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Clinical Science

Safety of KPI-121 Ophthalmic Suspension 0.25% in Patients With Dry Eye Disease: A Pooled Analysis of 4 Multicenter, Randomized, Vehicle-Controlled Studies

Korenfeld, Michael MD*; Nichols, Kelly K. OD, MPH, PhD; Goldberg, Damien MD; Evans, David OD§; Sall, Ken MD; Foulks, Gary MD; Coultas, Susan PhD**; Brazzell, Kim PhD**

Author Information
doi: 10.1097/ICO.0000000000002452
  • Open

Abstract

Dry eye disease (DED) is a highly prevalent, multifactorial, heterogeneous, and symptomatic ocular surface disease that imposes a large burden on patients and the healthcare system. Nearly 30 million US adults have symptoms consistent with DED.1,2 Among the most common symptoms are fluctuating vision, eye discomfort, dryness, irritation, foreign body sensation, and excessive tearing.3,4

Regardless of underlying etiology, ocular surface inflammation plays a prominent role in the pathogenesis of DED.5 Inflammation in dry eye is well documented and includes infiltration of the conjunctiva and lacrimal glands by immune cells and elevated levels of tear cytokines, resulting in perpetuating tear film instability.6 Like other chronic inflammatory diseases, DED also has patterns of episodic flare-ups in both ocular symptoms and signs. A significant proportion of patients with DED experience a short period of symptom flare-ups in response to triggers that include excessive screen time, cold weather, air conditioning or heating, exposure to allergens, and other environmental factors—which, taken together, can provide a year-round hazard for patients with dry eye.7–12

Current management of DED often begins with the use of lubricants and other palliative treatments and can often progress to include topical anti-inflammatories, surgical punctal occlusion, and/or amniotic membrane grafts.13 Three anti-inflammatory therapies are currently approved by the US FDA for the treatment of DED: cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan; Irvine, CA) and cyclosporine ophthalmic solution 0.09% (Cequa Sun Pharmaceutical Industries; Mumbai, India), and Lifitegrast ophthalmic solution 5% (Xiidra, Novartis; East Hanover, NJ). All are intended to be used longer term (>3 months) and have a slow onset of effect, taking weeks or months to achieve peak symptom relief. As such, none are effective for prompt relief of dry eye signs and symptoms. Therefore, there is an unmet need for a treatment option that provides rapid relief from the signs and symptoms of DED.

KPI-121 is an ophthalmic nanoparticle suspension of loteprednol etabonate (LE) formulated with a proprietary mucus-penetrating particle (MPP) technology that improves ocular drug delivery.14 KPI-121 ophthalmic suspension 0.25% is being developed for the short-term treatment of the signs and symptoms of DED. The clinical development program included 4 completed trials, one phase 2 and three phase 3 multicenter, randomized, double-masked, vehicle-controlled trials with similar designs to evaluate the safety and efficacy of KPI-121 0.25% when dosed QID for at least 2 weeks in subjects with clinical diagnosis of DED. In this article, we report the safety profile of KPI-121 0.25% from all 4 trials using pooled data for analysis.

MATERIALS AND METHODS

Trial Design

The safety of KPI-121 ophthalmic suspension 0.25% in subjects with DED was evaluated in each of the 4 trials conducted in subjects with a clinical diagnosis of DED and who exhibited signs and symptoms of DED at the time of enrollment. Each trial was multicenter, randomized, double-masked, and vehicle-controlled, conducted in the United States (US), and included 2 groups: KPI-121 0.25% (active) and vehicle (placebo). The data from these trials were pooled for analysis. A phase 2 trial first evaluated KPI-121 ophthalmic suspension 0.25% compared with vehicle in subjects with DED, administered in both eyes QID for 4 weeks. Three phase 3 trials of similar design were then conducted, wherein KPI-121 0.25% or vehicle was administered QID for 2 weeks. The phase 3 trials are referred to in this article as the short-term relief in dry eye (STRIDE) trials. The trials were registered at ClinicalTrials.gov with the identifiers NCT02188160, NCT02813265, NCT02819284, and NCT03616899 for phase 2, STRIDE 1, STRIDE 2, and STRIDE 3 trials, respectively. The vehicle formulation was identical to the active formulation except that it did not contain the active ingredient, LE. In all 4 trials, a run-in period preceded the randomized period wherein all subjects applied vehicle QID for 2 weeks. Eligible subjects who completed the run-in period were randomized to KPI-121 0.25% or vehicle in an approximate 1:1 ratio. Dosing with study product (active or vehicle) was initiated after randomization and was instilled in both eyes as 1 to 2 drops QID. The phase 2 trial included a 4-week period using randomized study products. STRIDE 1, STRIDE 2, and STRIDE 3 included 2-week periods using randomized study products (Fig. 1). In all trials, safety was evaluated based on adverse events (AEs), intraocular pressure (IOP) changes, and other ophthalmic examinations (best corrected visual acuity [BCVA], slit-lamp biomicroscopy, and dilated ophthalmoscopy).

