OTT166 in Diabetic Retinopathy (DR)

OTT166-201 A Phase 2 Randomized, Double-Masked, Vehicle-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of OTT166 Ophthalmic Solution in the Treatment of Diabetic Retinopathy (DR)

This study will evaluate the safety and efficacy of OTT166 Ophthalmic solution in participants with Diabetic Retinopathy.

This randomized, double-masked, vehicle controlled, phase 2 study will evaluate the safety and efficacy of OTT166 ophthalmic solution in participants with diabetic retinopathy and select an optimum dosing regimen for Phase 3 pivotal trials. Approximately 210 participants diagnosed with moderately severe to severe non-proliferative diabetic retinopathy (NPDR) or mild proliferative diabetic retinopathy (PDR) and who are treatment naïve (ie, no prior anti-vascular endothelial growth factor [anti-VEGF] or laser [focal, grid, pan-retinal photocoagulation (PRP)] administered) will be randomized into the following groups: OTT166 Cohort 1, OTT166 Cohort 2, Vehicle control Cohort 1, Vehicle control Cohort 2.

Diabetic Retinopathy, Ophthalmic solution, Non-proliferative diabetic retinopathy, Proliferative diabetic retinopathy

Proportion of participants who have improved by ≥ 2 steps from baseline in Diabetic Retinopathy Severity Scale (DRSS) scores

To characterize the efficacy of topical OTT166 in participants with DR. Difference between treatments in proportion of participants achieving ≥ 2 steps improvement from baseline as determined by central reading center assessment using the DRSS will be assessed. Greater DR scores confer a greater chance of converting to PDR. Higher scores are also associated with decreased vision-related quality of life measures.

To determine if topical OTT166 will prevent or delay the occurrence of visually threatening complications (VTC). VTC is defined as the composite outcome of PDR (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and/or anterior segment neovascularization (ASNV) (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle).

To determine if topical OTT166 will prevent or delay the occurrence of VTC. VTC is defined as the composite outcome of PDR (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and/or ASNV (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle).

To determine if topical OTT166 will prevent or delay the occurrence of VTC. VTC is defined as the composite outcome of PDR (inclusive of participants who have vitreous hemorrhage or tractional retinal detachment believed to be due to PDR) and/or ASNV (participants with neovascularization of the iris [at least 2 cumulative clock hours], and/or definitive neovascularization of the iridocorneal angle). Time to develop PDR worse than mild (DRSS 65 and above) will be assessed.

To determine if topical OTT166 will prevent or delay the occurrence of CI-DME. CI-DME is defined as the presence of fluid in the central subfield in participants who have no fluid at baseline or CST> 325 μm.

To determine if topical OTT166 will prevent or delay the occurrence of CI-DME. CI-DME is defined as the presence of fluid in the central subfield in participants who have no fluid at baseline or CST> 325 μm.

To determine the effect of OTT166 on DRSS in participants with moderately severe to severe NPDR and mild PDR treated with topical OTT166. Change in DRSS steps is defined as DR worsening or improving by 1, 2, or ≥ 3 steps.

Proportion of participants with mild PDR (DRSS score 61) at baseline who regress to NPDR (DRSS score ≤ 53)

To determine the effect of OTT166 on DRSS in participants with moderately severe to severe NPDR and mild PDR treated with topical OTT166.

To determine the effect of OTT166 on DRSS in participants with moderately severe to severe NPDR and mild PDR treated with topical OTT166. Change in DRSS steps is defined as DR worsening or improving by 1, 2, or ≥ 3 steps.

To determine the effect of OTT166 on BCVA in participants with moderately severe to severe NPDR and mild PDR. BCVA will be assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) letters score. A higher score represents better functioning.

To determine the effect of OTT166 on BCVA in participants with moderately severe to severe NPDR and mild PDR. Proportion of participants who gained/lost lines of BCVA (± 5, 10, and 15 ETDRS letters) will be assessed.

To determine the effect of OTT166 on BCVA in participants with moderately severe to severe NPDR and mild PDR. BCVA will be assessed by ETDRS letters score. A higher score represents better functioning.

To determine the effect of OTT166 on CST in participants with moderately severe to severe NPDR and mild PDR. CST will be assessed by optical coherence tomography (OCT).

To determine the effect of OTT166 on CST in participants with moderately severe to severe NPDR and mild PDR. CST will be assessed by OCT.

To determine the effect of OTT166 on the need for rescue therapy in participants with moderately severe to severe NPDR and mild PDR.

To determine the effect of OTT166 on the need for rescue therapy in participants with moderately severe to severe NPDR and mild PDR. Time required to meet rescue therapy criteria will be assessed.

