Abstract
Introduction
Lotilaner ophthalmic solution (0.25%) is the first United States Food and Drug Administration (US FDA)-approved drug for treating Demodex blepharitis. In pivotal trials, it was found to be well tolerated and demonstrated a significant reduction in collarettes and mite density after a 6-week treatment regimen. This study aimed to report the safety and efficacy profile of lotilaner ophthalmic solution (0.25%) from a pooled analysis of two pivotal trials in patients with Demodex blepharitis.
Methods
Pooled data were analyzed from two randomized, double-masked, vehicle-controlled clinical trials [phase 2b/3 Saturn-1 (NCT04475432) and phase 3 Saturn-2 (NCT04784091)] in which patients with Demodex blepharitis were randomly assigned in a 1:1 ratio to receive either lotilaner ophthalmic solution (0.25%) (study group) or the vehicle formulation without lotilaner (control group), twice daily for 6 weeks. The outcome measures were the proportion of patients with 0–2 collarettes (grade 0 collarettes), mite eradication, erythema cure, and the proportion of patients with ≤ 10 collarettes (grade 0 or 1 collarettes) at day 43.
Results
Overall, 833 participants were randomized to receive either the study drug (N = 415) or vehicle (N = 418). On day 43, 49.8% of patients in the study group vs. 9.9% in the control group (p < 0.0001) had collarette grade 0 (0–2 collarettes). A reduction to ≤ 10 collarettes (grade 0 or 1 collarettes) was achieved in 85.1% of patients in study group vs. 28.0% in control group (p < 0.0001). The proportion of patients achieving mite eradication (60.2% vs. 16.1%, p < 0.0001) and erythema cure (24.9% vs. 7.9%, p < 0.0001) were also statistically significantly higher in the study group compared to the control group. The rates of adverse events were low in both studies, with no serious drug-related ocular adverse events reported. As many as 92% of patients rated the study drop as neutral to very comfortable.
Conclusions
Twice-daily treatment with lotilaner ophthalmic solution (0.25%) for 6 weeks demonstrated statistical significance for all outcome measures compared to the vehicle control, with low rates of adverse events and a high rate of drop comfort.
Keywords: Blepharitis, Demodex blepharitis, Lotilaner ophthalmic solution 0.25%, Collarettes, Lid margin disease
Key Summary Points
| Why carry out this study? |
| Lotilaner ophthalmic solution (0.25%) is the first United States Food and Drug Administration (US FDA)-approved drug to target Demodex mites, the root cause of Demodex blepharitis. |
| The present study reports the safety and efficacy of lotilaner ophthalmic solution (0.25%) using pooled data of the two pivotal trials (Saturn-1 and Saturn-2) that collectively involved more than 800 patients. |
| What was learned from the study? |
| Following the 6-week treatment course, the study group treated with lotilaner ophthalmic solution (0.25%) achieved statistically significantly higher proportions of patients with mite eradication, collarette grade 0, reduction to ≤ 10 collarettes, 1- and 2-grade collarette improvement, and erythema cure than the vehicle control group. |
| The study drug was well tolerated, and the rate of adverse events was low, with most of the adverse events being mild and transient in nature. |
Introduction
Demodex blepharitis is caused by an infestation of Demodex mites, the most common ectoparasite in humans [1]. The prevalence of Demodex blepharitis has been documented to be as high as 57.7% among all patients visiting eye care clinics in the US [2]. Since Demodex blepharitis shares many clinical manifestations and subjective symptoms with other eyelid margin or ocular surface diseases, it is often misdiagnosed or underdiagnosed [3].
Demodex mites reside in the lash follicle and in the meibomian and sebaceous glands of the eyelids [1, 4]. They consume epithelial cells at the eyelash follicle and induce epithelial hyperplasia and hyperkeratinization, subsequently leading to the formation of collarettes, potential eyelash loss, and/or lash misdirection [5–7]. Demodex infestation has also been associated with direct mechanical damage to lash follicles as they burrow into the follicles and lay eggs [8].
