Abstract
Purpose
To evaluate the efficacy and safety of motugivatrep (SJP-0132) 0.3% ophthalmic suspension, a novel therapy targeting subjective symptoms, in patients with dry eye disease.
Patients and Methods
This pivotal, multicenter, randomized, double-masked, placebo-controlled Phase 3 study was conducted in Japan. Outpatients with dry eye-related subjective symptoms and short tear break-up times (TBUT; ≤5 seconds in both eyes) were randomized 1:1 to receive motugivatrep 0.3% ophthalmic suspension or placebo four times daily for 8 weeks. The primary endpoint was the change from baseline in total Dry Eye-related Quality of Life Score (DEQS) at week 4.
Results
A total of 535 patients were randomized to motugivatrep 0.3% (n=268) or placebo (n=267). The primary endpoint was met, with a significantly greater improvement in total DEQS at week 4 in the motugivatrep 0.3% group compared with placebo (least-squares mean [LSM] change from baseline −16.76 vs −14.36; LSM difference −2.40; 95% CI −4.72, −0.07; p=0.0433). Consistent improvements in total DEQS were observed with motugivatrep 0.3% vs placebo from week 1 through week 4 (all nominal p<0.05). Motugivatrep 0.3% also demonstrated early improvements in other subjective symptoms, with statistically significant improvements vs placebo in visual analog scale scores for eye dryness at weeks 1 and 4 (both nominal p<0.05).
No significant differences were observed between groups in changes in TBUTs or corneal fluorescein staining (CFS) scores overall. A subgroup analysis suggested greater and increasing improvements in total CFS scores with motugivatrep 0.3% compared with placebo in patients with corneal epithelial disorder, indicating potential benefit in this population. Motugivatrep 0.3% was generally well tolerated, with no major safety concerns identified.
Conclusion
Motugivatrep 0.3% ophthalmic suspension provided early improvements in subjective symptoms and quality of life and was well tolerated, representing a new therapeutic option for patients with dry eye disease.
Keywords: transient receptor potential cation channel subfamily V member 1 antagonist, TRPV1, DED, eye dryness, dry eye-related quality of life score, DEQS
Introduction
Dry eye is a multifactorial, symptomatic disease characterized by symptoms of eye discomfort, visual disturbance, and potentially ocular surface damage, resulting from a multifactorial etiology involving tear film instability and hyperosmolarity, ocular surface inflammation, and neurosensory abnormalities.1–3 Despite the numerous treatment options currently available for the treatment of dry eye (eg, artificial tears, secretagogues, and anti-inflammatory agents),2,4 more than half the patients discontinue treatment because of reasons such as inadequate symptom relief and slow onset of treatment effect, highlighting the unmet need for a treatment that is effective and fast acting.5–7
Ocular tissues express various ion channels that regulate the flux of ions, thereby maintaining ionic homeostasis needed for physiological processes such as signal transmission and visual processing.8 Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a non-selective cation channel expressed in the cornea, conjunctiva, corneal nerve fibers, lacrimal glands, trigeminal ganglion, and other tissues throughout the body.9–11 It is a thermo-sensitive channel that is activated by heat (>43°C), inflammatory mediators (eg, histamine, prostaglandin), hyperosmolarity, capsaicin, and low pH.10,11 Activation of TRPV1 in response to stimuli such as hyperosmotic stress can lead to action potential firing and perception of pain,10,12 enhanced production of pro-inflammatory cytokines,11,13 and the release of neuropeptides that mediate neurogenic inflammation,11,12,14 ultimately contributing to the symptoms and signs of dry eye. TRPV1 has been suggested to be involved in the pathophysiology of ocular surface diseases, but the clinical significance of TRPV1 antagonists in dry eye has not been fully established.
Motugivatrep (SJP-0132) is a potent and selective small-molecule TRPV1 antagonist. It was discovered by Mochida Pharmaceutical Co., Ltd. and is being developed by Senju Pharmaceutical Co., Ltd for the treatment of dry eye.15 Ocular administration of motugivatrep 0.3% ophthalmic suspension in a rat model of dry eye significantly decreased the superficial punctate keratitis score and the blink count, suggesting improvements in the signs and symptoms of disease and the potential usefulness of motugivatrep as a treatment for dry eye.16 In the Phase 1/2, randomized, double-masked, single-center, single- and multiple-ascending dose study in patients with dry eye disease (NCT04139122), motugivatrep ophthalmic suspension was safe and well tolerated and demonstrated an early onset of action (within 30 min after the first dose) with 0.1% and 0.3% doses.17
The Phase 2b randomized, double-masked, placebo-controlled, dose-response study (jRCT2031200243) showed generally dose-dependent safety and efficacy of motugivatrep.18 No statistically significant difference was seen between patients treated with motugivatrep 0.3% ophthalmic suspension four times daily for 4 weeks and those treated with placebo for the primary endpoint of the change from baseline in the total corneal fluorescein staining (CFS) score (sum of the scores for all zones - central, superior, nasal, temporal, and inferior) of the study eye at week 4.18 However, significant improvements in visual analog scale (VAS) scores for eye dryness and total Dry Eye-related Quality-of-life Scores (DEQS) were observed with motugivatrep 0.3% ophthalmic suspension vs placebo prior to first dose administration at week 1, and in VAS scores for eye dryness at 2 hours after the first dose at week 1.18 Here we report results from a randomized, double-masked, placebo-controlled, multicenter, Phase 3 study (jRCT2031220497) conducted from January 2023 to October 2023 that aimed to confirm the efficacy and safety of motugivatrep 0.3% ophthalmic suspension administered four times daily for 8 weeks in patients with dry eye disease.
Methods
Patients
The study included outpatients living in Japan who were aged ≥18 years and who had subjective symptoms related to dry eye disease in both eyes for more than 180 days prior to informed consent. Subjective symptoms were defined as at least one DEQS19 question score of ≥1, VAS score for eye dryness of ≥40, and 5-item Dry Eye Questionnaire (DEQ-5)20 total score of ≥6. Patients were also required to have tear break-up time (TBUT; the average of three measurements) of ≤5 seconds in both eyes.
Key exclusion criteria included: prior administration of motugivatrep in either eye; participation in another trial and treatment with another investigational product within 90 days of screening, or scheduled to participate in another trial during the study period; inability to discontinue wearing contact lenses over the study period; a history of corneal transplantation in either eye or punctal occlusion, or corneal transplantation or punctal occlusion planned to be performed before the end of the treatment period; using punctal plugs in either eye, punctal plugs coming off or removed within 30 days before screening, or scheduled to undergo punctal plug insertion before the end of the treatment period; history of ocular surgery that may damage the sensory nerves of the ocular surface of either eye, or surgery associated with morphological changes in the eye within 365 days prior to screening. Also excluded were: patients with active ocular disease other than dry eye (including infection of the eyeball or ocular adnexa, allergic disease, or proliferative disease) in either eye; patients with a disease potentially affecting the subjective symptoms of dry eye disease (eg, cataract) other than the diseases causing dry eye disease (eg, Sjögren’s disease, meibomian gland dysfunction); patients with hypersensitivity or significant adverse reaction to TRPV1 antagonists or any components of drugs to be used in this study (eg, fluorescein); patients with corrected visual acuity ≤0.2 in either eye; patients who could not discontinue administration of therapeutic agents for dry eye (eg, diquafosol sodium, rebamipide) or keratoconjunctival epithelial disorder (eg, sodium hyaluronate) from 28 days before the treatment period; patients who could not discontinue the use of all ophthalmic agents (including over-the-counter drugs and pharmaceuticals requiring guidance) or any treatment that may damage the eye surface or improve eye symptoms; patients with cancer, serious liver disorder, serious renal disorder, serious cardiovascular disorder, or systemic disease (eg, serious endocrine disease), or those with neuropsychiatric disorder (eg, depression) who were considered inappropriate for study participation.
