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Ophthalmic Surgery, Lasers and Imaging Retina, 2022;53(10):553–560
Published Online: by:2



To evaluate the safety, tolerability, and biological activity of a topical selective integrin inhibitor (OTT166) eyedrop administered BID for diabetic retinopathy (DR) and diabetic macular edema (DME).


A prospective, multicenter, randomized, double-masked Phase 1b study. Subjects with nonproliferative DR and DME with central subfield thickness (CST) > 325 microns were randomized to OTT166 eyedrops (2.5% or 5%) BID for 28 days. Subjects were followed for an additional 28 days after treatment cessation.


Forty-four subjects were enrolled. No drug-related serious adverse events (SAEs) and two drug-related adverse events (AEs) were reported. OTT166 was well-tolerated with no evidence of ocular toxicity. Best-corrected visual acuity (BCVA) remained stable. Mean central retinal thickness (CRT) overall was variable: +12.8/+1.8 microns at Day 28 (end of treatment) and −50.3/+5.5 microns at Day 56 (end of study) for the 2.5% and 5% groups, respectively. Median CRT overall demonstrated consistent reduction by end of study: −39.0/−16.5 microns for the 2.5% and 5% groups, respectively. Median responses were greater in the treatment-naïve group (−41.5/−26.0 microns for the 2.5% and 5% groups, respectively). Thirty-seven percent of ‘responder’ subjects exhibited a mean reduction in CRT of 46.6 microns on optical coherence tomography (OCT) at end of treatment (Day 28) which persisted to end of the study (Day 56) – mean reduction of 67.4 microns, suggesting a durable effect.


OTT166 eyedrops were safe, well-tolerated, and demonstrated biological activity in 37% of responders. These results warrant further evaluation of OTT166 eyedrops.

[Ophthalmic Surg Lasers Imaging Retina 2022;53:553–560.]


Diabetic retinopathy (DR) and diabetic macular edema (DME) are leading causes of new cases of legal blindness among working-age Americans representing leading causes of blindness in this age group worldwide. An estimated 31 million people have vision-threatening DR or DME.1 While DR and DME are leading causes of vision loss, early treatment may be effective in limiting damage to the retina.2 Current treatments for DR and DME include intravitreal anti-vascular endothelial growth factor (VEGF) agents, intravitreal or periocular steroids, laser photocoagulation, and tight glycemic control. PANORAMA, DRCR. net Protocol W and other trials have shown that VEGF inhibition can lead to improvements in DRSS scores, lower rates of progression to vision threatening complications or proliferative disease, and improvement in retinal ischemia.3–7 However, necessity for long-term, repeated, invasive therapy to achieve these outcomes can pose challenges that could be mitigated if noninvasive treatment options were available.7 Undertreatment of DR and DME are prevalent, despite increasing recognition that early and regular treatment are important to halting disease progression and preserving vision.3,7 With the rapid expansion of advanced diagnostics that can detect earlier disease and promise of longer term and less invasive therapeutics, early treatment of DR may lead to lower rates of vision-threatening complications, proliferative disease, and ultimately better long-term visual acuity.

The pathology of DR and DME starts at the blood-retinal barrier. The loss of pericytes along the retinal vasculature leads to obstruction or leakage from vessels creating areas of retinal ischemia and inflammation.8 Vascular damage and leakage is mediated by many pathways, including VEGF, fibroblast growth factor (FGF), and platelet derived growth factor (PDGF).9 Beyond ‘watch-and-wait,’ advocated for certain degrees of DR severity in the current American Academy of Ophthalmology's Preferred Practice Pattern on Diabetic Retinopathy, intravitreal anti-VEGF is the first-line treatment of DME and is effective in patients with both nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).4,10,11 Despite efficacy of anti-VEGF treatment, there remain challenges, including undertreatment and partial response to therapy. Intravitreal corticosteroids are the second line medical treatment for DME and while effective, have significant safety considerations including cataract formation and elevation of intraocular pressure (IOP). Laser treatments are used in PDR, high risk NPDR, and DME12 although use in patients with DME has decreased as pharmacotherapies have offered more efficacious alternatives. Nonetheless, these are still part of the treatment armamentarium and have well-known side effects. For example, pan-retinal photocoagulation (PRP) may induce DME or can lead to visual field restriction and compromised functional vision while driving at night.