Prior to 2023, there were no FDA-approved treatments or standardized approach to care, and the management of Demodex blepharitis included variations of the following lid hygiene option(s): warm compresses, eyelid scrubs, lid wipes or washes containing tea tree oil, manuka honey, or other over-the-counter compounds; variations of off-label use of prescription medications including topical or oral antibiotics, oral antiparasitic drugs ivermectin or metronidazole, and topical anti-inflammatory agents; and in-office procedures such as intense pulse light and microblepharoexfoliation [1, 4–6, 8–12]. These management options did not address the root cause of the disease and provided inconsistent and suboptimal efficacy, safety, and tolerability [13].
Lotilaner is an antiparasitic agent that eradicates Demodex through the inhibition of parasite-specific γ-aminobutyric acid (GABA)-chloride channels and causes paralysis of the mites. Lotilaner ophthalmic solution (0.25%), formerly known as TP-03 (XDEMVY, Tarsus Pharmaceuticals Inc., Irvine, CA), is the first FDA-approved drug for the treatment of Demodex blepharitis.
In phase 2 studies [14–17], lotilaner ophthalmic solution (0.25%) was well tolerated and demonstrated a significant reduction in collarettes and mite density after 4-week or 6-week treatment regimens [14–17].
The clinical development program for lotilaner ophthalmic solution (0.25%) also included two pivotal phase 2b/3 (Saturn-1) or phase 3 (Saturn-2) multicenter, randomized, double-masked, vehicle-controlled trials to evaluate the safety and efficacy of lotilaner ophthalmic solution (0.25%) when dosed twice daily for 6 weeks in subjects with Demodex blepharitis [18, 19]. In the present study, we report the safety and efficacy profile of lotilaner ophthalmic solution (0.25%) using pooled data from these two trials for analysis.
Methods
Studies
This was a post hoc pooled analysis of two randomized, double-masked, vehicle-controlled clinical trials [phase 2b/3 Saturn-1 (ClinicalTrials.gov Identifier: NCT04475432) and phase 3 Saturn-2 (ClinicalTrials.gov Identifier: NCT04784091)] evaluating lotilaner ophthalmic solution (0.25%) in patients with Demodex blepharitis. Saturn-1 recruited 421 patients (212 in the study group and 209 in the control group) across 15 US clinical sites from September 2020 to May 2021, and Saturn-2 recruited 412 patients (203 in the study group and 209 in the control group) across 21 US clinical sites from April 2021 to March 2022. Both studies were conducted under IRB-approved protocols that adhered to the tenets of the Declaration of Helsinki. All enrolled patients provided written informed consent using the IRB-approved informed consent form.
Study Participants
The key inclusion criteria for both studies were age ≥ 18 years, documented history of blepharitis, and presence of all the following in the same eye: (a) > 10 lashes with collarettes present on the upper lid (collarette scale grade 2 or worse); (b) at least mild erythema of the upper eyelid margin; and (c) average mite density of ≥ 1.5 mites per lash (upper and lower eyelids combined). Other recruitment criteria have been reported previously [18, 19].
Randomization and Treatment
In both studies, eligible patients were randomly assigned in a 1:1 ratio to receive either the study medication (lotilaner ophthalmic solution, 0.25%) (study group) or the vehicle formulation without lotilaner (control group) using a computer-generated, blocked randomization schedule. A distribution center provided drug kits per the randomization schedule to the sites in the Saturn-1 study, and an interactive response system was used in the Saturn-2 study to assign the treatment based on the randomization.
The eye that met all inclusion criteria was chosen as the analysis eye. If both eyes met the inclusion criteria, the eye with the higher mite density at the screening visit was considered the analysis eye; if both eyes had equal mite density, the right eye was the analysis eye.
The study drugs (lotilaner ophthalmic solution, 0.25% and vehicle) were indistinguishable based on appearance, consistency, and packaging (bottle size, shape, color, labeling, etc.). On day 1 (baseline visit), the first dose of study medication or vehicle was administered in the clinic. Subsequent doses were applied by the patients at home, with one drop in each eye twice daily (morning and evening). The dosing regimen continued for 6 weeks, and patients were evaluated at days 8, 15, 22, and 43. All subjects, investigators, and site personnel performing study assessments were masked to the study medication throughout the duration of the respective studies. Patients were not allowed to use any lid hygiene products, including lid scrubs, for the duration of the studies, and were instructed to refrain from using any cosmetics around the eyes on study visit days.