F1
FIGURE 1.:
Study design schema for phase 2, STRIDE 1, STRIDE 2, and STRIDE 3. ITT, intention to treat; QID, 4 times a day.

Every day after the screening visit, subjects recorded their ocular discomfort severity (ODS) and ocular discomfort frequency in a diary using a modified Symptom Assessment in Dry Eye (SANDE) 100 mm visual analog scale for each evaluation.15 Subjects also participated in trial visits at the investigational site at screening (14 ± 1 day before day 1); randomization/day 1, day 8 (±1 day), and day 15 (±1 day) (all trials); and 2 additional visits in the phase 2 trial, at day 22 (±1 day) and day 29 (±1 day). Day 8 (all trials) and day 22 (phase 2 only) were diary collection visits. Change in ODS scores was the key symptom efficacy endpoint, whereas the key sign efficacy endpoint was the assessment of changes in bulbar conjunctival hyperemia graded using the Cornea and Contact Lens Research Unit (CCLRU) grading scale, which is widely regarded as a standard efficacy outcome for topical ocular corticosteroids. Bulbar conjunctival hyperemia was evaluated at day 1 (all trials), day 15 (all trials), and day 29 (phase 2 only).

The trials were designed and monitored in accordance with the ethical principles of Good Clinical Practice and the tenets of the Declaration of Helsinki. Each site obtained institutional review board approval of the protocol and informed consent form. Written informed consent and Health Insurance Portability and Accountability Act authorization was obtained from all subjects before performing any trial-related procedures.

Subjects

The 4 trials enrolled 2871 subjects that included 150 subjects in the phase 2 trial from 9 investigative sites, 915 subjects in STRIDE 1 from 55 investigative sites, 905 subjects in STRIDE 2 from 58 investigative sites, and 901 subjects from 82 investigative sites in STRIDE 3, all in the United States. The randomized population for STRIDE 3 included 3 subjects who had previously participated in STRIDE 2; therefore, the safety population includes 2868 subjects. Of these, 1430 subjects were treated with KPI-121 0.25% QID and 1438 subjects were treated with vehicle QID. Subjects enrolled in the 4 trials were at least 18 years of age who had documented clinical diagnoses of DED in both eyes and signed a written informed consent form. To qualify, a subject must have had ongoing DED as defined by criteria associated with corneal fluorescein staining using the National Eye Institute scale at screening and day 1, bulbar conjunctival hyperemia as assessed using the CCLRU scale at screening and day 1, unanesthetized Schirmer test score at screening, and ODS score after screening and before day 1. Subjects who had a known hypersensitivity or contraindication to the study product, a history of glaucoma, current glaucoma, an IOP of greater than 21 mm Hg, and women who were pregnant or nursing were excluded from the trials. Also excluded were subjects who had used certain medications within the 60 days before enrollment, including topical cyclosporine, topical Lifitegrast, any form of topical LE, ocular, inhaled or intranasal corticosteroids, ocular or oral nonsteroidal anti-inflammatory drugs, topical ocular antibiotics, topical ocular antihistamines, mast cell stabilizers, oral antihistamines, and topical or nasal vasoconstrictors. Similarly, patients with a history of corneal refractive surgery or corneal transplantation were excluded. Safety analyses were conducted in the safety population, which was defined in all 4 trials as all randomized subjects who received at least one dose of study product and had at least 1 postbaseline safety assessment.