Integrins are a large family of dimeric transmembrane cell surface receptors which mediate cell adhesion, motility, migration, and proliferation.13 Arginyl-glycylaspartic acid (RGD) binding integrins are involved in key disease hallmarks of common retinal diseases such as DR, DME and neovascular age-related macular degeneration (nvAMD). There is compelling evidence that RGD-binding integrins are important modulators of chronic inflammation (or para-inflammation), retinal permeability and exudation, neovascularization and fibrosis.14 For example, integrin αvβ3 activation has been implicated in angiogenesis and exudation.15–17 In αvβ6-knock-out mice, reductions in ocular fibrosis have been reported,18 suggesting an antifibrotic effect with αvβ6 integrin inhibition. These specific integrin-mediated pathways could potentially be key targets in certain aspects of retinal disease.

OTT166 is a highly potent and selective small molecule inhibitor of key RGD binding integrins including αvβ3, αvβ6, and αvβ8, which collectively contribute to increased angiogenesis, exudation, inflammation, and fibrosis.14 Due to its physiochemical properties, including incorporation of fluorine atoms in specific positions on the molecule, OTT166 penetrates the conjunctiva and transverses the sclera and choroid, distributing to the retina from topical application. OTT166 has demonstrated pharmacologic effects in animal models of neovascularization, vascular leakage, and angiogenesis.14,19

The Phase 1b study reported herein evaluated two dose levels of OTT166 eyedrops given twice daily to subjects with DR/DME for 28 days, with an additional 28-day post-treatment observation period.

Patients/Materials and Methods

This study was registered at (NCT02914613) and conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization. The collection and evaluation of all protected patient health information was performed in a Health Insurance Portability and Accountability Act-compliant manner. The study was conducted at six sites across the United States and institutional review board approval was obtained prior to commencement. Informed consent was obtained prior to performing the procedure, including permission for publication of all photographs and images included herein.

Study Subjects

Subjects were included if they signed informed consent, were over the age of 18, not pregnant, and had diabetic retinopathy with a clinical diagnosis of DME with a best-corrected visual acuity (BCVA) between 78 and 25 letters and a central retinal thickness (CRT) at least 325 microns on spectral domain (SD)-optical coherence tomography (OCT). Subjects that were either treatment-naïve or had prior anti-VEGF IVT were selected to provide a broad assessment of safety and tolerability in a potential treatment population. The required anti-VEGF washout period was typical for other DME clinical studies and included 30 days for bevacizumab and ranibizumab and 60 days for aflibercept. Thirty (68%) of the 44 subjects that were enrolled were treatment-naïve. Subjects were excluded from the study if they had active proliferative diabetic retinopathy, active neovascularization, uncontrolled glaucoma, uncontrolled hypertension, a hemoglobin A1c greater than 12%, prior intravitreal implants during time periods, other history of vitrectomy or vitreoretinal pathology which may confound the study. Subjects with PRP in the study eye within 4 months of screening or with focal macular laser any time in the past were excluded. Treatment with fluocinolone intravitreal implants within 3 years of screening or dexamethasone intravitreal implants within 6 months of screening were excluded.

Study Design and Treatment

Eligible subjects were randomized to either the 2.5% or 5% OTT166 dose groups and asked to instill the OTT166 eyedrop into the study eye twice daily for 28 days. Pre-clinical toxicology studies had only been conducted through four weeks, which defined duration of dosing for this Phase 1b study. At the time of start of the Phase 2 study, pre-clinical toxicology evaluation had been carried out to 6 months with no local or systemic issues. Evaluations were conducted every 2 weeks for 8 weeks. Rescue therapy with anti-VEGF was allowed for subjects who lost more than 7 letters on BCVA evaluation or had an increase in CRT of greater than 75 microns on OCT. Adverse events, BCVA, OCT, and fundus photography were assessed at each visit. Fluorescein angiography was obtained at baseline and day 28.

Outcome Measures

The study was designed to evaluate the safety of two strengths of OTT166 as evaluated by BCVA, slit lamp and fundus examination, IOP, and adverse events. Potential for biological effect was evaluated by measurement of the CRT on OCT at each visit and independent expert evaluation of OCT scans for each subject in the study to classify subjects as ‘responders’ or ‘nonresponders’ based on clinical impression. OCT images were transferred to a central reading center for CRT measurements.