Study Parameters and Endpoints
The scales used to assign the collarette and erythema scores and the method of counting Demodex mites were identical in both studies [18, 19]. Collarettes were graded from 0 to 4 (Grade 0 = 0 to 2 lashes with collarettes per eyelid; Grade 1 = 3 to 10 lashes with collarettes; Grade 2 = > 10 to < 1/3 of the lashes; Grade 3 = ≥ 1/3 to < 2/3 of the lashes; and Grade 4 = ≥ 2/3 of the lashes). Erythema was graded from 0 to 3 in whole-unit increments (Grade 0 = none; Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe), with clinical descriptors and photos shown in a previous paper [18]. Collarettes and erythema were graded at screening and at all post-baseline visits. The number of Demodex mites observed and the number of lashes epilated were recorded, and mite density was calculated as the number of mites per lash. Mite eradication was defined as a mite density of 0 mites/lash.
The primary efficacy endpoint was the proportion of patients with a collarette grade of 0 (0–2 lashes with collarettes) for the upper eyelid of the analysis eye at day 43. The secondary efficacy endpoints included, among others, the percentage of patients with mite eradication (0 mites/lash for the analysis eye). Additional efficacy outcomes were erythema cure (erythema score of 0 for the upper eyelid of the analysis eye at day 43) and the proportion of patients with ≤ 10 collarettes (grade 0–1).
Responder rates, defined as at least a 1-grade or at least 2-grade improvement in collarette grade, were evaluated at each visit. Additionally, the proportion of patients with no change or ≥ 1-grade worsening in collarette grade and in erythema grade during the 6-week course of treatment in both groups were also evaluated. Adverse events (AEs) were evaluated at all visits in both studies.
Drop comfort was assessed at all visits through day 43 in both studies. Patients rated the comfort of the study medications as “very comfortable,” “slightly comfortable,” “neither comfortable nor uncomfortable” (i.e., neutral), “slightly uncomfortable,” or “very uncomfortable.”
Sample size calculations in Saturn-1 and 2 were based on the response rates achieved in previous clinical studies of lotilaner ophthalmic solution, 0.25% for the treatment of Demodex blepharitis [17]. A sample size of 300 patients (150 in each arm) provided 99% power to establish the superiority of the study drug to vehicle in patients meeting the primary and the secondary efficacy endpoints using a Pearson chi-squared test with a one-sided significance level of 0.025. Given that the COVID-19 pandemic was active at the time of planning the studies, a 30% discontinuation rate was used to calculate the sample size. Accordingly, approximately 209 subjects per study drug group (approximately 418 subjects each in Saturn-1 and Saturn-2) were planned to be randomized.
Statistical Analysis
All statistical analyses were conducted using the combined data from both studies using SAS (SAS Institute Inc, Cary NC). Categorical data were described using the patient count and percentage in each category. Comparisons between the proportions were made using a difference in the proportions test. When comparing the means between the two groups and the change from baseline, the statistical tests were one-sided at an alpha of 0.025.
Results
Participant Disposition
In total, 833 participants were enrolled and randomized to receive either study drug (N = 415) or vehicle (N = 418). Twenty-six patients (12 in the study group and 14 in the control group) were discontinued from this study before the studies ended, and 1 patient missed the final visit at day 43 (Fig. 1). The mean age and baseline demographic and clinical characteristics of all patients are presented in Table 1.
Fig. 1.
Patient disposition flowchart. AEs adverse events
Table 1.