Safety Assessments

Adverse Events

AEs were monitored throughout each trial, and details were recorded for onset, resolution, severity, seriousness, causality (relationship to use of trial product [unrelated, unlikely, possible, probable, or definite] based on the investigator's assessment), and outcome. AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA; Version 19.0 for integrated analysis) to the levels of System Organ Class (SOC) and Preferred Term. Treatment-emergent adverse events were defined as those events with onset after the first dose of randomized trial product or worsening after the first dose. A treatment-related TEAE was defined as any TEAE with a causality of possible, probably, or definite based on investigator's assessment. A serious TEAE (SAE) was defined as any TEAE resulting in death, hospitalization, significant incapacity to conduct normal life functions, a birth defect, or any TEAE deemed life-threatening by the investigator.

Intraocular Pressure Measurement

IOP measurements were made at screening, day 1 (all trials), day 15 (all trials), and day 29 (phase 2 only) using Goldmann applanation tonometry.

Other Ophthalmic Examinations

BCVA by Early Treatment Diabetic Retinopathy Study (ETDRS) was assessed at screening, day 1 (all trials), day 15 (all trials), and day 29 (phase 2 only). Slit-lamp biomicroscopy was assessed at most trial visits to assess lashes, eyelid margin hyperemia, character of meibomian gland content, expressibility of meibomian glands, eyelid edema, conjunctival edema, corneal infiltrates, cornea endothelial changes, cornea edema, anterior chamber cells, anterior chamber flare, lens pathology, and scleral injection. Dilated ophthalmoscopy assessment, including evaluation of the optic nerve head for pallor and cupping (cup-to-disc ratio), was performed at screening and at the end of study visit.

Statistical Analysis

Pooled safety analyses were conducted for TEAEs (hereafter referred to as AEs) and IOP data. AE's summaries included all AEs, treatment-related AEs, AEs by maximum severity, discontinuation of study product because of AEs, SAEs, and deaths. For IOP data, the pooled observed and change from baseline measurements were summarized, and summaries were prepared for the percentages of subjects in the pooled population with increases from baseline IOP of >5 mm Hg and of ≥10 mm Hg, with a corresponding observed IOP measurement of ≥21 mm Hg.

Analyses of the other ophthalmic examination data were conducted for each trial individually. For the purpose of efficacy analyses, a “study eye” was defined based on bulbar conjunctival hyperemia score at day 1. The results for ophthalmic safety measures were summarized for each eye separately with outputs for the study and fellow eyes. Changes from baseline were analyzed for BCVA. Biomicroscopy findings were summarized as the number and percentage of subjects with a given finding for dichotomous or 2-point scales and by descriptive statistics for all other findings. Descriptive statistics on a cup/disc ratio were provided.

RESULTS

Subjects

Across the 4 trials, 2868 of the 2871 subjects were included in the safety populations, this number accounts for 3 subjects who were in STRIDE 3 and had previously participated in STRIDE 2. Of the safety population, 1430 subjects received KPI-121 0.25% and 1438 received vehicle. Most subjects (≥99.0%) completed the trial according to the respective protocol. Twenty-eight subjects (1.0%) discontinued the trials early, primarily because of withdrawal by subject or other reasons. One subject withdrew from the trial early because of an AE of instillation site pain.

Table 1 summarizes the subject disposition in all 4 trials. The integrated safety population is the pooled safety populations from the phase 2 trial, STRIDE 1, STRIDE 2, and STRIDE 3 (excluding the 3 subjects who participated in STRIDE 3 but had also previously participated in STRIDE 2).