Statistical Methods

Outcome measures were evaluated in the intent-to-treat (ITT) population. This was an exploratory study and descriptive statistics were used to tabulate and summarize study outcomes. Continuous variables were summarized by descriptive statistics (sample size, mean and standard deviation, minimum and maximum). Discrete variables were summarized by frequencies and percentages. Twenty subjects in each treatment arm were selected as an adequate sample size to distinguish safety differences between dose groups and potential biological effect.


Disposition and Baseline Characteristics

A total of 44 subjects were randomized into the trial. Demographic characteristics were similar among treatment groups, with mean age of 66.2 years of age (Table 1). A slight predominance of males was noted (59.1% of the population). The majority of the subjects were white (81.8%), with 13.6% Black and 4.5% Asian. A higher percentage of Hispanic ethnicity was noted in the 2.5% treatment arm (40.9%) compared to the 5% treatment arm (13.6%). Four subjects (2 at each dose) discontinued the study, three due to withdrawal of consent and one due to an adverse event of a hypersensitivity reaction (Table 2). Mean study drug compliance was 95.3% in the 2.5% treatment arm and 95.5% in the 5% treatment arm as assessed by patient diaries.

Table 1

Table 1 Subject Demographics and Baseline Characteristics

ParameterOTT166 2.5% (N = 22)OTT166 5.0% (N = 22)Overall (N = 44)
Age (years)
  Min, max32, 8552, 8632, 86
Gender, n (%)
  Male11 (50.0%)15 (68.2%)26 (59.1%)
  Female11 (50.0%)7 (31.8%)18 (40.9%)
Race, n (%)
  White18 (81.8%)18 (81.8%)36 (81.8%)
  Black3 (13.6%)3 (13.6%)6 (13.6%)
  Asian1 (4.5%)1 (4.5%)2 (4.5%)
Ethnicity, n (%)
  Hispanic/Latino9 (40.9%)3 (13.6%)12 (27.3%)
  Not Hispanic/Latino13 (59.1%)19 (86.4%)32 (72.7%)
Iris color, n (%)
  Blue4 (18.2%)10 (45.5%)14 (31.8%)
  Brown14 (63.6%)10 (45.5%)24 (54.5%)
  Green2 (9.1%)1 (4.5%)3 (6.8%)
  Hazel2 (9.1%)1 (4.5%)3 (6.8%)
Other clinical parameters
  Mean BCVA (letters)646464
  Mean CRT (microns)389435
  Mean HbA1c7.48.0

SD = standard deviation; BCVA = best-corrected visual acuity; CRT = central retinal thickness

Table 2

Table 2 Subject Disposition (Randomized Subjects)

CategoryOTT166 2.5% (N = 22) n (%)OTT166 5.0% (N = 22) n (%)Overall (N =44) n (%)
Completed study20 (90.9%)20 (90.9%)40 (90.9%)
Subjects withdrawn early from study2 (9.1%)2 (9.1%)4 (9.1%)
Reasons for discontinuation of study
  Subject withdrawal1 (50.0%)2 (100.0%)3 (75.0%)
  AE1 (50.0%)01 (25.0%)

AE = adverse event

Safety and Tolerability

Overall, none of the ophthalmic examinations (eg, IOP, slit-lamp, dilated fundoscopy, FA) were indicative of safety concerns for either OTT166 dose. Additionally, OTT166 was tolerable with no reports of stinging or burning in the study eye. There was one drug-related treatment-emergent adverse event (TEAE) in the study eye and one nonocular drug-related TEAE (Table 3). The ocular drug-related TEAE was development of mild hyperemia in one subject in the 5% treatment arm. In the 2.5% treatment arm, one subject developed a hypersensitivity reaction which included entire body itching. There were no localized ocular signs or symptoms. This subject declined rechallenge with study medication and elected to be discontinued from the trial. Two subjects, one in each treatment group, developed conjunctival hemorrhage in the study eye. There were no other adverse events which occurred in more than one subject. There was no identification of corneal changes or ocular hypertension on examination by slit lamp evaluation and IOP measurement, respectively.