Demographic and baseline characteristics
| Lotilaner ophthalmic solution (0.25%) N = 415 | Vehicle, N = 418 | All subjects, N = 833 | |
|---|---|---|---|
| Age (years), mean ± SD | 65.0 ± 13.70 | 66.5 ± 13.05 | 65.7 ± 13.39 |
| Sex, n (%) | |||
| Male | 195 (47.0) | 198 (47.4) | 393 (47.2) |
| Female | 220 (53.0) | 220 (52.6) | 440 (52.8) |
| Race, n (%) | |||
| White | 371 (89.4) | 374 (89.5) | 745 (89.4) |
| Black or African American | 31 (7.5) | 31 (7.4) | 62 (7.4) |
| Asian | 6 (1.4) | 5 (1.2) | 11 (1.3) |
| American Indian or Alaska Native | 2 (0.5) | 2 (0.5) | 4 (0.5) |
| Native Hawaiian or Other Pacific Islander | 2 (0.5) | 0 | 2 (0.2) |
| Multiple | 3 (0.7) | 3 (0.7) | 6 (0.7) |
| Other | 0 | 3 (0.7) | 3 (0.4) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 31 (7.5) | 28 (6.7) | 59 (7.1) |
| Not Hispanic or Latino | 384 (92.5) | 390 (93.3) | 774 (92.9) |
| Baseline collarette grade, n (%) | |||
| 2 | 157 (37.8) | 138 (33.0) | 295 (35.4) |
| 3 | 160 (38.6) | 174 (41.6) | 334 (40.1) |
| 4 | 98 (23.6) | 106 (25.4) | 204 (24.5) |
| Baseline mite density, mean ± SD | 3.17 ± 1.554 | 3.25 ± 1.651 | 3.21 ± 1.603 |
| Baseline erythema score, n (%) | |||
| 1 | 221 (53.3) | 211 (50.5) | 432 (51.9) |
| 2 | 171 (41.2) | 184 (44.0) | 355 (42.6) |
| 3 | 23 (5.5) | 23 (5.5) | 46 (5.5) |
SD standard deviation
Collarette Reduction
At day 43, the proportion of patients who achieved collarette grade 0 (0–2 collarettes) was 49.8% in the study group vs. 9.9% in the control group (p < 0.0001) (Fig. 2). The proportion of patients with ≤ 10 collarettes was 85.1% of patients in the study group compared to 28.0% in the control group (p < 0.0001) (Fig. 3). Likewise, the proportion of patients demonstrating at least a 1-grade or 2-grade collarette improvement in the upper eyelid of the analysis eye was statistically significantly higher in the study group than the control group [1-grade improvement (94.5% vs. 58.2%); 2-grade improvement (76.1% vs. 22.8%)] (both p < 0.0001). (Fig. 4).
Fig. 2.
Proportion of patients with collarette grade 0 (≤ 2 lashes with collarettes) in the upper eyelid of the analysis eye in the study and control groups
Fig. 3.
Proportion of patients with collarette grade 0–1 (≤ 10 lashes with collarettes) in the upper eyelid of the analysis eye in the study and control groups
Fig. 4.
Proportion of patients with collarette improvement by at least two grades in the upper eyelid of the analysis eye in the study and control groups
Figure 5 represents the proportion of patients with no change and ≥ 1-grade worsening of collarettes in the upper eyelid of the analysis eye in the study and control group. At day 43, only 5.5% of patients in the study group had no improvement or worsening of collarette grade, compared to 41.9% in the vehicle group (p < 0.0001).
Fig. 5.
Proportion of patients with collarette grade shift during the 6-week treatment duration in the upper eyelid of the analysis eye in the study and control groups. Compared to 5.5% of patients in the study group, 41.9% of patients in the control group had no improvement or worsening of collarette grade at day 43
Mite Eradication
The proportion of patients achieving mite eradication (mite density of 0 mites/lash in the analysis eye) was statistically significantly higher in the study group compared to the control group at all visits at which mite density was measured (day 15, day 22, and day 43) (p < 0.0001) (Fig. 6).
Fig. 6.
Proportion of patients with mite eradication (mite density of 0 mites/lash) in the analysis eye of the study and control groups
At day 43, 90.8% of the eyes in the study group had a mean mite density ≤ 0.5 mites/lash, compared to 35.2% in the control group (p < 0.0001).
Erythema Cure
The proportion of patients who improved to and achieved an erythema cure (grade 0 erythema) at day 43 was statistically significantly higher in the study group compared to the control group (24.9% vs. 7.9%; p < 0.0001) (Fig. 7).
Fig. 7.
Proportion of patients with erythema cure (grade 0 erythema) in the upper eyelid of the analysis eye in the study and control groups
Figure 8 represents the proportion of patients with no change and ≥ 1-grade erythema worsening in the upper eyelid of the analysis eye in the study and control group. At day 43, 50.7% of patients in the study group had no improvement or worsening of erythema grade, compared to 67.8% in the vehicle group (p < 0.0001).
Fig. 8.