The study protocol was amended to include an additional exclusion criterion to exclude patients with a history of treatment with intense pulsed light (IPL) or thermal pulsation within the past 1 year or those who were scheduled to undergo such treatment before the end of the treatment period in consideration of the possible impact on the efficacy assessment of the investigational drug.
Patients with a chronic local eye disease that did not require treatment and was unlikely to progress until the end of the treatment period were permitted in the study.
Study Design
This was a randomized, double-masked, placebo-controlled multicenter, Phase 3 study in patients with dry eye disease. Figure 1 depicts the study design. The study was conducted in compliance with the ethical principles of the Declaration of Helsinki and the International Council for Harmonisation-Good Clinical Practice guideline. The conduct of the study was reviewed and approved by the Institutional Review Boards and approved by the heads of the institutions. Patients provided written informed consent prior to study entry.
Figure 1.
Schematic of study design.
Abbreviation: QID, four times daily.
After a placebo (four times daily) run-in period of 2 weeks, patients were randomized 1:1 using dynamic allocation to receive motugivatrep 0.3% ophthalmic suspension or placebo four times daily for 8 weeks. Motugivatrep 0.3% ophthalmic suspension was selected as the study dose based on the results of the Phase 2b dose-finding study.18 No dose modification was permitted in the study. The eye with the higher total CFS score (sum of the scores for all zones - central, superior, nasal, temporal, and inferior) on the start date of the treatment period was considered as the study eye. If both eyes had the same total CFS score, the right eye was selected as the study eye. Both eyes were evaluated for safety.
Additional study details on randomization, blinding, and prohibited concomitant medications are provided in the Supplementary material.
Endpoints
Efficacy was evaluated on days 1 (week 0), 8 (week 1), 15 (week 2), 29 (week 4), and 57 (week 8) and safety was evaluated from screening through to the end of treatment. The primary endpoint was the change from baseline in total DEQS at week 4. Baseline is defined as the measurement at week 0 (day 1; Visit 3) prior to administration of the first dose.
Secondary endpoints included the actual values and changes from baseline at each assessment in the following: DEQS, VAS scores for eye dryness related to dry eye disease, CFS scores using the Baylor scale, and TBUTs. The effect of dry eye on a patient’s daily life was measured using the DEQS questionnaire, which comprises two subscales (bothersome ocular symptoms [six questions] and impact on daily life [nine questions]) assessing the frequency of symptoms (0 [never] to 4 [always]) and the degree of severity (1 [not very bothersome] to 4 [very bothersome]), and an overall assessment of dry eye symptoms and their effects on daily life (1 [extremely good] to 6 [extremely bad]).19 The total DEQS was calculated from the scores for the two subscales, giving a total score ranging from 0 to 100, with higher scores indicating greater disability.19 The VAS score for eye dryness was measured on a scale of 0 (no symptoms) to 100 (most severe symptoms). A modified version of the Baylor scale21–24 was used to calculate the corneal staining scores (assessing the severity of ocular damage) by counting the number of staining dots (0, 1, 2, 3, and 4 points for 0, 1–5, 6–15, 16–30, and ≥31 dots, respectively) in each of the five corneal zones (central, superior, nasal, temporal, and inferior) and adding points for confluence (one area of confluence was given 1 point, ≥2 areas of confluence were given 2 points for a score of 1–3 and 1 point for score of 4), resulting in a maximum score of 5 for each zone and a total maximum score of 25 for all corneal zones. The TBUT was measured by administering fluorescein, with the patient then asked to keep eyes open after blinking several times to determine the time it takes for tear breakup; the test was repeated several times until three values were obtained that differed by <3 seconds and the average of the three measurements was calculated.
All efficacy outcomes were assessed before dose administration at each visit. VAS assessments were additionally performed 2 hours after the first dose on Day 1.
Safety endpoints included the frequency and severity of treatment-emergent adverse events (AEs) and treatment-related AEs, including serious, nonserious, and significant AEs, ophthalmic examinations (corrected visual acuity, slit-lamp biomicroscopic findings, intraocular pressure, and ophthalmoscopic findings) and their changes from baseline, and assessment of vital signs (body temperature, blood pressure, and pulse rate) and their changes from baseline. AE was defined as an untoward or unintended disease or its sign occurring in patients who received the study drug or placebo or used a medical device in the study regardless of causality with the drug, placebo, or device used in the study. Treatment-emergent AE was an AE that occurred during the treatment period, an AE that occurred before the start of treatment and worsened after the start of treatment, or a concomitant disease that worsened after the start of treatment. Significant AEs were defined as AEs leading to discontinuation of the investigational product over the treatment period. A serious AE was an AE resulting in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was a medically important event or reaction.
Statistical Analysis
Based on the Phase 2b dose-finding study of motugivatrep,18 a sample size of 448 evaluable patients (224 patients per group) was estimated to provide 90% power to detect a difference of −3.5 (standard deviation of 11.4) between the motugivatrep 0.3% group and the placebo group for the change from baseline in DEQS at week 4 (primary endpoint), with a two-sided significance level of 5%. Accounting for possible patient dropouts etc, the sample size was set at 498 patients, with up to 249 patients per group.
Efficacy analyses were conducted in the full analysis set (FAS) and safety analyses were performed in the safety set. The FAS included all randomized patients who received at least one dose of the investigational product during the treatment period. The safety set included all patients who received at least one dose of the investigational product and could be evaluated for safety.
The primary endpoint of the change from baseline in total DEQS at week 4 was analyzed using a mixed-effects model for repeated measures (MMRM) with restricted maximum likelihood, assuming a missing-at-random mechanism, to compare the motugivatrep 0.3% group with the placebo group. This model (hereafter referred to as MMRM model 1) used data from weeks 1, 2, and 4 and included treatment group, visit, and the interaction between treatment group and visit as fixed effects, and total DEQS at baseline as covariate. Motugivatrep 0.3% and placebo groups were compared at week 4 at a two-sided significance level of 0.05 and the hypothesis test was performed based on the least-squares mean (LSM) of the between-group difference. MIXED Procedure of SAS Software was used for the analysis. To confirm the robustness of the results, sensitivity analyses of the primary endpoint were performed.
For the secondary endpoints, changes from baseline up to week 8 in DEQS in the motugivatrep 0.3% and placebo groups were analyzed in the same manner as the primary endpoint and compared using MMRM based on data from weeks 1, 2, 4, and 8 (hereafter referred to as MMRM model 2). For the VAS scores for eye dryness, CFS scores of the study eye, and TBUTs for the study eye, summary statistics of the actual values and changes from baseline were calculated for each treatment group at each assessment, and between-group comparisons were performed at each assessment using the t-test; no multiplicity adjustment was applied for these endpoints. Additionally, the effect of motugivatrep 0.3% on the total CFS score of the study eye was assessed in a subgroup of the FAS population who had corneal epithelial disorder (a population equivalent to the study population of the Phase 2b dose-finding study).18 Patients with corneal epithelial disorder had baseline CFS scores in the study eye of ≥2 to ≤4 in the central zone, ≥4 to ≤20 for all zones, and ≥1 for the total of superior, temporal, nasal, and inferior zones.