Table 3

Table 3 Summary and Description of Treatment-Emergent Adverse Events (TEAEs)

CategoryOTT166 2.5% (N = 22) n (%)OTT166 5.0% (N = 22) n (%)
No. of subjects with at least 1 drug-related TEAE1 (4.5%)1 (4.5%)
  Ocular (study eye)01 (4.5%); ocular hyperemia
  Ocular (non-study eye)00
  Non-ocular1 (4.5%); hypersensitivity reaction0
No. of subjects who discontinued due to a TEAE1(4.5%)0
  Ocular (study eye)00
  Ocular (non-study eye)00
No. of subjects who required treatment interruption due to a TEAE00

Best-Corrected Visual Acuity

BCVA was evaluated at each time point and remained stable in both groups. The proportion of subjects gaining or losing 4 or more letters was analyzed (Table 4) and is shown in Figure 1 for the combined treatment group. There were no notable trends in either group or the combined group overall.

Table 4

Table 4 Proportion of Subjects Gaining or Losing at Least 4 Letters on the Visual Acuity Chart From Baseline

Gain of 4 or more letters n/N (%)Loss of 4 or more letters n/N (%)
Time PointOTT166 2.5% (N = 22)OTT166 5.0% (N = 22)OTT166 Overall (N = 44)OTT166 2.5% (N = 22)OTT166 5.0% (N = 22)OTT166 Overall (N = 44)
Visit 2/Day 145/21 (23.8%)2/21 (9.5%)7/42 (16.7%)4/21 (19.0%)7/21 (33.3%)11/42 (26.2%)
Visit 3/Day 284/20 (20.0%)4/19 (21.1%)8/39 (20.5%)6/20 (30.0%)4/19 (21.1%)10/39 (25.6%)
Visit 4/Day 425/17 (29.4%)2/20 (10.0%)7/37 (18.9%)3/17 (17.6%)3/20 (15.0%)6/37 (16.2%)
Visit 5/Day 564/17 (23.5%)2/19 (10.5%)6/36 (16.7%)3/17 (17.6%)2/19 (10.5%)5/36 (13.9%)
Figure 1.
Figure 1.

Distribution of change in best-corrected visual acuity over time for combined treatment groups.

OCT Evaluation

Subjects were evaluated at each study visit with SD-OCT. The CRT was evaluated by a central reading center. The mean CRT at baseline in the 2.5% treatment arm was 388.6 microns (range, 139.5 to 929.0) and 435.2 microns (range 226.0 to 1005.5) in the 5% treatment arm. At the end of treatment, day 28, the mean CRT increased by 12.8 microns in the 2.5% treatment arm and 1.8 microns in the 5% treatment arm. At the end of the study, day 56, the mean CRT decreased by 50.3 microns in the 2.5% treatment arm and increased by 5.5 microns in the 5% treatment arm. Median responses at day 56 exhibited more consistent CRT reduction, −39.0 microns in the 2.5% arm and −16.5 microns in the 5% arm. There was no clear dose response in the OCT measurements.

Subjects were enrolled based on the presence of diabetic macular edema, regardless of their prior treatment status (for those subjects who had been treated with anti-VEGF IVT, an appropriate washout was instituted (see Methods section). Table 5 provides means, standard deviations, and median CRT results for baseline and change from baseline at all subsequent visits for the overall subject population, for treatment-naive and treatment-exposed subjects, further divided by exposure to 2.5% and 5% OTTI66. Figure 2 suggests a trend toward greater CRT resolution over time, especially for the median values, and greater in the treatment-naïve group compared to the treatment-experienced group. This suggests that the means are being influenced by outliers in this heterogeneous population and that longer duration of treatment (as will be evaluated in the upcoming Phase 2 clinical trial) may have led to even greater reductions in macular edema. Further, these findings suggest that treating patients earlier in disease progression, before anti-VEGF IVT is needed, may result in greater disease control.

Table 5

Table 5 Mean, Standard Deviation, and Median Change in CRT From Baseline in the Overall Subject, Treatment-Naïve and Non-Naïve Groups, Further Separated by 2.5% and 5% OTT166 Exposure

VisitChange in CRTAll SubjectsAnti-VEGF Naïve SUBJECTSAnti-VEGF Non-Naïve Subjects
Visit 1 - Day 0n2222171656
Visit 2 - Day 14 Change from Baselinen2121171546
Visit 3 - Day 28 Change from Baselinen2019161346
Visit 4 - Day 42 Change from Baselinen1720141436
Visit 5 - Day 56 Change from Baselinen1719141336

SD = standard deviation; CRT = central retinal thickness

Figure 2.
Figure 2.