TABLE 1. - Subject Disposition for Trials of Dry Eye Disease (Integrated Safety Population)
KPI-121 0.25% (N = 1430) Vehicle (N = 1438) Overall (N = 2868)
Completed trial 1411 (98.7%) 1429 (99.4%) 2840 (99.0%)
Subjects withdrawn early from the trial 19 (1.3%) 9 (0.6%) 28 (1.0%)
Reason for early withdrawal
 Withdrawal by subject 7 (0.5%) 3 (0.2%) 10 (0.3%)
 Adverse event 4 (0.3%) 0 4 (0.1%)
 Lost to follow up 2 (0.1%) 2 (0.1%) 4 (0.1%)
 Physician decision 0 0 0
 Pregnancy 0 0 0
 Other 6 (0.4%) 4 (0.3%) 10 (0.3%)
The integrated safety population is the pooled safety populations from the phase 2 Trial, STRIDE 1, STRIDE 2, and STRIDE 3 (but excluding 3 subjects who participated in STRIDE 3 but had also previously participated in STRIDE 2).
QID, 4 times daily.

Table 2 summarizes demographic characteristics by group for the integrated safety population of the 4 dry eye trials. Subjects were predominantly white women (76%), with a mean age of 58 years. No important differences were observed between groups for any of the demographic characteristics (ie, age, sex, and race).

TABLE 2. - Summary of Demographic Characteristics (Integrated Safety Population)
KPI-121 0.25% (N = 1430) Vehicle (N = 1438)
Age in years, mean (SD); min–max 58.2 (15.14); 18–91 58.1 (14.99); 18–93
Female, n (%) 1091 (76.3) 1102 (76.6)
Not Hispanic/Latino, n (%) 1121 (78.4) 1130 (78.6)
Race, n (%)
 White 1108 (77.5) 1116 (77.6)
 Black/African American 208 (14.5) 205 (14.3)
 Asian 86 (6.0) 94 (6.5)
 Other races 28 (1.9) 23 (1.6)
Max = maximum; Min = minimum.

Adverse Events

Table 3 summarizes all AEs, ocular AEs, severe AEs, treatment-related AEs, AEs leading to discontinuation of study product, SAEs, and deaths for the KPI-121 0.25% and vehicle groups in the 4 trials. Overall, most AEs reported were mild or moderate in severity.

TABLE 3. - Number (%) of Subjects Reporting AEs by Category (Integrated Safety Population)
Category KPI-121 0.25% (N = 1430) Vehicle (N = 1438)
Any AEs 185 (12.9) 150 (10.4)
Ocular AEs 135 (9.4) 126 (8.8)
Severe AEs* 8 (0.6) 1 (0.1)
AEs related to treatment 121 (8.5) 103 (7.2)
AEs leading to discontinuation of study treatment 10 (0.7) 5 (0.3)
Serious AEs 7 (0.5) 1 (0.1)
Deaths 0 0
For all categories, subjects reporting more than 1 AE in the category are counted once.
*Subjects reporting one or more AEs are counted once at the maximum severity of all AEs.
Subjects reporting one or more AEs are counted at the greatest relationship of all AEs. The categories of “possibly,” “probably,” and “definitely” are summarized as treatment-related.

AEs were reported by 12.9% (185/1430) and 10.4% (150/1438) of subjects in the KPI-121 0.25% and vehicle groups, respectively (Table 4). The most frequently reported AE was instillation site pain, which was reported by 5.2% of subjects in the KPI-121 0.25% group and 4.4% of subjects in the vehicle group. All other AEs were reported by ≤0.8% of subjects in the KPI-121 0.25% group.

TABLE 4. - Number (%) of Subjects Reporting Common (≥1% in Either Group) AEs (Integrated Safety Population)
System Organ Class Preferred Term KPI-121 0.25% (N = 1430) Vehicle (N = 1438)
No. (%) of subjects reporting any AE* 185 (12.9) 150 (10.4)
General disorders and administration site conditions* 82 (5.7) 69 (4.8)
 Instillation site pain 74 (5.2) 63 (4.4)
At each level of summarization, subjects reporting more than one AE are only counted once. AEs coded using MedDRA Version 19.
*The numbers and percentages for overall AEs and AEs by SOC are inclusive of all PTs. PTs are only included in the table if ≥1% of subjects in either group reported that AE.
PT, preferred term; SOC, system organ class.