Proportion of patients with erythema grade shift during the 6-week treatment duration in the upper eyelid of the analysis eye in the study and control groups. Compared to 50.7% of patients in the study group, 67.8% of patients in the control group had no improvement or worsening of erythema grade at day 43
Drop comfort
Figure 9 demonstrates the proportion of patients in the study group who rated the drop as neutral to “very comfortable” on days 1 (baseline visit), 8, 15, 22, and 43. At day 43, 91.5% of patients in the study group, compared with 88.9% of patients in the control group, found the drops to be neutral to “very comfortable.” Averaged across all visits, 92.1% of patients in the study group and 90.1% in the control group reported the drops as neutral to “very comfortable.”
Fig. 9.
Proportion of patients in the study and control groups who rated the drop as neutral to very comfortable
Adverse Events
The proportion of patients with any drug-related ocular treatment-emergent AE was 18.1% (75/415) in the study group and 14.8% (62/418) in the control group. Most of the AEs were mild and transient in nature and resolved with no need for any intervention.
The ocular drug-related treatment-emergent AEs with ≥ 1.0% incidence in either study or control group included eye pain (1.0% vs. 0.5%), visual acuity reduced (1.0% vs. 1.9%), instillation site pain (9.9% vs. 7.2%) and instillation site pruritus (1.0% vs. 1.9%). The ocular drug-related treatment-emergent AEs are shown in Table 2.
Table 2.
Study drug-related ocular treatment-emergent adverse events (TEAE) in the study and control groups
| Ocular TEAEs | Lotilaner ophthalmic solution, 0.25% N = 415 n (%) |
Vehicle N = 418 n (%) |
|---|---|---|
| Instillation site pain | 41 (9.9) | 30 (7.2) |
| Visual acuity reduced | 4 (1.0) | 8 (1.9) |
| Instillation site pruritus | 4 (1.0) | 8 (1.9) |
| Eye pain | 4 (1.0) | 2 (0.5) |
| Dry eye | 3 (0.7) | 2 (0.5) |
| Eye pruritus | 2 (0.5) | 3 (0.7) |
| Vision blurred | 2 (0.5) | 3 (0.7) |
| Eye discharge | 3 (0.7) | 1 (0.2) |
| Photophobia | 3 (0.7) | 1 (0.2) |
| Conjunctival hyperemia | 2 (0.5) | 1 (0.2) |
| Swelling of eyelid | 1 (0.2) | 2 (0.5) |
| Chalazion | 2 (0.5) | 0 (0.0) |
| Erythema of eyelid | 2 (0.5) | 0 (0.0) |
| Eyelid pruritus | 2 (0.5) | 0 (0.0) |
| Visual impairment | 0 (0.0) | 2 (0.5) |
| Instillation site erythema | 2 (0.5) | 0 (0.0) |
| Instillation site irritation | 2 (0.5) | 0 (0.0) |
| Vital dye staining cornea present | 2 (0.5) | 0 (0.0) |
| Eye irritation | 1 (0.2) | 1 (0.2) |
| Eyelid edema | 1 (0.2) | 1 (0.2) |
| Instillation site lacrimation | 1 (0.2) | 1 (0.2) |
| Hordeolum | 1 (0.2) | 1 (0.2) |
| Asthenopia | 0 (0.0) | 1 (0.2) |
| Conjunctival cyst | 1 (0.2) | 0 (0.0) |
| Conjunctival hemorrhage | 1 (0.2) | 0 (0.0) |
| Conjunctival edema | 1 (0.2) | 0 (0.0) |
| Conjunctivochalasis | 1 (0.2) | 0 (0.0) |
| Corneal lesion | 0 (0.0) | 1 (0.2) |
| Eye paraesthesia | 0 (0.0) | 1 (0.2) |
| Eyelid margin crusting | 0 (0.0) | 1 (0.2) |
| Eyelid pain | 1 (0.2) | 0 (0.0) |
| Foreign body sensation in eyes | 1 (0.2) | 0 (0.0) |
| Keratitis | 0 (0.0) | 1 (0.2) |
| Lacrimation increased | 0 (0.0) | 1 (0.2) |
| Ocular discomfort | 0 (0.0) | 1 (0.2) |
| Ocular hyperemia | 1 (0.2) | 0 (0.0) |
| Instillation site discharge | 1 (0.2) | 0 (0.0) |
| Instillation site foreign body sensation | 0 (0.0) | 1 (0.2) |
| Intraocular pressure increased | 1 (0.2) | 0 (0.0) |
Discussion
Lotilaner ophthalmic solution (0.25%) is the first FDA-approved drug to target Demodex mites, the root cause of Demodex blepharitis. In previous trials of lotilaner ophthalmic solution (0.25%) as well as a few systematic reviews and meta-analyses based on them, lotilaner ophthalmic solution, 0.25% was found to be an effective and well-tolerated drug in treating patients with Demodex blepharitis [14–22]. Consistent with these earlier results, the pooled analysis of the Saturn-1 and Saturn-2 trials showed that following the 6-week treatment course, the study group treated with lotilaner ophthalmic solution (0.25%) achieved statistically significant higher proportions of patients with collarette grade 0 (0–2 collarettes), reduction to ≤ 10 collarettes, 1- or 2-grade collarette improvement, mite eradication, and erythema cure than the vehicle control group.