A post hoc analysis was undertaken to determine the proportions of patients at weeks 4 and 8 who had total DEQS below the proposed diagnostic cutoff for dry eye disease (15.0 points) and according to severity of dry eye disease (mild: 15.0 to <20.0; moderate: 20.0 to <26.8; severe ≥26.8),25 as well as the proportion of patients with mean TBUT exceeding the Japanese diagnostic threshold (≤5 seconds).
For demographic and clinical characteristics, frequencies were tabulated and summary statistics calculated. Treatment compliance (%) was calculated as the number of days administered at a specified dosing frequency and dosing interval in both eyes ÷ total number of days of administration × 100. For safety outcomes, incidences were calculated for treatment-emergent AEs by Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term.
Results
Patients
Figure 2 presents the overall patient disposition. Of the 704 patients recruited, 535 were randomized and received at least one dose of motugivatrep 0.3% (n=268) or placebo (n=267) and comprised the FAS population. Of the randomized patients, 260 patients in the motugivatrep 0.3% group and 259 in the placebo group completed treatment.
Figure 2.
Patient disposition. aThe safety set included one patient who was not randomized but was administered motugivatrep 0.3%.
Baseline demographics, disease and ocular characteristics were generally well balanced between the motugivatrep 0.3% and placebo groups (Table 1 and Table 2). At baseline, patients had a mean age of 50.8 years, all patients were Asian except for one, 72.0% were female and 85.0% had brown iris color. The most common type of dry eye disease was evaporative dry eye in 74.6% of patients, 31.8% of patients had received prior medication for dry eye in the study eye, 15.0% had ocular concomitant disease in the study eye, and two patients (0.4%) in the placebo group had received concomitant ocular medication in the study eye. Ocular concomitant diseases at baseline are summarized in Table S1. At baseline, 17.5% of patients in the motugivatrep 0.3% group and 18.0% of patients in the placebo group had a total CFS score of 0 for the study eye and 51.5% and 51.7% of patients, respectively, had a score of 0–3.
Table 1.
Demographic and Disease Characteristics at Baseline
| Characteristic | Placebo (N = 267) |
Motugivatrep 0.3% (N = 268) |
Total (N = 535) |
|---|---|---|---|
| Age years, mean (SD) | 51.3 (14.88) | 50.3 (14.76) | 50.8 (14.81) |
| ≥18 to <40, n (%) | 57 (21.3) | 64 (23.9) | 121 (22.6) |
| ≥40 to <65, n (%) | 156 (58.4) | 162 (60.4) | 318 (59.4) |
| ≥65, n (%) | 54 (20.2) | 42 (15.7) | 96 (17.9) |
| Female, n (%) | 191 (71.5) | 194 (72.4) | 385 (72.0) |
| Race, n (%) | |||
| Asian | 267 (100.0) | 267 (99.6) | 534 (99.8) |
| More than one race | 0 | 1 (0.4) | 1 (0.2) |
| Iris color (study eye), n (%) | |||
| Black | 36 (13.5) | 41 (15.3) | 77 (14.4) |
| Brown | 230 (86.1) | 225 (84.0) | 455 (85.0) |
| Gray | 0 | 1 (0.4) | 1 (0.2) |
| Hazel | 1 (0.4) | 1 (0.4) | 2 (0.4) |
| Primary and related disease, n (%) | |||
| Primary Sjögren’s disease | 1 (0.4) | 5 (1.9) | 6 (1.1) |
| Secondary Sjögren’s disease | 1 (0.4) | 0 | 1 (0.2) |
| Other | 265 (99.3) | 263 (98.1) | 528 (98.7) |
| After cataract operation | 0 | 1 (0.4) | 1 (0.2) |
| Basedow’s disease | 1 (0.4) | 0 | 1 (0.2) |
| Conjunctivochalasis | 3 (1.1) | 4 (1.5) | 7 (1.3) |
| Decreased wettabilitya | 15 (5.7) | 9 (3.4) | 24 (4.5) |
| Evaporative dry eye | 202 (76.2) | 192 (73.0) | 394 (74.6) |
| Graft-versus-host disease | 0 | 1 (0.4) | 1 (0.2) |
| Laser-Assisted in Situ Keratomileusis | 0 | 2 (0.8) | 2 (0.4) |
| Meibomian gland dysfunction | 9 (3.4) | 6 (2.3) | 15 (2.8) |
| Tear deficient dry eye | 46 (17.4) | 49 (18.6) | 95 (18.0) |
| Wearing contact lens | 5 (1.9) | 10 (3.8) | 15 (2.8) |
| Prior medication for dry eye (study eye), n (%) | |||
| Yes | 81 (30.3) | 89 (33.2) | 170 (31.8) |
| No | 186 (69.7) | 179 (66.8) | 365 (68.2) |
| Ocular concomitant disease (study eye), n (%) | |||
| Yes | 34 (12.7) | 46 (17.2) | 80 (15.0) |
| No | 233 (87.3) | 222 (82.8) | 455 (85.0) |
| Nonocular concomitant disease, n (%) | |||
| Yes | 128 (47.9) | 130 (48.5) | 258 (48.2) |
| No | 139 (52.1) | 138 (51.5) | 277 (51.8) |
| Ocular concomitant medication (study eye), n (%) | |||
| Yes | 2 (0.7) | 0 | 2 (0.4) |
| No | 265 (99.3) | 268 (100.0) | 533 (99.6) |
| Nonocular concomitant medication, n (%) | |||
| Yes | 103 (38.6) | 103 (38.4) | 206 (38.5) |
| No | 164 (61.4) | 165 (61.6) | 329 (61.5) |
Notes: aDecreased wettability dry eye is due to insufficient membrane associated-mucins (especially MUC16), resulting in spot or dimple fluorescein breakup patterns.26
Abbreviation: N, full analysis set; SD, standard deviation.
Table 2.
Baseline Ocular Characteristics
| Ocular Characteristics | Placebo (N = 267) | Motugivatrep 0.3% (N = 268) |
|---|---|---|
| Total DEQS, mean (SD) | 38.85 (20.203) | 37.74 (20.766) |
| Bothersome ocular symptoms DEQS subscale score | 44.76 (20.096) | 43.86 (20.170) |
| Impact on daily life DEQS subscale score | 34.90 (22.515) | 33.65 (23.078) |
| VAS score for eye dryness, mean (SD) | 67.1 (13.66) | 66.7 (12.81) |
| CFS score (total of all zones of the study eye), mean (SD) | 4.3 (4.23) | 4.5 (4.47) |
| TBUT (study eye) [sec], mean (SD) | 2.886 (1.0229) | 2.943 (1.0570) |
Abbreviations: CFS, corneal fluoresceine staining; DEQS, Dry Eye-related Quality of Life Score; N, full analysis set; SD, standard deviation; TBUT, tear break-up time; VAS, visual analog scale.
The mean duration of treatment was 55.2 days in both the motugivatrep 0.3% and placebo groups, mean±SD treatment compliance was 98.50±3.68% (range 73.2% to 100%) in the motugivatrep 0.3% group and 97.95±6.96% (range 30.8% to 105.9%) in the placebo group, and 99.6% and 97.4% of patients, respectively, had treatment compliance of ≥75% to ≤100%.