Relative mean and median change in central retinal thickness from baseline in the overall subject, treatment-narrative and nonnaïve groups, further separated by 2.5% and 5% OTT166 exposure.

OCT images were evaluated by a group of three retina specialists (JSH, DSB, PKK) and classified as either responders or nonresponders based upon their clinical assessment when considering change from baseline in retinal morphology and thickness. Given no apparent dose response in the overall CRT measurements, the two doses were pooled for the responder analysis. The group identified 37% of subjects as responders and 63% as nonresponders. In the responder group, average decrease in CRT was 46.6 microns at day 28 and 67.4 microns at day 56 (Figure 3). In the nonresponder group, average CRT increased by 46.3 and 37.7 microns at days 28 and 56, respectively. The median change from baseline in CRT in the responder group was −47.3 and −60.5 microns at days 28 and 56, respectively. The median change from baseline in CRT in the nonresponder group was 29.0 and −1.5 microns at days 28 and 56, respectively, demonstrating a potential late biological effect in the nonresponder group. Of 14 responders identified, 11 were treatment-naïve and three had received prior anti-VEGF treatment and had completed the mandated washout period. Two representative cases from the responder group are shown in Figure 4.

Figure 3.
Figure 3.

Mean change in central retinal thickness from baseline by responder status. *Statistically significant difference between responders and non-responders (P = .003) at day 28. **Statistically significant difference between responders and non-responders (P = .009) at day 56.

Figure 4.
Figure 4.

Two examples of optical coherence tomography responders.


This Phase 1b trial evaluated safety of a novel, selective integrin inhibitor, OTT166, given topically as an eyedrop twice daily at 2.5% and 5% concentrations for 28 days. OTT166 appears to be generally safe and well-tolerated at both concentrations throughout the study. Slit lamp examination did not reveal any toxicity and visual acuity remained stable.

The study included subjects with DR/DME who were treatment-naïve, those who had received prior treatment with anti-VEGF therapies, and those with prior treatment with intravitreal steroids. Study excluded prior focal laser to the macula. Overall BCVA remained stable and there were no clear dose-response relationships in mean or median CRT responses, although there was a trend toward greater CRT reduction in the treatment-naïve group compared to the treatment-experienced group, suggesting earlier active treatment of DR/DME, before anti-VEGF IVT is required, may provide better disease control.

Of these subjects a subgroup of responders was identified. This subgroup accounted for 37% of the study population and these subjects had an improvement in CRT on OCT, suggesting biological activity in the retina following topical eyedrop administration of OTT166 in some subjects. It is interesting to note there was a demonstrated durability of treatment effect as evidenced by the improvement in median CRT at day 56 (end of study) compared to day 28 (end of treatment) for both responder and nonresponder subjects. This may represent a sequestration and slow elution of OTT166 from the sclera (acting as a reservoir or depot20) over time, as well as possible down-regulation of target receptors for various growth factors in the retina.21

It is unclear why some subjects responded to OTT166, and some did not in this heterogeneous DR/DME patient population. The nonresponders may have had subtherapeutic penetration of the topically delivered drug to the macula. Alternatively, perhaps differing levels of cytokine expression created groups of subjects who either responded or did not respond to the study drug. As noted above, the median CRT results in the nonresponder subgroup did show a trend toward response between day 28 and day 56, indicating that treatment for longer than 4 weeks may result in further morphologic improvement in the DR/DME of this heterogeneous patient population.

The study was limited by the treatment duration of only 28 days and lack of a vehicle control arm. Due to the limited number of subjects enrolled, cause and effect conclusions regarding efficacy of OTT166 cannot be made. However, evidence of biologic activity in this diverse subject population was clearly identified while achieving the overall primary endpoint of safety and tolerability. Formal DRSS evaluation was unable to be conducted due to imaging quality, variability in technique (subjects were not selected for DR severity and, as such, standard 7-field color fundus photos were not obtained consistently) and availability.

Overall, OTT166 eyedrops appear to be safe and well tolerated with the potential for a durable biological effect in patients with DR/DME. A substantial portion of subjects responded on OCT. OTT166 warrants further evaluation in diabetic eye disease. A Phase 2 study is currently underway to evaluate the effect of OTT166 on severity of DR and vision threatening complications, including DME. The design of this study will appropriately power for efficacy conclusions regarding OTT166 for treating DR that cannot be made (nor was the intent) with this Phase 1b study. Results are expected in the first half of 2024.

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