The presence of collarettes is pathognomonic for Demodex blepharitis [23–25]. Collarette grade 0 was the primary efficacy endpoint in phase 2 and 3 clinical trials of lotilaner ophthalmic solution, 0.25% [14–19]. This pooled analysis of efficacy data from both pivotal studies confirms that 6-week, twice-daily treatment with lotilaner ophthalmic solution (0.25%) is effective for reducing collarettes compared with the vehicle control. At day 43, the proportion of patients achieving collarette grade 0 in the study group was almost 40% higher (49.8% vs. 9.9%) than that achieved in the control group (Fig. 2). When analyzing collarette reduction to ≤ 10 collarettes, 57% more patients in the study group than the control group achieved the endpoint (Fig. 3). Likewise, a collarette improvement of at least two grades was achieved in 53% more patients in the study group than in the control group (Fig. 4). Of note, the collarette grading scale is nonlinear; as such, a 2-grade collarette improvement (i.e., from grade 3 to grade 1) can reflect a 90% reduction in the number of collarettes per lid. The proportion of patients with no change or ≥ 1-grade collarette worsening was significantly higher in the vehicle group than in the study group at all time points (Fig. 5).
In the Saturn pivotal studies, individuals at each site were trained to perform mite counts in a consistent manner. Compared to the vehicle group, a statistically significant higher rate of complete mite eradication was observed in the study group as early as week 2. Following six-week treatment with lotilaner ophthalmic solution (0.25%) the difference between the study and control groups in the proportion of patients who achieved mite eradication was 50.3% (67.9% vs. 17.6%) and 37.2% (51.8% vs. 14.6%) in Saturn-1 and Saturn-2 studies, respectively. The pooled analysis also demonstrated similar results, with 44% more patients (60.2% vs. 16.1%) in the study group than the vehicle group achieving mite eradication (0 mites) by week 6 (Fig. 6). Patients were instructed to refrain from the use of any mechanical lid scrubbing or other lid hygiene therapies during the studies. As such, the results of mite eradication in the individual studies as well as in the present pooled analysis indicate the efficacy of the study drug itself.
Improvement in lid margin erythema was generally consistent with the individual studies. Nearly one-fourth (24.9%) of study group patients, compared to 7.9% in the vehicle group, experienced complete resolution of lid erythema by the conclusion of the study. Statistically significant differences between the study and control groups were seen by week 2; however, the rate of erythema cure peaked later at the week 6 timepoint. It is hypothesized that after mites have been eradicated and collarettes resolved, continued healing of the lid margin may then lead to resolution of lid erythema in the weeks following the final study visit. The appearance of lid erythema is partly caused by chronic inflammation that results in a combination of vascular dilation and neovascular growth [26]. While resolution of vascular engorgement can provide a rather quick decrease in lid erythema, neovascular growth may take longer to subside, with a delayed erythema resolution. A non-interventional extension study provides further evidence of this hypothesis [27]. Similar to the collarette findings, the proportion of patients with no change or ≥ 1-grade worsening of erythema was significantly higher in the vehicle group than in the study group at all visits from day 15 onwards during the 6-week course of treatment (Fig. 8).
