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Safety and efficacy of risuteganib ophthalmic solution in the treatment of dry eye disease: A prospective, randomized, double-masked, vehicle-controlled study
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Received: ,
Accepted: ,
How to cite this article: Donnenfeld E, Holland E, Lindstrom R, Karageozian V, Park J, Shao Z, et al. Safety and efficacy of risuteganib ophthalmic solution in the treatment of dry eye disease: A prospective, randomized, double-masked, vehicle-controlled study. Am J Ophthalmic Clin Trails 2022;5:1.
Abstract
Objectives:
The aim of the study was to compare the safety and efficacy of ALG-1007 (0.125% sodium hyaluronate [SH] + 0.6% risuteganib [RSG] ophthalmic solution) to 0.6% RSG alone, 0.125% SH alone, and vehicle alone in subjects with dry eye disease (DED).
Material and Methods:
Eligible participants aged ≥18 years old with symptoms of DED for ≥ 6 months were randomized into four treatment groups: ALG-1007, RSG, SH, and vehicle. The treatment for all groups was administered one drop twice a day and subjects were evaluated at weeks 2, 4, 8, and 12. Primary efficacy endpoints were change in nasal conjunctival staining and change in Dry Eye Management Scale (DEMS) score from baseline to week 12. Secondary efficacy endpoints were changes in tear breakup time (TBUT), total ocular staining (TOS), inferior corneal staining score, and individual and combined reported symptoms by Visual Analog Scale (VAS), from baseline to week 12.
Results:
All parameters tested and analyzed – nasal conjunctival staining, DEMS, TBUT, inferior corneal staining score, and VAS (combined, burning, discomfort, dryness, foreign body sensation, and photophobia) – improved in all study groups over the 12-week observation period. The greatest improvements in all parameters tested were seen in the ALG-1007 group followed by RSG only, SH only, and then vehicle. Comparison of 12-week change from baseline (CFB) values demonstrated statistically significant differences in all group comparisons for all the measurements done except for comparison of ALG-1007 versus RSG (P = 0.3154) for nasal conjunctival staining. No adverse events were reported.
Conclusion:
0.60% RSG topical ophthalmic solution was effective in improving the signs and symptoms of DED and demonstrated therapeutic properties. ALG-1007, a combination of 0.60% RSG + 0.125% SH, was superior to RSG alone and will provide the most therapeutic benefit to patients with DED. ALG-1007 and RSG were well-tolerated with no drug-related AEs or SAEs reported over a 12-week observation period.
Keywords
Dry Eye Management Scale
Integrin
Keratoconjunctivitis sicca
Ocular staining
Visual Analog Scale
INTRODUCTION
Dry eye disease (DED), also referred to as keratoconjunctivitis sicca, is a “multifactorial disease of the ocular surface characterized by a lack of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation, and neurosensory abnormalities play etiological roles.”[1,2] Approximately 6.8% of the United States adult population was estimated to have diagnosed DED, while another 2.4% was reported to have undiagnosed DED.[3] Together, diagnosed and undiagnosed DED comprise 9.2% of the US population, which amounts to approximately 22.4 million individuals.