Treatment-Related Adverse Events

Treatment-related AEs were reported by 8.5% (121/1430) and 7.2% (103/1438) of subjects in the KPI-121 0.25% and vehicle groups, respectively (Fig. 2). The most frequently reported treatment-related AE was instillation site pain, which was reported by 5.2% of subjects in the KPI-121 0.25% group and 4.4% of subjects in the vehicle group (ie, all cases of AE were considered by the investigator as treatment related). All other treatment-related AEs were reported by ≤0.4% of subjects in the KPI-121 0.25% group.

F2
FIGURE 2.:
Percentage of subjects reporting common treatment-related AEs (integrated safety population). AE, adverse event. aThe numbers and percentages for overall AEs are inclusive of all preferred terms. Terms are only included in the figure if ≥0.3% of subjects in either group reported that AE. At each level of summarization, subjects reporting more than one AE are only counted once at the greatest relationship. The categories of “possibly,” “probably,” and “definitely” were summarized as treatment related. AEs were coded using MedDRA version 19.

Adverse Events by Maximum Severity

Overall, most AEs were mild to moderate in severity. AEs were reported as severe for 0.6% (8/983) of subjects in the KPI-121 0.25% group and 0.1% (1/987) in the vehicle group. Severe AEs in the KPI-121 0.25% group included instillation site pain, hip fracture, migraine, nerve compression, toothache, intervertebral disc protrusion, cholelithiasis, and atrioventricular block. Severe AEs in the vehicle group included eye irritation, blurred vision, and nausea.

Serious Adverse Events

In the KPI-121 0.25% and vehicle groups of the 4 dry eye trials, SAEs were reported by 0.5% (7/1430) and 0.1% (1/1438) of subjects, respectively. The SAEs reported in the KPI-121 0.25% group were hip fracture, joint dislocation, atrioventricular block, diverticulum intestinal, cholelithiasis, intervertebral disc protrusion, delusional disorder, and schizoaffective disorder (1 subject each). None were considered to be related to use of the study product by the investigator. No deaths were reported.

Adverse Events Leading to Permanent Withdrawal of the Study Product

In the 4 dry eye trials, treatment-emergent AEs leading to permanent withdrawal of study product were reported in 0.7% (10/1430) and 0.3% (5/1438) of subjects in the KPI-121 0.25% and vehicle groups, respectively (Table 5). The AEs leading to permanent withdrawal of study product in the KPI-121 0.25% group were conjunctival hyperemia, conjunctival edema, eye pruritus, ocular hyperemia, hip fracture, palpitations, instillation site pain, cholelithiasis, drug hypersensitivity, blood pressure increase, neck pain, headache, delusional disorder, schizoaffective disorder, dyspnea, and rash (1 subject each). Of these, conjunctival hyperemia, conjunctival edema, eye pruritus, ocular hyperemia, headache, drug hypersensitivity, and dyspnea were considered to be related to treatment by the investigator.

TABLE 5. - Number (%) of Subjects Reporting AEs Leading to Permanent Withdrawal of Study Treatment (Integrated Safety Population)
System Organ Class Preferred Term KPI-121 0.25% QID (N = 1430) Vehicle QID (N = 1438)
No. (%) of subjects reporting any AE leading to permanent withdrawal of study treatment 10 (0.7%) 5 (0.3%)
 Conjunctival hyperemia 1 (0.1%) 0
 Conjunctival edema 1 (0.1%) 0
 Corneal infiltrates 0 1 (0.1%)
 Eye irritation 0 1 (0.1%)
 Eye pruritus 1 (0.1%) 0
 Ocular hyperemia 1 (0.1%) 0
 Vision blurred 0 1 (0.1%)
 Herpes zoster 0 1 (0.1%)
 Nasopharyngitis 0 1 (0.1%)
 Eyelid injury 0 1 (0.1%)
 Hip fracture 1 (0.1%) 0
 Palpitations 1 (0.1%) 0
 Nausea 0 1 (0.1%)
 Instillation site pain 1 (0.1%) 0
 Cholelithiasis 1 (0.1%) 0
 Drug hypersensitivity 1 (0.1%) 0
 Blood pressure increased 1 (0.1%) 0
 Neck pain 1 (0.1%) 0
 Headache 1 (0.1%) 0
 Delusional disorder, unspecified type 1 (0.1%) 0
 Schizoaffective disorder 1 (0.1%) 0
 Dyspnea 1 (0.1%) 0
 Rash 1 (0.1%) 0
The integrated safety population is the pooled safety populations from the phase 2 Trial, STRIDE 1, STRIDE 2, and STRIDE 3 (but excluding 3 subjects who participated in STRIDE 3 but had also previously participated in STRIDE 2). At each level of summarization, subjects reporting more than one AE are only counted once. AEs coded using MedDRA Version 19.
QID, 4 times daily.

