; VEGF, vascular endothelial growth factor.
Table 3. Efficacy and Safety Results in Trials of Sustained-release Tyrosinase Kinase Inhibitors for nAMDa
  GB-10240,48 1 mg EYP-190128,46,49 0.44-3.09 mg OTX-TKI25,43 0.2-0.6 mg
Change in BCVA (ETDRS) from baseline (6/12 months) -5.7/-11.5 letters -2.5/-4.1 letters +1.3/+1.1 lettersb
Change in CST from baseline (6/12 months) +44.3/+44.2 µm -3.4/-2.8 µm -103.9/-86.8 µmb
Rescue-free patients at 6/12 months 48%/30% 53%/35% 61%/ongoingb
Dispersion/migration to the anterior chamber 3/21 patients None None
Vitreous floaters 5/21 patients None None
Ocular or systemic SAEs None None None
Time to complete implant disappearance Unknownc Essentially drug-depleted at 8 months, but it is unclear the length of time needed for the PVA coating to erode completely Complete degradation at 9-10.5 months
Note: Phase 1 trials (EYP-1901 & OTX-TKI) have multiple cohorts receiving different doses of the study drug. CLS-AX is not included in this table due to a lack of significant follow-up (>6 months).aRegulatory agencies have made no conclusions about the efficacy and safety results shown in this table.
bInterim results as most patients have not reached 12 months of follow-up.
cData from clinical trials are not available yet. In preclinical studies, the depot is fully resorbed by 12 to 14 weeks.50
Abbreviations: BCVA: best-corrected visual acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; CST: central subfield thickness; PVA, polyvinyl alcohol; SAE: serious adverse event.

CLS-AX has been investigated in a phase 1/2a trial (OASIS) in which 2 cohorts of patients received 0.03 mg to 0.1 mg of CLS-AX administered through suprachoroidal injection, following a single intravitreal aflibercept injection, with an additional cohort planned to receive 0.5 mg of CLS-AX. A preliminary safety overview revealed no serious adverse events (SAEs); no treatment-emergent adverse events (TEAEs) related to aflibercept, CLS-AX, or suprachoroidal injection procedure; no dispersion into the vitreous; and no AEs related to intraocular pressure, inflammation, or vasculitis. No study suspension or stopping rules were met. Efficacy analysis is limited given the absence of a follow-up longer than 3 months and other study limitations.38

GB-102 is currently the only candidate in phase 2b stage of development. The ALTISSIMO trial was initially designed to have 2 dose cohorts of 1 mg and 2 mg, injected every 6 months.39 Based on interim safety analysis, the 2 mg strength was discontinued after the first dose, and patients in that cohort received 1 mg for their second dose instead. In the 1 mg cohort, based on the interim analysis, there were no drug-related SAEs, no TEAEs leading to drug discontinuation, no AEs requiring surgical intervention, and no vision-threatening inflammation. However, drug dispersion was noticed in the clinical trial. In the 1 mg cohort, 4 of 21 patients had intraocular inflammation that resolved with a short course of topical steroids, 3 of 21 patients had transient particles in the anterior chamber, and 5 of 21 patients had vitreous floaters. It is suspected that the particle dispersion caused a decrease in BCVA in some patients. Following the trial results, a third formulation version of GB-102 is being designed to improve aggregation performance of the microparticles and stability.40

EYP-1901 has been studied in a phase 1 trial (DAVIO), with 4 cohorts receiving doses ranging from 0.44 to 3.09 mg. Patients received 1 to 3 intravitreal implants depending on the dose. At 6 and 12 months, 53% and 35% of patients did not require a rescue anti-VEGF injection, respectively, with stable mean BCVA and CSFT. There was a U-shaped dose-response curve with rates of treatment burden reduction in the low, mid, and high doses of 66%, 88%, and 47%, respectively. There were no significant safety findings, no drug-related ocular or systemic SAEs, dose-limiting toxicity, vitreous floaters, endophthalmitis, retinal detachment, implant migration to the anterior chamber, posterior-segment inflammation, occlusive events, or retinal vasculitis. Drug release from the PVA implant is essentially depleted past 8 months, but it is unclear the length of time needed for the implant coat to erode completely.41 Of note, in preclinical studies, the implants were still visible 12 months after injection.28 A phase 2 randomized study (DAVIO 2) of EYP-1901 2.06 mg (2 implants) and 3.09 mg (3 implants) compared to aflibercept in subjects with nAMD is ongoing.42