Inflammation has been recognized as the fundamental driver for the progression of DED and is the target of existing medications such as topical corticosteroids and the newer prescription FDA-approved therapies for the treatment of DED: Cyclosporine A (Restasis®; Allergan, Irvine, CA, USA and Cequaâ®; Sun Pharmaceutical, Mumbai, India), an immunosuppressive agent, and lifitegrast (Xiidra®; Shire, Lexington, USA), an integrin antagonist that interferes with lymphocyte function-associated antigen-1 – intracellular adhesion molecule-1 (LFA1-ICAM1) interaction.[4,5] Long-term use of these medications may be limited in patients with DED due to the risk of developing secondary ocular disease[6] or due to the development of ocular symptoms which result in discontinuation of use.[7,8]
ALG-1007 (Allegro Ophthalmics, San Juan Capistrano, CA, USA) is a topical form of 0.125% sodium hyaluronate (SH) plus risuteganib (RSG), an integrin regulator that modulates integrin αM and β2 subunits to reduce ocular surface inflammation and mitigate signs and symptoms of DED.[9-11] Regulation of integrin αM and β2 subunits likely results in downregulation of inflammation by interfering with leukocyte adhesion and transendothelial migration.[9]
In the pilot Phase I open-label, randomized, and dose-ranging clinical trial, twice daily administration of ALG-1007 topical ophthalmic solution was shown to improve signs (tear breakup time [TBUT] and SICCA) and symptoms (Visual Analog Scale [VAS] composite score) of DED in four tested doses (0.125% SH plus 0.125%, 0.25%, 0.4%, or 0.6% RSG), with no reports of ocular irritation or other adverse events.[9]
Topical SH is a widely used ocular lubricant for DED. It has been shown to improve signs and symptoms in multiple studies, due to its water retentive properties and through ocular surface barrier and tear film stabilization.[12] The present study aims to determine the effect of each formulation ingredient by comparing ALG-1007 (0.125% SH + 0.6% RSG) – the dose which consistently demonstrated the greatest improvement in both signs and symptoms in the pilot study – to 0.6% RSG only, 0.125% SH only, and vehicle only.
MATERIAL AND METHODS
This was a prospective, randomized, double-masked, vehicle-controlled, single-center clinical study. The study was conducted between January 29 and May 29, 2020, under the approval of an Institutional Review Board, and adhered to good clinical practice and the provisions of the Declaration of Helsinki and its amendments.
Participants
Eligible participants were adults aged ≥18 years with symptoms of DED for ≥6 months. Subjects needed to meet all three inclusion criteria: 1. Inferior cornea staining score ≥2, 2. nasal conjunctival staining score ≥2, and 3. Dry Eye Management Scale (DEMS) ≥5.
Exclusion criteria included known allergies to any of the drug ingredients, contact lens use (or refusal to discontinue contact lens use), current ocular infection, inflammation or acute allergic conjunctivitis, history of ocular herpetic keratitis, ocular surgery (within the past 6 months), LASIK, or use of glaucoma medicine, and use of any topical medication or antibiotic for blepharitis or meibomian gland disease. Patients with neurotrophic keratitis, eyelid abnormalities or extensive ocular scarring, and those with DED secondary to scarring or destruction of conjunctival cells (i.e., chemical burn) were also excluded from participation. A washout period of 45 days was required for any patient who was on active DED treatment (i.e., lifitegrast, cyclosporine, mast cell stabilizers, antihistamines, or corticosteroids). Participation in any other investigational drug or device study within 60 or 30 days, respectively, excluded patients from participation.
Study design
After informed consent, eligible subjects with DED were randomized to one of four treatment groups: ALG-1007 (0.125% SH + 0.6% RSG), 0.6% RSG, 0.125% SH, and vehicle. The treatment for all groups was administered one drop twice a day. Subjects were seen for follow-up at weeks 2, 4, 8, and 12.
Outcome measures
Primary efficacy endpoints were change in nasal conjunctival staining and change in DEMS score from baseline to week 12. Secondary efficacy endpoints were changes in TBUT, total ocular staining (TOS), inferior corneal staining score, and individual and combined reported symptoms (by VAS), from baseline to week 12.
The cornea was stained using fluorescein and the conjunctiva was stained using lissamine green. Grading was performed using the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) schema.[13] The cornea was divided into five sectors (central, superior, inferior, temporal, and nasal) while the conjunctiva was divided into four sectors (superior, inferior, temporal, and nasal). Each sector was graded on a scale of 0–4, with 0.5 increments.
Ocular symptoms were graded using the UNC DEMS and VAS systems. The DEMS is a single item validated patient reported outcomes questionnaire that evaluates a subject’s overall symptoms, graded on a scale of 1–10. The VAS includes seven specific symptoms (burning, itchiness, foreign body sensation (FBS), dryness, discomfort, photophobia, and pain), graded on a scale of 0–100.
Safety outcomes were adverse events and slit lamp findings, assessed at baseline and at each follow-up visit.
Analysis
All subjects who received the study drug were included in the study analysis. Efficacy analysis was performed using the modified intent-to-treat population, which included all randomized subjects who received at least one dose of study drug and had at least one follow-up visit.