Intraocular Pressure

In the pooled analysis, the mean IOP values in the study and fellow eyes were similar in the KPI-121 0.25% and vehicle groups at all scheduled trial visits in both the phase 2 trial and all 3 phase 3 trials (Table 6).

TABLE 6. - Observed IOP (mm Hg) in the Study and Fellow Eyes (Integrated Safety Population)
Study Eye Fellow Eye
KPI-121 0.25% (N = 1430) Vehicle (N = 1438) KPI-121 0.25% (N = 1430) Vehicle (N = 1438)
Baseline,* n 1430 1438 1430 1438
 Mean (SD) 14.9 (2.54) 14.9 (2.54) 15.0 (2.51) 14.9 (2.48)
 Min, max 7, 21 7, 21 8, 21 7, 21
Day 15, n 1411 1430 1411 1430
 Mean (SD) 15.2 (2.65) 14.8 (2.56) 15.3 (2.61) 14.9 (2.51)
 Min, max 8, 30 7, 25 9, 30 7, 24
Day 29, n 72 78 72 78
 Mean (SD) 15.6 (3.12) 15.1 (2.80) 15.6 (2.77) 15.3 (2.70)
 Min, max 10, 30 8, 22 10, 27 9, 22
*Baseline is defined as the last nonmissing measurement before the first randomized dose at the day 1/randomization visit (visit 2). If the data from visit 2 were missing, then the value obtained at visit 1 (screening) was used as baseline.
Day 29 only conducted in the phase 2 study.
Max, maximum; Min, minimum.

Table 7 presents a summary of increases from baseline for IOP measurements by category, inclusive of all scheduled and unscheduled postbaseline visits. In the KPI-121 0.25% and vehicle groups, respectively, 0.6% (9/1430) and 0.3% (4/1438) of subjects experienced a >5 mm Hg increase from baseline resulting in an IOP measurement of ≥21 mm Hg in one or both eyes at any postbaseline visit. These numbers include 3 subjects (0.2%) in the KPI-121 0.25% group and 1 subject (0.1%) in the vehicle group who had a ≥10 mm Hg increase from baseline resulting in an IOP measurement of ≥21 mm Hg in one or both eyes at any postbaseline visit.

TABLE 7. - Number (%) of Subjects With Increased IOP Measurements Compared With Baseline at Any Postbaseline Visit by Category and Eye (Integrated Safety Population)
Study Eye Fellow Eye
KPI-121 0.25% (N = 1430) Vehicle (N = 1438) KPI-121 0.25% (N = 1430) Vehicle (N = 1438)
>5 mm Hg increase from BL 30 (2.1%) 22 (1.5%) 33 (2.3%) 20 (1.4%)
>5 mm Hg increase from BL and ≥21 mm Hg measurement 9 (0.6%) 3 (0.2%) 8 (0.6%) 4 (0.3%)
≥10 mm Hg increase from BL 4 (0.3%) 0 3 (0.2%) 1 (0.1%)
≥10 mm Hg increase from BL and ≥21 mm Hg measurement 3 (0.2%) 0 2 (0.1%) 1 (0.1%)
BL, baseline; QID, 4 times daily.