Most drug-related ocular treatment-emergent AEs in participants receiving lotilaner ophthalmic solution (0.25%) were mild and transient in nature and resolved with no need for intervention. In addition, the study drug appeared to be well tolerated, with 92% of the subjects reporting the drops to be neutral to very comfortable. Additionally, good tolerance of the study drug might be one of the reasons for a low dropout rate observed in this study.
Demodex blepharitis is associated with significant symptomatic and psychosocial burden that negatively affects daily life in the vast majority of patients with the disease [28]. Almost all (99%) patients with Demodex blepharitis experience symptoms such as dryness, itching, and foreign body sensation; more than 40% of patients experience difficulty when driving at night; and nearly one-third required additional time for their daily hygiene routine [29]. Moreover, untreated Demodex blepharitis leads to more frequent eye care visits and increased health care costs [2]. Therefore, a timely diagnosis of Demodex blepharitis and a safe and effective treatment that targets the root cause is very important. For almost two decades, collarettes have been widely accepted to be pathognomonic for Demodex blepharitis. A Demodex Expert Panel on Treatment and Eyelid Health (DEPTH) recently recommended treating Demodex blepharitis patients if collarettes are present, regardless of the presence or absence of symptoms of blepharitis [3, 13]. In the present study, the resolution of collarettes tracked closely with mite eradication, validating the causative nature of the Demodex mites and confirming the presence of collarettes to be pathognomonic for Demodex mite infestation. DEPTH panelists agreed that slit-lamp examination with the patient looking down to grade collarettes is a more clinically efficient way to diagnose Demodex blepharitis than the practice of epilating lashes and counting mites and therefore, recommended incorporating slit-lamp examination with the patient looking down into the routine eye examination [3, 13].
Given the negative impact of Demodex blepharitis on patients’ daily activities and quality of life, its effective treatment is expected to relieve the associated symptom burden and reduce unwanted psychosocial effects [3, 28]. Future studies evaluating the effect of lotilaner ophthalmic solution, 0.25% on patients’ quality of life would help assess the real-world benefits beyond ocular health.
It is important to highlight that Demodex blepharitis is a chronic, progressive disease that will not remit or resolve on its own. In the vehicle group, 41.9% and 67.8% of patients did not see any changes or even experienced worsening of collarette and erythema at day 43, significantly higher than the 5.5% and 50.7% of patients in the study group who remained the same or worsened (p < 0.0001) (Figs. 5, 8). The recurrence of collarettes after treatment cessation is a potential concern, given the chances of reinfestation of Demodex mites from their residence in other areas of the face. In phase 2b/3 and phase 3 studies, patients were followed for up to 6 weeks [18, 19]. A long-term follow-up study from Saturn-1 to evaluate the long-term efficacy and safety profile of lotilaner ophthalmic solution (0.25%) up to one year following the initial instillation of the study drug suggests the treatment response is quite durable [27]. Additional studies assessing the duration of the lotilaner effect and the recurrence rate of Demodex blepharitis following treatment cessation may help validate the findings.
Demodex infestation has been implicated in meibomian gland disease (MGD) and severely immunocompromised patients [30]. As high as 90% of MGD patients have concomitant Demodex infestation [31–33]. Future studies to assess the efficacy of lotilaner in such high-risk patients may provide valuable insights.
The present study pooled the data from the well-designed Saturn-1 and Saturn-2 clinical trials and yielded scientifically robust results. The lack of extensive patient-reported outcomes data is one limitation of the study. Patients were not asked to evaluate ocular discomfort, fatigue, itch, dryness, or any other subjective variables other than drop comfort during the study. Erythema may be noted as a clinical outcome by the doctor or as a patient-reported outcome; in the present study, it was evaluated only by the investigators. Additional patient-reported outcomes data in patients treated with lotilaner ophthalmic solution (0.25%) would add to the clinical relevance of these findings.
Conclusions
This pooled data analysis of Saturn-1 and Saturn-2 studies showed that twice-daily treatment with lotilaner ophthalmic solution (0.25%) for 6 weeks resulted in statistically significant reductions in mites, collarettes, and erythema compared to the vehicle. The study drug was well tolerated, with low rates of adverse events, and 92% of patients reporting lotilaner ophthalmic drops as neutral to very comfortable.