Measured values and CFB values were summarized at each visit. CFB in signs and symptoms was analyzed at week 12 using a repeated-measures analysis of variance, due to dependence between paired eyes. Group comparisons were made using post hoc adjustment by the Tukey-Kramer method: ALG-1007 versus RSG; ALG-1007 versus SH; ALG-1007 versus vehicle; RSG versus SH; RSG versus vehicle; and SH versus vehicle.
RESULTS
Participants
Sixty-four eyes from 32 subjects with DED from a single site in Yerevan, Armenia were enrolled and randomized into the four treatment groups in a 1:1:1:1 ratio. Each treatment group included 16 eyes from eight subjects. All subjects completed the 12-week treatment and evaluation period and were included in the safety population, modified intent to treat population and per protocol population.
Baseline characteristics [Table 1] were similar between treatment groups. All subjects were Caucasian, with 14 males and 50 females. Age ranged from 21 to 70 years, with a mean (SD) of 52.9 (12.5). Mean baseline values for TBUT, nasal conjunctival staining, inferior corneal staining, and DEMS were similar across treatment groups. None of the subjects reported pain or itching at baseline. Mean baseline values for other VAS parameters were comparable across treatment groups.
| Characteristic | Vehicle (n=16) |
SH (n=16) |
0.60% RSG (n=16) |
0.60% RSG + SH (n=16) |
Overall (n=64) |
|---|---|---|---|---|---|
| Age, years n Mean (SD) Median Minimum, maximum |
16 56.8 (15.9) 61.5 21, 70 |
16 51.6 (9.2) 52.5 39, 65 |
16 50.9 (12.7) 50 26, 67 |
16 52.5 (11.8) 52 36, 67 |
64 52.9 (12.5) 53 21, 70 |
| Gender, n(%) Male Female |
0 (0) 16 (100) |
6 (37.5) 10 (62.5) |
6 (37.5) 10 (62.5) |
2 (12.5) 14 (87.5) |
14 (21.9) 50 (78.1) |
| Race, n(%) Black or African American Native Hawaiian or Other Pacific Islander Other Caucasian |
0 0 0 16 (100) |
0 0 0 16 (100) |
0 0 0 16 (100) |
0 0 0 16 (100) |
0 0 0 64 (100) |
| Ethnicity, n(%) Hispanic or Latino Not Hispanic or Latino |
0 16 (100) |
0 16 (100) |
0 16 (100) |
0 16 (100) |
0 64 (100) |
| Iris color, n(%) Blue/Green Brown Hazel Other |
0 16 (100) 0 0 |
1 (6.3) 15 (93.7) 0 0 |
1 (6.3) 15 (93.7) 0 0 |
1 (6.3) 15 (93.7) 0 0 |
3 (4.7) 63 (95.3) 0 0 |
| Tear break up time, s n Mean (SD) Median Minimum, maximum |
16 3.6 (0.33) 3.7 3, 4 |
16 4.4 (0.68) 4.3 3, 6 |
16 4.2 (0.57) 4.3 3, 5 |
16 3.7 (0.52) 3.7 3, 5 |
64 3.9 (0.62) 3.7 3, 6 |
| Nasal conjunctival staining n Mean (SD) Median Minimum, maximum |
16 2.6 (0.22) 2.5 2.5, 3 |
16 2.6 (0.31) 2.5 2, 3 |
16 2.6 (0.33) 2.5 2, 3 |
16 2.7 (0.24) 2.5 2.5, 3 |
64 2.6 (0.27) 2.5 2, 3 |
| Inferior corneal staining n Mean (SD) Median Minimum, maximum |
16 2.5 (0.13) 2.5 2.5, 3 |
16 2.5 (0.22) 2.5 2, 3 |
16 2.5 (0.26) 2.5 2, 3 |
16 2.6 (0.17) 2.5 2.5, 3 |
64 2.5 (0.20) 2.5 2, 3 |
| DEMS n Mean (SD) Median Minimum, maximum |
16 8.4 (0.69) 8.8 7.25, 9.25 |
16 8.3 (0.65) 8.4 7.25, 9.25 |
16 8.3 (0.77) 8.4 6.5, 9.25 |
16 8.4 (0.66) 8.3 7.25, 9.25 |
64 8.3 (0.68) 8.5 6.5, 9.25 |