Other Ophthalmic Examination Measures

In all 4 dry eye trials, review of BCVA data revealed no clinically important differences between the KPI-121 0.25% group and the vehicle group in mean changes from baseline at any postbaseline assessment. Similarly, no clinically important differences were observed based on safety evaluations of slit-lamp biomicroscopy in the KPI-121 0.25% groups compared with the vehicle groups. Review of dilated ophthalmoscopy data showed no clinically meaningful differences in ophthalmoscopy evaluations between baseline and end of trial in either group.

DISCUSSION

Because ocular surface inflammation plays an important role in the pathogenesis of DED, topical anti-inflammatories are often used for treatment.16,17 Mucus, which covers the corneal and conjunctival surface, can hinder drug delivery by limiting drug exposure to those tissues and creating a less optimal therapeutic effect.18 MPPs have been specifically engineered to avoid mucus binding and minimize mucus-driven clearance that allows improved drug delivery into ocular surface tissues, making it a good option for the treatment of ocular surface diseases such as DED. KPI-121 0.25% is an ophthalmic nanoparticle suspension of LE formulated with the proprietary MPP technology.14 LE is an ester-based topical ophthalmic corticosteroid designed to be quickly metabolized into inactive metabolites by cellular esterase in ocular tissues, leading to an improved safety profile relative to ketone-based corticosteroids and reducing the potential side effects typically associated with topical corticosteroid use, such as elevated IOP and cataract formation while maintaining potent anti-inflammatory properties.19–23 Although off-label, corticosteroids are currently recommended in several DED treatment paradigms.4,13,24 LE is often preferred in DED therapy because of its favorable safety profile, given its long history of use as an ophthalmic corticosteroid for over 20 years.

The 4 clinical trials reported in the article consist of 2871 subjects, making it one of the largest DED registration programs to date. This large body of safety data demonstrated that there was a low incidence of treatment-related AEs, severe AEs, and SAEs in each trial individually and when evaluated in pooled analysis. No serious ocular treatment-related AEs were reported by subjects in either group. The discontinuation rate because of AEs was very low, at 0.7% for the KPI-121 0.25% group. Most AEs reported were local to the site of administration, transient, and mild or moderate in severity. Instillation site pain was the only AE reported by subjects with an incidence of ≥1% in the KPI-121 0.25% group. Incidence of IOP elevation, another common side effect associated with the use of ocular corticosteroids was low in the KPI-121 0.25% group. Mean IOP measurements at every time point were similar between the KPI-121 0.25% and vehicle groups. Other safety measurements include BCVA, slit-lamp biomicroscopy, and dilated ophthalmoscopy; no safety signals were observed.

One limitation of the safety data is the relatively short exposure time subjects had to KPI-121 0.25%. Most of the trial population in the pooled analysis applied study product for a period of 2 weeks (phase 2: up to 4 weeks). Elevated IOP, cataract formation, and other AEs associated with ophthalmic corticosteroid use may not be observed during a short exposure period; however, corticosteroid use for the treatment of DED is intended as a short-term therapy. The design and duration of the clinical trials of KPI-121 0.25% reflect this intended use.

Another limitation of the safety data is that the subjects enrolled in this large clinical series had overall higher baseline symptomology. In a real-world setting, patients with dry eye exhibit a wide range of symptom severity, thus the tolerability finding of KPI-121 0.25% in this large trial set may not be applicable to all. In addition, these safety results have been evaluated in the specific population included in the trial, and one should use caution in generalizing to those who were excluded, such as patients with glaucoma.

In conclusion, based on the results of the 4 randomized, double-masked, vehicle-controlled trials, with over 2800 subjects, KPI-121 0.25% applied QID for 2 weeks in subjects with DED seemed to be safe and well tolerated with no unexpected treatment-related AEs. The discontinuation rate because of AEs was very low, at 0.7% (10/1430) for the KPI-121 0.25% group. Finally, there were no serious ocular treatment-related AEs reported.

ACKNOWLEDGMENTS

The authors thank Tracy Lovejoy, PharmD of CD Chun Associates, and Desiree Owen, OD, MBA, of Kala Pharmaceuticals for medical writing assistance, funded by Kala Pharmaceuticals.

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Keywords:

dry eye disease; loteprednol etabonate; adverse drug reaction; randomized controlled trial; safety

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.