Inclusion Criteria: Men or women ≥ 18 years of age with type 1 or 2 diabetes mellitus who have moderately severe to severe NPDR [DRSS levels 47 or 53], or mild PDR [DRSS level 61] NVE < 0.5 DA in 1 + quadrants], in whom PRP and/or anti-VEGF IVT can be safely deferred for at least 6 months per the Investigator BCVA ETDRS letter score in the study eye of ≥ 69 letters (approximate Snellen equivalent of 20/40 or better) Normal foveal contour Treatment naïve (ie, no previous anti-VEGF or steroid treatment or PRP or laser) Willing and able to return for all study visits and comply with study-related procedures Able to adhere to the study dosing requirements Understands and signs the written Informed Consent Form Exclusion Criteria: CST of > 325 μm a. Fluid in the central subfield is allowed so long as CST is ≤325 μm Any prior focal or grid laser photocoagulation or any prior PRP in the study eye as it pertains to treatment of DME or DR (peripheral retinal hole treated with laser is allowed) Eyes with DRSS score 61 with fibrous proliferations at disc or fibrous proliferations elsewhere a. DRSS score 61B with NVE only is allowed. Any sign of fibrosis proliferation is exclusionary Any prior systemic anti-VEGF treatment or IVT anti-VEGF treatment in the study eye Any prior intraocular steroid injection in the study eye, inclusive of Iluvien® and Retisert® a. History of Ozurdex® and triamcinolone use prior to 12 months before study enrollment is allowed Current ASNV, vitreous hemorrhage, or tractional retinal detachment visible at the screening assessments in the study eye Uncontrolled glaucoma or ocular hypertension in the study eye defined as an IOP > 25 mmHg regardless of concomitant treatment with IOP-lowering medications Hypertension defined as systolic > 180 mmHg or > 160 mmHg on 2 consecutive measurements (during the same visit) or diastolic > 100 mmHg Screening HbA1c blood test > 12.0% Renal failure (stage 4 or end-stage), dialysis, or history of renal transplant History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect interpretation of the results of the study or render the participant at high risk for treatment complications Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months Epiretinal membrane, posterior hyaloidal traction, and/or vitreomacular traction in the study eye as determined to be significant by the Investigator Previous pars plana vitrectomy in the study eye Any intraocular surgery in the study eye within 90 days (3 months) prior to study enrollment YAG laser treatment in the study eye within 90 days prior to study enrollment Concomitant use of any topical ophthalmic medications in the study eye, including dry eye or glaucoma medications, unless on a stable dose for at least 90 days prior to study enrollment and expected to stay on stable dose throughout study participation. Topical eyedrops are allowed but not within ±10 minutes of study drop application Contact lens use from time of screening throughout the study Central corneal changes from dry eye that are visually significant and/or Sjogren's syndrome Visually significant Fuchs endothelial dystrophy or other diagnosed conditions of corneal compromise including Anterior Basement Membrane Dystrophy, or any corneal dystrophy affecting central vision (peripheral processes are not exclusionary) Chronic or recurrent uveitis in the study eye Ongoing ocular infection or inflammation in either eye A history of cataract surgery complicated by vitreous loss in the study eye Congenital eye malformations in the study eye A history of penetrating ocular trauma in the study eye Cognitive impairment that, in the opinion of the investigator, could compromise compliance with the requirements of the study Females of childbearing potential (ie, who are not postmenopausal for at least 1 year or surgically sterile for at least 6 weeks prior to Visit 1 - Screening/Randomization) who are lactating, or who are pregnant as determined by a positive serum pregnancy test at Visit 1 -Screening/Randomization. Women of childbearing potential must agree to use acceptable methods of birth control throughout the study a. Women who are breastfeeding or who have a positive serum hCG/urine pregnancy test at the screening or BL Visit Females and males of childbearing potential unwilling or unable to utilize the following acceptable methods of birth control: tubal ligation, transdermal patch, intrauterine devices/systems, oral/implantable/injectable or contraceptives, diaphragm or cervical cap with spermicide, or vasectomized partner for females; condoms with spermicidal agent and vasectomy for males; or sexual abstinence for males and females Participation in any other investigational device or drug clinical research study within 12 weeks of Visit 1 - Screening/Randomization and during the duration of enrollment Contraindication to the study medications or fluorescein dye Other ocular pathologies that, in the investigator's opinion, would interfere with the participant's vision in the study eye Ocular media of insufficient quality to obtain fundus photographs, fluorescein angiography, and OCT images in the study eye Concomitant use of Semaglutide (Wegovy™, Ozempic®, Rybelsus®) or Thiazolidinediones (Actos®, Avandia®) within 12 months prior to Visit 1 (allowed if a stable dose has been established for at least 1 year of use) a. Plans to start concomitant use of Semaglutide or Thiazolidinediones during the study duration is exclusionary