| VAS combined n Mean (SD) Median Minimum, maximum |
16 59.4 (3.93) 60.5 52.6, 64.1 |
16 58.3 (4.03) 58.4 51.4, 63.9 |
16 57.5 (5.83) 58.5 45.3, 63.9 |
16 59.5 (4.79) 59.9 52.7, 66.4 |
64 58.7 (4.67) 59.3 45.3, 66.4 |
| VAS burning n Mean (SD) Median Minimum, maximum |
16 86.3 (5.62) 88.0 74, 94 |
16 84.9 (5.32) 85.5 76, 92 |
16 8.38 (8.80) 86.5 66, 94 |
16 85.3 (7.23) 87.0 75, 95 |
64 85.1 (6.78) 86.0 66, 95 |
| VAS itching n Mean (SD) Median Minimum, maximum |
16 0 (0.0) 0.0 0, 0 |
16 0 (0.0) 0.0 0, 0 |
16 0 (0.0) 0.0 0, 0 |
16 0 (0.0) 0.0 0, 0 |
64 0 (0.0) 0.0 0, 0 |
| VAS FBS n Mean (SD) Median Minimum, maximum |
16 84.1 (5.24) 85.0 75, 90 |
16 81.9 (6.09) 82.5 70, 90 |
16 81.4 (8.37) 82.5 64, 90 |
16 83.7 (6.85) 84.0 75, 95 |
64 82.8 (6.68) 83.5 64, 95 |
| VAS discomfort n Mean (SD) Median Minimum, maximum |
16 83.1 (6.39) 85.0 70, 90 |
16 81.7 (5.87) 82.0 71, 90 |
16 80.4 (7.74) 82.5 65, 90 |
16 83.6 (6.65) 84.0 75, 95 |
64 82.2 (6.66) 84.0 65, 95 |
| VAS dryness n Mean (SD) Median Minimum, maximum |
16 82.9 (5.70) 83.0 74, 91 |
16 81.6 (5.69) 81.5 70, 91 |
16 79.8 (8.23) 80.5 61, 90 |
16 83.5 (7.16) 85.5 70, 94 |
64 82.0 (6.77) 82.0 61, 94 |
| VAS photophobia n Mean (SD) Median Minimum, maximum |
16 79.6 (6.00) 80.0 69, 86 |
16 78.0 (5.80) 77.5 69, 86 |
16 76.8 (8.11) 77.0 60, 86 |
16 80.1 (6.54) 80.0 70, 89 |
64 78.6 (6.64) 80.0 60, 89 |
| VAS pain n Mean (SD) Median Minimum, maximum |
16 0 (0.0) 0.0 0, 0 |
16 0 (0.0) 0.0 0, 0 |
16 0 (0.0) 0.0 0, 0 |
16 0 (0.0) 0.0 0, 0 |
64 0 (0.0) 0.0 0, 0 |
DEMS: Dry eye management scale, VAS: Visual Analog Score, FBS: Foreign body sensation
TOS score and VAS individual analysis of pain and itchiness were removed from analysis. Individual analysis of itchiness and pain was omitted because all subjects had a score of 0 in VAS itchiness and pain at baseline and all follow-up visits. TOS score was not analyzed because data might be skewed due to the disparity in baseline staining scores; staining scores were worst in the inferior cornea and nasal conjunctiva while the other sectors showed only mild staining, with minimal chance of improvement.
Nasal conjunctival and inferior cornea staining score, tear film breakup time, DEMS and VAS
All parameters tested trended toward improvement in all four study groups over the 12-week observation period. Nasal conjunctival staining scores [Figure 1], inferior cornea staining scores [Figure 2], DEMS [Figure 3], and VAS (combined [Figure 4], burning, dryness, discomfort, FBS, and photophobia; [Figure 5]) progressively decreased while TBUT [Figure 6] progressively increased. The greatest improvements in all parameters tested were seen in the ALG-1007 group followed by RSG only, SH only, then vehicle. Differences in CFB values were statistically significant (P < 0.005) in all the measurements done when comparing all groups at 12 weeks using Tukey-Kramer adjusted P-values, except for comparison of ALG-1007 versus RSG (P= 0.3154, [Figure 1]) for nasal conjunctival staining.