OTX-TKI was studied in 2 phase 1 studies. The first phase 1a trial included 4 cohorts receiving 0.2 (1 implant) to 0.6 mg (3 implants in early cohorts, 1 implant in later cohorts) of the drug. A notable difference in this study design compared to the other studies mentioned above was the inclusion of both previously treated and treatment-naïve nAMD patients. Similar to the other TKI candidates, OTX-TKI was generally well tolerated with no significant safety findings. There were no ocular SAEs, such as endophthalmitis or retinal detachment, no implant migration to the anterior chamber, no observation of elevated intraocular pressure, and no retinal vasculitis. A preliminary biologic signal of clinically meaningful decrease in the retinal fluid was observed by month 2 in the higher-dose cohorts. Of note, in the highest-dose cohort (0.6 mg), 5 of 6 patients were treatment-naïve, and 80% did not require rescue by month 6, with meaningful reductions in retinal fluid without any anti-VEGF injection. Figure 2 shows one of these participants showing an excellent clinical response without the need for rescue anti-VEGF injections for up to 15 months, demonstrating the potential of TKIs as monotherapy for nAMD patients, with complete resolution of the retinal fluid. The hydrogel matrix of the implant biodegraded by 7.5 to 8 months, and any remaining drug visually cleared by 9 to 10.5 months (single implant of 0.2 mg).25,43 A second phase 1b study with randomization of patients to an OTX-TKI 0.6 mg single implant versus intravitreal aflibercept dosed on label is expected to be reported at the American Academy of Ophthalmology meeting in 2022.44

 

Figure 2. Case study. Preliminary biological signal of efficacy in a phase 1 clinical trial for a sustained-release TKI investigational candidate. A treatment-naïve participant diagnosed with neovascular AMD received OTX-TKI 600 µg intravitreally in the left eye. A substantial reduction of central subfield thickness from 484 µm at baseline was seen as early as 2 months (236 μm) after the procedure and was maintained until month 15 (249 μm) without the need for additional anti-VEGF injections.
Figure 2. Case study. Preliminary biological signal of efficacy in a phase 1 clinical trial for a sustained-release TKI investigational candidate. A treatment-naïve participant diagnosed with neovascular AMD received OTX-TKI 600 µg intravitreally in the left eye. A substantial reduction of central subfield thickness from 484 µm at baseline was seen as early as 2 months (236 μm) after the procedure and was maintained until month 15 (249 μm) without the need for additional anti-VEGF injections.

 

FUTURE CONSIDERATIONS

It is encouraging to see a class of drugs with a 2-pronged approach to address the unmet needs of nAMD patients: a novel mechanism of action and prolonged, consistent dosing. Sustained-release TKIs will likely also be helpful for the treatment of other vascular retinal diseases, such as diabetic retinopathy, diabetic macular edema, and retinal vein occlusion. An ideal sustained-release TKI may have the following characteristics: (1) pan-VEGF inhibition by a potent and selective TKI; (2) an implant with no dispersion-associated or inflammation-associated issues, that can be delivered with the smallest possible needle; (3) near-zero order drug release; (4) complete degradation of the implant into constituent components that are well tolerated by the eye at a known and reproducible rate; (5) durable treatment effect (≥6 months) with minimal rescue treatments required; (6) consistent retinal thickness reduction with minimal fluid fluctuations between treatments; (7) stable or improved BCVA (dependent on the enrolled population). The preliminary results from clinical trials show promise that one or more of these investigational candidates meet these criteria and will soon be available in our clinical practices. RP

Arshad M. Khanani, MD, is the director of clinical research at Sierra Eye Associates and a clinical associate professor at the University of Nevada in Reno, Nevada. Dr. Khanani reports consultancy to Abbvie, Adverum Biotechnologies, AGTC, Aldebaran Therapeutics, Alimera Sciences, Apellis Pharmaceuticals, Arrowhead Pharmaceuticals, Asclepix Therapeutics, Aviceda Therapeutics, Bausch + Lomb, Broadwing Bio, Cholgene, 4DMT, Eyepoint Pharmaceuticals, Frontera Therapeutics, Gemini Therapeutics, Genentech, Glaukos, Graybug Vision, Gyroscope Therapeutics, Iveric Bio, Janssen, Kartos Therapeutics, Kato Pharma, Kriya Therapeutics, Kodiak Sciences, Ocular Therapeutix, Oculis, Ocuterra Therapeutics, Opthea, Oxurion, Nanoscope Therapeutics, Novartis, Perfuse Therapeutics, Polyphotonix, Recens Medical, Regeneron, Retrotope, Regenxbio, Revopsis, Roche, Stealth Biotherapeutics, Thea, Unity Bio, and Vanotech.