Efficacy
Primary Endpoint
At week 4, the LSM±standard error change from baseline in total DEQS was −16.76±0.836 in the motugivatrep 0.3% group (n=259/268) compared with −14.36±0.838 in the placebo group (n=258/267) [Figure 3; MMRM model 1 analysis], indicating a significantly greater improvement in quality of life with motugivatrep 0.3% than with placebo (LSM between-group difference −2.40; 95% CI −4.72, −0.07; p=0.0433). Sensitivity analyses against alternative assumptions of variance-covariance structure and missing data mechanism confirmed the robustness of the results, with findings consistent with those of the primary analysis (Table S2).
Figure 3.
Difference between motugivatrep 0.3% and placebo for the primary endpoint of the LSM change from baseline in total DEQS at week 4 in the full analysis set (MMRM analysis model 1). MMRM model 1 includes treatment group, visit, and the interaction between treatment group and visit as fixed effects, and total DEQS at baseline as covariate. Visits used in the model are week 1, week 2, and week 4. The covariance structure is implemented as “unstructured”. The estimation method is restricted maximum likelihood. Degree of freedom is estimated using the kenward-roger method.
Abbreviations: CI, confidence interval; DEQS, Dry Eye-related Quality of life Score; LSM, least-squares mean; MMRM, mixed-effects models for repeated measures.
Subjective Symptoms
LSM total DEQS decreased (improvement) from baseline to a greater extent with motugivatrep 0.3% than with placebo at all assessments over the 8-week treatment period, with statistically significant between-group differences of −2.56 (95% CI −4.55, −0.57; p=0.0117) at week 1, −2.48 (95% CI −4.73, −0.23; p=0.0307) at week 2, and −2.46 (95% CI −4.78, −0.14; p=0.0375) at week 4, and a statistically nonsignificant between-group difference of −1.59 (95% CI −3.96, 0.77; p=0.1861) at week 8 (Table 3 and Figure 4; MMRM model 2 analysis and nominal P values). The LSM scores for the bothersome ocular symptoms and impacts on daily life subscales also improved from baseline to a greater extent with motugivatrep 0.3% relative to placebo at all assessments, with statistically significant between-group differences demonstrated at week 1 (−2.92; 95% CI −5.20, −0.63; p=0.0124) and week 2 (−2.93; 95% CI −5.37, −0.48; p=0.0189) for the bothersome ocular symptoms subscale scores and at week 1 (−2.37; 95% CI −4.53, −0.21; p=0.0313) and week 4 (−2.74; 95% CI −5.18, −0.29; p=0.0285) for the impacts on daily life subscale scores (Table 3; nominal P values).
Table 3.
Change from Baseline in LSM Total DEQS and LSM DEQS Subscale Scores Over 8 weeks of Treatment in the Full Analysis Set (MMRM Analysis Model 2). Significant P-Values (Nominal) for Motugivatrep 0.3% vs Placebo are Bolded
| Timepoint | LSM (SE) change from baseline in total DEQS | Difference to placebo (95% Confidence Interval) |
P−value | |||
|---|---|---|---|---|---|---|
| Placebo (N = 267) | Motugivatrep 0.3% (N = 268) | |||||
| Total DEQS | ||||||
| n | n | |||||
| Week 1 | 263 | −10.04 (0.718) | 267 | −12.60 (0.714) | −2.56 (−4.55, −0.57) | 0.0117 |
| Week 2 | 262 | −13.29 (0.809) | 259 | −15.77 (0.809) | −2.48 (−4.73, −0.23) | 0.0307 |
| Week 4 | 258 | −14.30 (0.836) | 259 | −16.77 (0.834) | −2.46 (−4.78, −0.14) | 0.0375 |
| Week 8 | 255 | −16.53 (0.851) | 252 | −18.12 (0.852) | −1.59 (−3.96, 0.77) | 0.1861 |
| Bothersome ocular symptoms DEQS subscale score | ||||||
| Week 1 | 263 | −11.50 (0.824) | 267 | −14.42 (0.820) | −2.92 (−5.20, −0.63) | 0.0124 |
| Week 2 | 262 | −14.29 (0.879) | 259 | −17.22 (0.879) | −2.93 (−5.37, −0.48) | 0.0189 |
| Week 4 | 258 | −16.04 (0.900) | 259 | −18.18 (0.898) | −2.13 (−4.63, 0.36) | 0.0940 |
| Week 8 | 255 | −18.75 (0.936) | 252 | −20.37 (0.937) | −1.62 (−4.22, 0.98) | 0.2218 |
| Impact on daily life DEQS subscale score | ||||||
| Week 1 | 263 | −9.04 (0.780) | 267 | −11.41 (0.775) | −2.37 (−4.53, −0.21) | 0.0313 |
| Week 2 | 262 | −12.60 (0.877) | 259 | −14.85 (0.876) | −2.24 (−4.68, 0.19) | 0.0711 |
| Week 4 | 258 | −13.11 (0.882) | 259 | −15.85 (0.880) | −2.74 (−5.18, −0.29) | 0.0285 |
| Week 8 | 255 | −15.04 (0.894) | 252 | −16.65 (0.895) | −1.62 (−4.10, 0.87) | 0.2023 |
Notes: The MMRM model 2 includes treatment group, visit, and the interaction between treatment group and visit as fixed effects, and total DEQS at baseline as covariate. Visits used in the model are week 1, week 2, week 4, and week 8. The covariance structure is implemented as “Unstructured”. The estimation method is restricted maximum likelihood. Degree of freedom is estimated using the Kenward-Roger method.
Abbreviations: DEQS, Dry Eye-related Quality of Life Score; LSM, least-squares mean; MMRM, mixed-effects models for repeated measures; n, number analyzed; N, full analysis set; SE, standard error.
Figure 4.
Least-squares mean change from baseline in total DEQS (MMRM model 2) (full analysis set). The MMRM model 2 includes treatment group, visit, and the interaction between treatment group and visit as fixed effects, and total DEQS at baseline as covariate. Visits used in the model are week 1, week 2, week 4, and week 8. The covariance structure is implemented as “unstructured”. The estimation method is restricted maximum likelihood. Degree of freedom is estimated using the kenward-roger method.* nominal (unadjusted for multiplicity) P < 0.05.
Abbreviations: DEQS, Dry Eye-related Quality of Life Score; MMRM, mixed-effects models for repeated measures; SE, standard error.
Patients treated with motugivatrep 0.3% had greater decreases (improvements) from baseline in mean VAS scores for eye dryness at all assessments than patients who received placebo, with statistically significantly greater improvements seen with motugivatrep 0.3% at the first assessment at week 1 (mean change −24.5 vs −19.6; p=0.0118) and at week 4 (mean change −34.5 vs −29.8; p=0.0289) [Table 4; nominal P values].
Table 4.
Mean Change from Baseline in the Visual Analog Scale Score for Eye Dryness Over 8 weeks of Treatment in the Full Analysis Set. Significant P-Values (Nominal) for Motugivatrep 0.3% vs Placebo are Bolded
| Timepoint | Change from baseline, mean (SD) | P-valuea | |||
|---|---|---|---|---|---|
| Placebo (N = 267) | Motugivatrep 0.3% (N = 268) | ||||
| n | n | ||||
| Week 1 | 262 | −19.6 (22.97) | 266 | −24.5 (22.26) | 0.0118 |
| Week 2 | 262 | −25.8 (24.24) | 259 | −29.1 (23.97) | 0.1185 |
| Week 4 | 257 | −29.8 (24.49) | 259 | −34.5 (24.41) | 0.0289 |
| Week 8 | 255 | −36.2 (25.22) | 252 | −39.5 (24.16) | 0.1299 |
Notes: aP-value calculated using the t-test.