Safety
Slit lamp examination did not reveal any significant findings during the 12-week study period. None of the subjects reported prolonged blurring of vision or eye irritation related to administration of the study drugs. No AEs or SAEs were reported for the duration of the study.
DISCUSSION
This prospective, randomized, double-masked, vehicle-controlled study evaluated the safety and efficacy of 0.60% RSG ophthalmic solution and ALG-1007 (0.60% RSG + 0.125% SH) ophthalmic solution for the treatment of DED. SH is an ocular lubricant that has been shown to provide some relief in DED patients.[14] To determine the individual efficacy contribution of RSG and SH, results were compared to SH and vehicle solutions.
The degree of improvement in all parameters tested and analyzed for both signs (nasal conjunctival staining, inferior corneal staining, and TBUT) and symptoms (VAS and DEMS) was consistently greatest in the group that received RSG + SH, followed by the group that received RSG alone, SH alone, then vehicle alone. The onset of improvement was seen as early as 2 weeks after initiation of treatment in the RSG + SH group and was progressive throughout the observation period. There was a high intercorrelation among individual symptoms and combining the scores into “combined VAS” preserved the integrity of the measurements. Improvement in all parameters tested was greater in the SH group versus vehicle, RSG group versus vehicle, RSG group versus SH, and RSG + SH group versus SH. The positive effect of RSG + SH appears to be synergistic rather than just additive. All these differences were statistically significant except the comparison between ALG-1007 and RSG for nasal conjunctival staining. Although this difference was not statistically significant, the trend was the same with ALG-1007 resulting in a more rapid and greater improvement in nasal conjunctival staining compared to RSG alone. The nasal conjunctival staining score decreased to almost zero, leaving little room for improvement, which may be the reason for the lack of statistical significance.
The investigational products in this study – 0.60% RSG only and 0.60% RSG + 0.125% SH – showed a direct correlation in improvement of both signs and symptoms of DED in a single study, which can be attributed to the lubricating, anti-inflammatory, and non-irritating properties of the solution. This is significant due to the observation that many clinical trials for DED treatments fail because there is a lack of correlation between signs and symptoms in DED.[15]
The results of this study demonstrate that 0.60% RSG solution is superior to the vehicle control in improving both signs and symptoms of subjects with DED. The results also demonstrate that ALG-1007 (0.60% RSG + 0.125% SH) solution is superior to 0.125% SH alone in improving both signs and symptoms of DED, indicating that 0.60% RSG has demonstrable therapeutic properties. The combination of 0.60% RSG + 0.125% SH solution demonstrated a statistically significant greater efficacy in improving both signs and symptoms of DED than 0.60% RSG alone.
CONCLUSION
0.60% RSG topical ophthalmic solution is effective in improving the signs and symptoms of DED, but ALG-1007, a combination of 0.60% RSG + 0.125% SH, was superior to RSG alone and will provide the most therapeutic benefit to patients with DED. The drug was well-tolerated with no drug-related AEs or SAEs reported over a 12-week observation period.
Despite the relatively small size of the study, the superiority of ALG-1007 was demonstrated over RSG alone. However, a larger sample size would permit us to estimate the magnitude of the treatment effect more precisely than can be done in the present study. The results warrant further investigation in a larger study population with a more diverse degree of dry eye severity.
Acknowledgements
The authors would like to thank Gerard Smits, PhD, for performing statistical analysis and Kalayaan Bilbao, MD, for providing medical writing assistance.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent.
Financial support and sponsorship
Nil.
Conflicts of interest
Eric Donnenfeld, Edward Holland, and Richard Lindstrom are consultants for Allegro Ophthalmics, LLC, and own shares of stock. Vicken Karageozian, John Park, Zixuan Shao, Melvin Sarayba, Lisa Karageozian, Janine Aubel, and Hampar Karageozian are employees of Allegro Ophthalmics, LLC, and own shares of stock.
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