Carl D. Regillo, MD, is a professor of ophthalmology at Thomas Jefferson University, chief of the retina service of Wills Eye Hospital, and founder of the Wills Eye Clinical Retina Research Unit in Philadelphia, Pennsylvania. Dr. Regillo reports consultancy to Adverum Biotechnologies, Allergan, Annexon Biosciences, Apellis Pharmaceuticals, Bausch + Lomb, Clearside Biomedical, Coherus Biosciences, Eyepoint Pharmaceuticals, Genentech, Graybug Vision, Iveric Bio, Kodiak Sciences, Merck, NGM Biopharmaceuticals, Notal Vision, Novartis, Opthea, Regenxbio, Stealth Biotherapeutics, Takeda, Thea Pharma, and Zeiss Meditec.

Charles C. Wykoff, MD, PhD, is director of research at Retina Consultants of Texas, chairman of research and clinical trials committee at Retina Consultants of America, and deputy chair for ophthalmology at Blanton Eye Institute of Houston Methodist Hospital in Houston, Texas. Dr. Wykoff reports consultancy to 4DMT, Abbvie, Adverum Biotechnologies, AGTC, Annexon Biosciences, Apellis Pharmaceuticals, Bayer, Boehringer Ingelheim, Clearside Biomedical, Curacle, Eyepoint Pharmaceuticals, Genentech, Gyroscope Therapeutics, IACTA, Iveric Bio, Janssen, Kato, Kiora Pharmaceuticals, Kodiak Sciences, Merck, NGM Biopharmaceuticals, Novartis, Ocular Therapeutix, Opthea, Regeneron, Regenxbio, Roche, Stealth Biotherapeutics, and Valo.

Andrew A. Moshfeghi, MD, is an associate professor of clinical ophthalmology, director of clinical trials, and medical director at the University of Southern California, Roski Eye Institute in Los Angeles, California. Dr. Moshfeghi reports consultancy to Allergan, Genentech, Graybug Vision, Novartis, Ocular Therapeutix, Placid0, Pr3vent, Regeneron, and Regenxbio.

Christina Y. Weng, MD, MBA, is a professor of ophthalmology at the Baylor College of Medicine in Houston, Texas. Dr. Weng reports consultancy to Alcon, Alimera Sciences, Allergan/Abbvie, Dutch Ophthalmic Research Center, Genentech, Novartis, Regeneron, and Regenxbio.

Sophie J. Bakri, MD, MBA, is chair of the department of ophthalmology at Mayo Clinic in Rochester, Minnesota, and holds the Whitney and Betty MacMillan Professorship in Ophthalmology in Honor of Robert R. Waller, MD. Dr. Bakri reports consultancy to Abbvie, Adverum Biotechnologies, Alimera Sciences, Allergan, Apellis Pharmaceuticals, Eyepoint Pharmaceuticals, Ilumen, Iveric Bio, Kala, Genentech, Novartis, Outlook Therapeutics, Pixium, Rejuvitas, Revana, and Roche.

Peter K. Kaiser, MD, is the Chaney Family Endowed Chair in Ophthalmology Research and a professor of ophthalmology at Cole Eye Institute of Cleveland Clinic Lerner College of Medicine in Cleveland, Ohio. Dr. Kaiser reports consultancy to Affamed Therapeutics, Applied Genetic Technologies Corporation (AGTC), Allegro Ophthalmics, Allergan, Allgenesis, Asclepix Therapeutics, Bayer, Bausch + Lomb, Biogen Idec, Boerenger Ingelheim, Clearside Biomedical, Coherus Biosciences, Delsitech, Dompe, Innovent, Iveric Bio, Jcyte, Chengdu Kanghong Pharmaceuticals, Kodiak Sciences, Kriya Therapeutics, Novartis, Ocular Therapeutix, Regeneron, Regenxbio, Samsung Bioepis, SGN Nanopharma Inc, and Stealth Biotherapeutics. Reach Dr. Kaiser at pkkaiser@gmail.com.

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