Abbreviations: n, number analyzed; N, full analysis set; SD, standard deviation.
Objective Signs
The mean TBUTs (the average of three measurements) for the study eye tended to increase (improvement) with motugivatrep 0.3% vs placebo at weeks 1, 4, and 8, but the differences between the groups were not statistically significant (Table 5). The mean total CFS scores for the study eye tended to decrease (improve) from baseline with motugivatrep 0.3% vs placebo at weeks 4 and 8, but the differences between treatment groups were not statistically significant (Table 5).
Table 5.
Mean Changes from Baseline in Objective Signs of Tear Break-Up Time and Corneal Fluorescein Staining Score for All Zones in the Study Eye of Patients in the Full Analysis Set and in the Subgroup of Patients with Corneal Epithelial Disorder Over 8 weeks of Treatment
| Timepoint | Change from baseline, Mean (SD) | P-valuea | |||
|---|---|---|---|---|---|
| Placebo | Motugivatrep 0.3% | ||||
| TBUT in the study eye (sec), meanb (SD) | |||||
| Full analysis seta | N = 267 | N = 268 | |||
| n | n | ||||
| Week 1 | 263 | 0.399 (1.1612) | 267 | 0.452 (1.0546) | 0.5858 |
| Week 2 | 262 | 0.572 (1.4277) | 259 | 0.544 (1.2794) | 0.8168 |
| Week 4 | 257 | 0.677 (1.8374) | 259 | 0.737 (1.4077) | 0.6777 |
| Week 8 | 255 | 0.687 (1.4454) | 252 | 0.844 (1.5228) | 0.2327 |
| Total CFS score of the study eye (Baylor scale), mean (SD) | |||||
| Full analysis set | N = 267 | N = 268 | |||
| n | n | ||||
| Week 1 | 263 | −1.1 (2.87) | 267 | −0.7 (2.77) | 0.1674 |
| Week 2 | 262 | −1.3 (2.95) | 259 | −1.3 (3.32) | 0.9313 |
| Week 4 | 257 | −1.2 (3.33) | 259 | −1.3 (3.19) | 0.5303 |
| Week 8 | 255 | −1.5 (3.45) | 252 | −1.8 (3.33) | 0.3466 |
| Subgroup of patients with corneal epithelial disorderc | N = 28 | N = 35 | |||
| n | n | ||||
| Week 1 | 27 | −3.4 (3.19) | 35 | −2.8 (4.28) | 0.5649 |
| Week 2 | 27 | −3.2 (3.95) | 32 | −4.7 (3.94) | 0.1608 |
| Week 4 | 26 | −2.9 (4.55) | 35 | −4.6 (4.17) | 0.1338 |
| Week 8 | 28 | −3.3 (4.74) | 34 | −5.1 (4.17) | 0.1236 |
Notes: P-value (nominal) = motugivatrep 0.3% vs placebo. aP-value calculated using the t-test. bThe average of three measurements for the study eye. cSubgroup of patients with baseline CFS score of ≥2 to ≤4 for the central zone, total of ≥4 to ≤20 for all zones, and total of ≥1 for the superior, temporal, nasal, and inferior zones. Baseline mean (SD) CFS score was 10.0 (3.81) in the placebo group and 10.9 (4.12) in the motugivatrep 0.3% group.
Abbreviations: CFS, corneal fluorescein staining; n, number analyzed; N, full analysis set; SD, standard deviation; TBUT, tear break-up time.
Additionally, in a subgroup analysis of patients with corneal epithelial disorder (baseline CFS scores in the study eye of ≥2 to ≤4 in the central zone, ≥4 to ≤20 in all zones, and ≥1 for the total of superior, temporal, nasal, and inferior zones), patients treated with motugivatrep 0.3% had greater decreases (improvements) from baseline in the total CFS scores in the study eye from weeks 2 to 8 than patients who received placebo, with the differences between the groups tending to increase over time (Table 5). However, these improvements in CFS scores with motugivatrep 0.3% vs placebo were not statistically significant.
Post Hoc Analysis
A post hoc analysis examining the proportions of patients with total DEQS below the diagnostic cutoff of dry eye disease and according to the severity of dry eye disease, and those with mean TBUT exceeding the Japanese diagnostic criteria showed that across all criteria and at both time points (weeks 4 and 8), the proportions were consistently numerically higher in the motugivatrep 0.3% group than in the placebo group (Table S3).
Adverse Events
AEs occurring in the safety set (n=536) during the 8-week treatment period are summarized in Table 6. The safety set included one patient who was not randomized but was administered motugivatrep 0.3%. In the motugivatrep 0.3% and placebo groups, treatment-emergent AEs occurred in 19.7% and 14.6% of patients, respectively, and treatment-related AEs in 5.6% and 3.7% of patients. The majority of treatment-emergent and treatment-related AEs were of mild or moderate severity, with no severe treatment-emergent or treatment-related AEs occurring in any group.
Table 6.
Overall Summary of Adverse Events During the 8-Week Treatment Period (Safety Set)
| Adverse Event | Placebo (N = 267) | Motugivatrep 0.3% (N = 269) |
|---|---|---|
| n (%) [no. of events] | n (%) [no. of events] | |
| Any TEAEs | 39 (14.6) [47] | 53 (19.7) [81] |
| Mild | 33 (12.4) [41] | 47 (17.5) [74] |
| Moderate | 6 (2.2) [6] | 6 (2.2) [7] |
| Severe | 0 | 0 |
| Significant TEAEs | 3 (1.1) [3] | 3 (1.1) [5] |
| Any TRAEs | 10 (3.7) [11] | 15 (5.6) [22] |
| Mild | 9 (3.4) [10] | 13 (4.8) [19] |
| Moderate | 1 (0.4) [1] | 2 (0.7) [3] |
| Severe | 0 | 0 |
| Significant TRAEs | 1 (0.4) [1] | 1 (0.4) [2] |
| TEAEs or TRAEs leading to death | 0 | 0 |
| Serious TEAEs or TRAEs | 0 | 0 |
| Patients with ≥1 ocular TEAE (both eyes) | 18 (6.7) [19] | 25 (9.3) [35] |
| Patients with ≥1 ocular TRAE (both eyes) | 9 (3.4) [9] | 10 (3.7) [13] |
| Ocular TRAEs (both eyes) | ||
| Abnormal sensation in eye | 0 | 4 (1.5) [4] |
| Vision blurred | 0 | 3 (1.1) [3] |
| Eye pruritus | 2 (0.7) [2] | 1 (0.4) [1] |
| Conjunctivitis allergic | 1 (0.4) [1] | 1 (0.4) [1] |
| Corneal erosion | 1 (0.4) [1] | 1 (0.4) [1] |
| Lacrimation increased | 0 | 1 (0.4) [1] |
| Foreign body sensation in eyes | 0 | 1 (0.4) [1] |
| Ocular discomfort | 0 | 1 (0.4) [1] |
| Conjunctival cyst | 1 (0.4) [1] | 0 |
| Dry eye | 1 (0.4) [1] | 0 |
| Eye irritation | 1 (0.4) [1] | 0 |
| Lacrimation decreased | 1 (0.4) [1] | 0 |
| Visual acuity reduced | 1 (0.4) [1] | 0 |
| Patients with ≥1 non-ocular TEAE | 24 (9.0) [28] | 35 (13.0) [46] |
| Patients with ≥1 non-ocular TRAE | 2 (0.7) [2] | 7 (2.6) [9] |
| Non-ocular TRAEs | ||
| Feeling cold | 0 | 6 (2.2) [7] |
| Rhinitis allergic | 0 | 1 (0.4) [1] |
| Paraesthesia oral | 0 | 1 (0.4) [1] |
| Glossitis | 1 (0.4) [1] | 0 |
| Drug eruption | 1 (0.4) [1] | 0 |
Abbreviations: N, safety set; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event;.
Treatment-related ocular AEs occurred in 3.7% and 3.4% of patients in the motugivatrep 0.3% and placebo groups, respectively, and treatment-related non-ocular AEs in 2.6% and 0.7% of patients. The most commonly reported treatment-related ocular AEs in the motugivatrep 0.3% group were abnormal sensation in the eye (four vs no patients in the placebo group) and blurred vision (three vs no patients). Among the four patients in the motugivatrep 0.3% group who experienced abnormal sensation in eye, three patients had a symptom of feeling cold in the eye. Treatment-related non-ocular AEs with motugivatrep 0.3% were feeling cold (six vs no patients with placebo), rhinitis allergic (one vs no patients) and paresthesia oral (one vs no patients). All the treatment-related ocular and non-ocular AEs in the motugivatrep 0.3% and placebo groups were of mild or moderate severity. Treatment-related ocular AEs of moderate severity occurred in two patients in the motugivatrep 0.3% group (conjunctivitis allergic and lacrimation increased in one patient each) and one patient in the placebo group (dry eye). One patient in the motugivatrep 0.3% group had a non-ocular treatment-related AE of moderate severity (rhinitis allergic). All patients with moderate ocular or non-ocular treatment-related AEs were recovering/had recovered.
Significant treatment-emergent AEs (ie those leading to treatment discontinuation) occurred in three patients each in the motugivatrep 0.3% and placebo groups. Significant AEs were conjunctivitis allergic and rhinitis allergic (in the same patient), abdominal pain upper and hypoesthesia (in the same patient), and eye pain occurring in one patient each in the motugivatrep 0.3% group, and conjunctivitis allergic, conjunctivitis viral, and drug eruption in one patient each in the placebo group. Of these AEs, moderate conjunctivitis allergic and rhinitis allergic in the motugivatrep 0.3% group and mild drug eruption in the placebo group were considered related to treatment. All significant AEs resolved without requiring treatment.
There were no deaths due to treatment-emergent or treatment-related AEs and there were no serious treatment-emergent or treatment-related AEs in the motugivatrep 0.3% and placebo groups. The proportions of patients with clinically significant abnormal findings in slit-lamp biomicroscopy or abnormal ophthalmoscopic findings did not differ markedly after treatment administration. While corrected visual acuity fluctuated sporadically before and after treatment, there was no consistent trend in either group. There were also no obvious changes in intraocular pressure or vital signs before and after treatment in either group.
Discussion
This randomized, placebo-controlled Phase 3 study confirmed the efficacy and safety of motugivatrep 0.3% ophthalmic suspension administered four times daily for 8 weeks in patients with all severity of dry eye disease. Treatment with motugivatrep 0.3% significantly improved quality of life in patients with dry eye, as assessed by the primary endpoint at week 4, with significant or numeric improvements also seen in subjective symptoms and a tendency for improvement in objective signs.
In terms of the primary endpoint, a significantly greater decrease from baseline (improvement) in LSM total DEQS was observed at week 4 with motugivatrep 0.3% vs placebo, indicating improved quality of life. Sensitivity analyses confirmed the robustness of these findings, showing consistent and statistically significant differences between the motugivatrep 0.3% and placebo groups for the primary endpoint. In Japan, the diagnostic criteria for dry eye disease are the presence of subjective symptoms and TBUT of ≤5 seconds;2 therefore, we consider it appropriate to use these outcomes as endpoints for the development of therapeutic agents for dry eye disease in Japan. DEQS was selected as the primary endpoint in this study because in addition to eye dryness (the major symptom of dry eye disease), DEQS enables evaluation of various other subjective symptoms, such as eye discomfort and abnormal visual function. Furthermore, placebo-controlled evaluation of efficacy was considered appropriate as drugs that could potentially be used as comparator drugs had been approved prior to the revision of dry eye diagnostic criteria in Japan in 2016, and their efficacy for the primary endpoint selected for this study had not been evaluated.
The minimum clinically important difference for the change in total DEQS has not been established. However, a previous report proposed cutoff values of total DEQS for diagnosing dry eye disease and for classifying its severity, with a cutoff value of ≥15.0 considered optimal for the diagnosis of dry eye disease and severity categories defined as mild (15.0 to <20.0), moderate (20.0 to <26.8), and severe (≥26.8).25 Therefore, we considered demonstrating a shift to below the proposed DEQS diagnostic cutoff or to a milder severity category after treatment as providing supportive evidence of the clinical relevance of motugivatrep in post hoc analyses. Results of these analyses showed that, at both time points (weeks 4 and 8), the proportions of patients who met the total DEQS threshold for a diagnosis of dry eye disease and for classification of its severity were consistently higher in the motugivatrep 0.3% treatment group than in the placebo group across all criteria.
The interpretation of the clinical relevance of the observed between-group difference in total DEQS warrants further discussion in light of the prespecified assumptions used in the study design. Although the between-group difference in the change in total DEQS did not reach the prespecified value defined in the study design, a statistically significant between-group difference was observed. As this prespecified target was not intended to represent a threshold of clinical relevance, and considering the overall improvement in DEQS together with the results of the post hoc analyses, these findings are considered clinically meaningful and support the efficacy of this drug for the treatment of dry eye disease.
In terms of secondary endpoints, the LSM total DEQS decreased (improved) from baseline to a greater extent with motugivatrep 0.3% than with placebo at all assessments over the 8-week treatment period, with statistically significant between-group differences seen at weeks 1, 2 and 4, but not at week 8. The lack of a significant difference in total DEQS at Week 8 is likely attributable to the fact that total DEQS in patients who had <15 (n=65/535) or <20 (n=110/535) scores at the start of the study had already decreased substantially from baseline, leaving limited room for further improvement and making it difficult to detect a difference between the motugivatrep 0.3% and placebo groups. The mean VAS score for eye dryness was also significantly improved with motugivatrep 0.3% vs placebo at the first assessment at week 1 and at week 4. In addition to motugivatrep 0.3% outperforming placebo in terms of total DEQS and VAS scores in this trial, consistent improvements in subjective symptoms exceeding placebo were observed in both the Phase 1/2 study17 and the phase 2b study18 — a notable finding given that placebo effects are often pronounced in placebo-controlled dry eye trials, making it difficult to control for placebo responses, particularly for composite symptom scores,27 and challenging the reproducibility of efficacy results.
In this study, no significant differences between motugivatrep 0.3% and placebo were found in the objective signs (total CFS scores and TBUTs). This is likely to be primarily attributable to the fact that approximately half the patients had no or only minimal objective signs at baseline (total CFS score of the study eye: 0–3). Additionally, an exploratory subgroup analysis undertaken to confirm the reproducibility of the efficacy of motugivatrep in patients with corneal epithelial disorders (a subgroup equivalent to the study population of the Phase 2b study)18 found greater improvements in CFS scores with motugivatrep 0.3% than placebo from weeks 2 to 8. Although not statistically significant, the difference in CFS scores between the motugivatrep 0.3% and placebo groups tended to increase over time, suggesting that motugivatrep 0.3% may contribute to the improvement in objective signs during longer-term therapy.
Motugivatrep 0.3% ophthalmic suspension administered four times daily for 8 weeks was generally well tolerated. Treatment-emergent AEs occurred in 20% of patients in the motugivatrep 0.3% group compared with 15% of patients in the placebo group, with all AEs being mild or moderate in severity. No treatment-emergent or treatment-related AEs resulted in death, and no severe or serious treatment-emergent or treatment-related AEs occurred in either treatment group. Motugivatrep has been associated with the ocular and non-ocular AE of feeling cold. It is known that TRPV1 antagonists in general can cause abnormalities in thermal sensation in a plasma concentration-dependent manner.28,29 In this study, feeling cold was observed as a TRAE of motugivatrep, but no increase in body temperature was observed. Since feeling cold was reported only by patients who received motugivatrep 0.3% in clinical trials, we cannot rule out the risk of abnormalities in thermal sensation with motugivatrep. Although the detailed mechanism linking TRPV1 to feeling cold remains unclear, motugivatrep plasma concentrations have been shown to increase in a dose‑dependent manner,17 and feeling cold was reported more frequently at higher doses of motugivatrep in previous clinical studies.18 In this study, the AE of feeling cold was tolerable and no patient discontinued treatment because of this AE.
The strength of our study is its randomized, double-masked, placebo-controlled, multicenter design, and the inclusion of patients that met the diagnostic criteria for dry eye in Japan. We also acknowledge the limitations of our study, including the use of the DEQS questionnaire, which is not used as commonly as the Ocular Surface Disease Index,30 and the inclusion of only patients residing in Japan. Therefore, study results may not be generalizable to other regions of the world. In addition, selection of patients with high treatment adherence through the placebo run-in period may limit generalizability to real-world clinical practice. This study was not designed to evaluate differences between motugivatrep 0.3% and placebo in subgroup analyses. We also did not undertake assessment for potential center-related confounding. Although the treatment period in the present study was limited to 8 weeks, the longer-term safety and efficacy of motugivatrep 0.3% have been evaluated in a recently completed 52-week, open-label, multicenter, Phase 3 study (jRCT2031220392), results for which will be available in due course.
To conclude, this Phase 3 study demonstrated the efficacy of motugivatrep 0.3% in significantly improving quality of life (total DEQS) at week 4, although the treatment effect vs placebo was less than the prespecified target value. Statistically significant improvements with motugivatrep 0.3% vs placebo were also seen in total DEQS at all assessments up to week 4 and in the VAS score for eye dryness at weeks 1 and 4, with a subgroup analysis suggesting greater improvements in objective signs (CFS scores) with motugivatrep 0.3% among patients with corneal epithelial disorder. Treatment with motugivatrep 0.3% was generally well tolerated, with no major safety concerns identified. These results further bolster the efficacy and safety of motugivatrep 0.3% ophthalmic suspension in patients with dry eye disease.
Acknowledgments
Medical writing support, under the guidance of the authors, was provided by Sohita Dhillon PhD, Content Ed Net, with funding from Senju Pharmaceutical Co., Ltd. This study has been registered at the Japan Registry of Clinical Trials (identifier: jRCT2031220497).
Funding Statement
This study was supported by Senju Pharmaceutical Co., Ltd. The funders had a role in the design and conduct of the study, data management, data analysis, interpretation of the data, and the preparation, review, and approval of the manuscript.
Contributor Information
the SJP-0132 Clinical Study Investigators:
Namie Kobayashi, Motoko Kawashima, Naoki Hamada, Tomohito Nonoyama, Reiko Arita, Shima Fukuoka, Yuko Shibuya, Keigo Sato, Densen Hayashi, Saeko Yagi, Yumiko Yoshimi, Michitaka Sugahara, Makoto Ubuka, Masatada Mitsuhashi, Takuji Kato, Sakae Matsuzaki, Setsuko Hashida, Isao Sato, Norihiko Honda, Takuya Nakajima, Tomoyuki Muramatsu, Junji Ono, Koji Hirano, Yasutaka Kubota, Kunihiro Musashi, Kohei Takayama, Kaori Inazawa, Kenji Sawada, Ayako Eno, Tatsuki Kitahata, Akiyasu Kanamori, Shinichiro Numa, Chika Ohara, Mikki Arai, Fumihide Abe, Minoru Tsuruda, Ryuhei Hara, Seiya Miyajima, Shozo Sonoda, Yoshinori Takahashi, Osamu Miyauchi, Mariko Shirayama, Masami Nakajima, Miki Sakata, Junko Watanabe, Kazuhiko Dannoue, Akihiko Ohira, Yuzuru Yoshimura, Masamaru Inaba, Hideyuki Konno, Eri Ishikawa, Kenichi Takahashi, Osamu Matsuoka, Hiroko Kobashigawa, Satoshi Inoue, Misaki Ishioka, Tetsuhiro Kawata, Hiroko Shimizu, Takuya Kikuchi, Hirofumi Sakuma, Toshiki Sugimoto, and Miki Uchino
Data Sharing Statement
Data from this study are currently not available for sharing due to patient privacy considerations and commercially confidential information.
Ethics Approval and Informed Consent
The study was conducted in compliance with the ethical principles of the Declaration of Helsinki and the International Council for Harmonisation-Good Clinical Practice guideline. Approval was received from independent external institutional review boards responsible for participating study sites, including the Shin-Akasaka Clinic Aoyama Institutional Review Board, Adachi Kyosai Hospital Institutional Review Board, Sugiura Clinic Institutional Review Board, the Institutional Review Board of Southern TOHOKU General Hospital, OPHAC Hospital Institutional Review Board, Jimbo Orthopaedic Surgery Institutional Review Board, and the Review Board of Human Rights and Ethics for Clinical Studies Institutional Review Board. Written informed consent was obtained from patients before study entry.
Disclosure
Yuichi Hori is a board member of the Japan Dry Eye Society and the Asia Dry Eye Society, and has received consulting Fees, honoraria for speaking engagements and travel support from Senju Pharmaceutical Co., Ltd. Tomoyuki Wada and Kazunori Omatsu are employees of Senju Pharmaceutical Co., Ltd.
Data included in this manuscript were presented at the following congresses:
1. The American Academy of Ophthalmology Annual Meeting, October 2025, Orlando, USA, as a poster presentation available from https://aao.scientificposters.com/epsAbstractAAO.cfm?id=1.
2. The 79th Annual Congress of Japan Clinical Ophthalmology, October 2025, Osaka, Japan as an oral presentation.
3. The 41st Asia-Pacific Academy of Ophthalmology Congress, February 2026, Hong Kong as an oral presentation, with the abstract available at https://2026.apaophth.org/wp-content/uploads/sites/8/abstract-book_all-in-one_v2.pdf.
References
- 1.Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017;15(3):276–17. doi: 10.1016/j.jtos.2017.05.008 [DOI] [PubMed] [Google Scholar]
- 2.Dry Eye Society Clinical Practice Guideline Committee. Dry eye clinical practice guidelines. J Jpn Ophthalmol Soc. 2019;123(5):489–592. [Google Scholar]
- 3.Tsubota K, Yokoi N, Shimazaki J, et al. New perspectives on dry eye definition and diagnosis: a consensus report by the Asia Dry Eye Society. Ocul Surf. 2017;15(1):65–76. doi: 10.1016/j.jtos.2016.09.003 [DOI] [PubMed] [Google Scholar]
- 4.Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15(3):575–628. doi: 10.1016/j.jtos.2017.05.006 [DOI] [PubMed] [Google Scholar]
- 5.Uchino M, Yokoi N, Kawashima M, et al. Treatment trends in dry eye disease and factors associated with ophthalmic follow-up discontinuation in Japan. J Clin Med. 2019;8(8):1120. doi: 10.3390/jcm8081120 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.White DE, Zhao Y, Jayapalan H, et al. Treatment satisfaction among patients using anti-inflammatory topical medications for dry eye disease. Clin Ophthalmol. 2020;14:875–883. doi: 10.2147/OPTH.S233194 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.White DE, Zhao Y, Ogundele A, et al. Real-world treatment patterns of cyclosporine ophthalmic emulsion and lifitegrast ophthalmic solution among patients with dry eye. Clin Ophthalmol. 2019;13:2285–2292. doi: 10.2147/OPTH.S226168 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kabra M, Pattnaik BR. Sensing through non-sensing ocular ion channels. Int J Mol Sci. 2020;21(18):6925. doi: 10.3390/ijms21186925 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Ashok N, Khamar P, D’Souza S, et al. Ion channels in dry eye disease. Indian J Ophthalmol. 2023;71(4):1215–1226. doi: 10.4103/IJO.IJO_3020_22 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Fakih D, Migeon T, Moreau N, Baudouin C, Réaux-Le Goazigo A, Mélik Parsadaniantz S. Transient receptor potential channels: important players in ocular pain and dry eye disease. Pharmaceutics. 2022;14(9):1859. doi: 10.3390/pharmaceutics14091859 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Gou Q, Song Z, Gong Y, Li J. TRPV1 in dry eye disease. Front Biosci (Landmark Ed). 2024;29(5):175. doi: 10.31083/j.fbl2905175 [DOI] [PubMed] [Google Scholar]
- 12.Silverman HA, Chen A, Kravatz NL, Chavan SS, Chang EH. Involvement of neural transient receptor potential channels in peripheral inflammation. Front Immunol. 2020;11:590261. doi: 10.3389/fimmu.2020.590261 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Pan Z, Wang Z, Yang H, Zhang F, Reinach PS. TRPV1 activation is required for hypertonicity-stimulated inflammatory cytokine release in human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2011;52(1):485–493. doi: 10.1167/iovs.10-5801 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Guzman M, Miglio M, Keitelman I, et al. Transient tear hyperosmolarity disrupts the neuroimmune homeostasis of the ocular surface and facilitates dry eye onset. Immunology. 2020;161(2):148–161. doi: 10.1111/imm.13243 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Tarui T, Kobayashi S. Pharmaceutical drug containing heterocyclidene acetamide derivative. World Intellectual Property Organization Patent WO2021/066144; 2021. Available from: https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021066144&_cid=P10-MFM4OS-69710-1. Accessed April 8, 2026.
- 16.Atsumi Y, Kobayashi S, Wada T, Kanda A. Effects of a novel TRPV1 antagonist, SJP-0132, on ocular surface dysfunctions in scopolamine-induced dry eye rat model. Paper Presented At: World Ophthalmology Congress; 2024. August 16–19; Vancouver, Canada. [Google Scholar]
- 17.Wada T, Omatsu K, Pflugfelder SC. Results of a randomized, double-masked, placebo-controlled Phase 1/2 study of a TRPV1 antagonist SJP-0132 in participants with dry eye disease. Am J Ophthalmol. 2026;284:216–225. doi: 10.1016/j.ajo.2026.01.009 [DOI] [PubMed] [Google Scholar]
- 18.Hori Y, Wada T, Omatsu K; On behalf of the SJP-0132 clinical study investigators. Efficacy and safety of SJP-0132 in patients with dry eye disease: a Phase 2b randomized, Double-masked, dose-finding study. Am J Ophthalmol. 2026;283:163–175. doi: 10.1016/j.ajo.2025.11.036 [DOI] [PubMed] [Google Scholar]
- 19.Sakane Y, Yamaguchi M, Yokoi N, et al. Development and validation of the dry eye-related quality-of-life score questionnaire. JAMA Ophthalmol. 2013;131(10):1331–1338. doi: 10.1001/jamaophthalmol.2013.4503 [DOI] [PubMed] [Google Scholar]
- 20.Chalmers RL, Begley CG, Caffery B. Validation of the 5-item dry eye questionnaire (DEQ-5): discrimination across self-assessed severity and aqueous tear deficient dry eye diagnoses. Cont Lens Anterior Eye. 2010;33(2):55–60. doi: 10.1016/j.clae.2009.12.010 [DOI] [PubMed] [Google Scholar]
- 21.De Paiva CS, Chen Z, Koch DD, et al. The incidence and risk factors for developing dry eye after myopic LASIK. Am J Ophthalmol. 2006;141(3):438–445. doi: 10.1016/j.ajo.2005.10.006 [DOI] [PubMed] [Google Scholar]
- 22.De Paiva CS, Pflugfelder SC. Corneal epitheliopathy of dry eye induces hyperesthesia to mechanical air jet stimulation. Am J Ophthalmol. 2004;137(1):109–115. doi: 10.1016/s0002-9394(03)00897-3 [DOI] [PubMed] [Google Scholar]
- 23.Dell SJ, Gaster RN, Barbarino SC, Cunningham DN. Prospective evaluation of intense pulsed light and meibomian gland expression efficacy on relieving signs and symptoms of dry eye disease due to meibomian gland dysfunction. Clin Ophthalmol. 2017;11:817–827. doi: 10.2147/OPTH.S130706 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Fenner BJ, Tong L. Corneal staining characteristics in limited zones compared with whole cornea documentation for the detection of dry eye subtypes. Invest Ophthalmol Vis Sci. 2013;54(13):8013–8019. doi: 10.1167/iovs.13-12802 [DOI] [PubMed] [Google Scholar]
- 25.Zou X, Nagino K, Okumura Y, et al. Optimal cutoff value of the dry eye-related quality-of-life score for diagnosing dry eye disease. Sci Rep. 2024;14(1):4623. doi: 10.1038/s41598-024-55358-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Yokoi N, Georgiev GA. Tear film-oriented diagnosis and tear film-oriented therapy for dry eye based on tear film dynamics. Invest Ophthalmol Vis Sci. 2018;59(14):DES13–DES22. doi: 10.1167/iovs.17-23700 [DOI] [PubMed] [Google Scholar]
- 27.Imanaka T, Sato I, Tanaka S, Kawakami K. Predictive factors for the placebo effect in clinical trials for dry eye: a pooled analysis of three clinical trials. Br J Ophthalmol. 2017;101(11):1471–1474. doi: 10.1136/bjophthalmol-2016-309887 [DOI] [PubMed] [Google Scholar]
- 28.Garami A, Pakai E, McDonald HA, et al. TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development. Acta Physiol. 2018;223(3):e13038. doi: 10.1111/apha.13038 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Gavva NR, Treanor JJ, Garami A, et al. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain. 2008;136(1–2):202–210. doi: 10.1016/j.pain.2008.01.024 [DOI] [PubMed] [Google Scholar]
- 30.Sanchez-Brau M, Segui-Crespo M, Canto-Sancho N, Tauste A, Ramada JM. What are the dry eye questionnaires available in the scientific literature used for? A scoping review. Am J Ophthalmol. 2023;246:174–191. doi: 10.1016/j.ajo.2022.10.019 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data from this study are currently not available for sharing due to patient privacy considerations and commercially confidential information.