Acknowledgements
Medical Writing/Editorial Assistance
The authors wish to thank Jan Beiting (Wordsmith Consulting) and Raman Bedi, MD (IrisARC—Analytics, Research & Consulting) for assistance in preparing this manuscript. Funding for editorial support in the drafting of this manuscript was provided by Tarsus Pharmaceuticals.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Author Contributions
Conceptualization and Methodology: Elizabeth Yeu and Sesha Neervannan; Formal analysis, investigation, and data interpretation: Elizabeth Yeu, James D. Paauw, Patrick Vollmer, Gregg J. Berdy, William E. Whitson, John Meyer, Blake Simmons, Jared D. Peterson, Laura M. Periman, Blair E. Boehmer, Marc R. Bloomenstein, Walter O. Whitley, Cecelia Koetting, Kavita Dhamdhere, Sesha Neervannan, Joseph B. Ciolino; Writing—original draft preparation: Elizabeth Yeu; Writing—review and editing: all authors; Resources: Kavita Dhamdhere and Sesha Neervannan; Supervision: Elizabeth Yeu, Kavita Dhamdhere and Sesha Neervannan.
Funding
Funding for the Saturn-1 and Saturn-2 clinical trials was provided by Tarsus Pharmaceuticals. As the sponsor of these trials, Tarsus Pharmaceuticals was involved in the design and conduct of the study and the collection, management, analysis, and interpretation of the data. Funding for editorial support in the drafting of this manuscript and for the Rapid Service Fee was provided by Tarsus Pharmaceuticals.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of Interest
Elizabeth Yeu had received consulting fees from, served on the board of directors of, and was an equity stakeholder in Tarsus Pharmaceuticals during the conduct of Saturn-1 and Saturn-2 trials and the planning and execution of this pooled analysis, before becoming an employee of Tarsus Pharmaceuticals. William E. Whitson is an equity stakeholder in Tarsus Pharmaceuticals. Marc R. Bloomenstein, Joseph B. Ciolino, Cecelia Koetting, Laura M. Periman, Patrick Vollmer, and Walter O. Whitley have received consulting fees from Tarsus Pharmaceuticals. Elizabeth Yeu, Kavita Dhamdhere and Sesha Neervannan are employees of Tarsus Pharmaceuticals. Joseph B. Ciolino, Jared D. Peterson, James D. Paauw, and Patrick Vollmer received research fees from Tarsus Pharmaceuticals or Ora Clinical Research. Blake Simmons, Gregg J. Berdy, John Meyer, and Blair E. Boehmer report no conflicts of interest related to this manuscript.
Ethical Approval
The two studies analyzed in this post hoc analysis adhered to the tenets of the Declaration of Helsinki and were approved by the Institutional Review Board (IRB). All enrolled patients provided written informed consent using the IRB-approved informed consent forms.
Footnotes
Prior Presentation: Parts of this work have been presented at the annual meetings of the American Society of Cataract and Refractive Surgery, 2023, San Diego, CA, USA, the European Society of Cataract and Refractive Surgeons, 2024, Barcelona, Spain, and the Women in Ophthalmology 2024 Summer Symposium, Carlsbad, CA, USA.
References
- 1.Zhang AC, Muntz A, Wang MTM, Craig JP, Downie LE. Ocular Demodex: a systematic review of the clinical literature. Ophthalmic Physiol Opt. 2020;40(4):389–432. 10.1111/opo.12691. [DOI] [PubMed] [Google Scholar]
- 2.Trattler W, Karpecki P, Rapoport Y, et al. The prevalence of Demodex blepharitis in US Eye Care clinic patients as determined by collarettes: a pathognomonic sign. Clin Ophthalmol. 2022;16:1153–64. 10.2147/OPTH.S354692. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ayres BD, Donnenfeld E, Farid M, et al. Clinical diagnosis and management of Demodex blepharitis: the Demodex Expert Panel on Treatment and Eyelid Health (DEPTH). Eye. 2023;37(15):3249–3255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Holzchuh FG, Hida RY, Moscovici BK, et al. Clinical treatment of ocular Demodex folliculorum by systemic ivermectin. Am J Ophthalmol. 2011;151(6):1030–4. 10.1016/j.ajo.2010.11.024. [DOI] [PubMed] [Google Scholar]
- 5.Messaoud R, El Fekih L, Mahmoud A, et al. Improvement in ocular symptoms and signs in patients with Demodex anterior blepharitis using a novel terpinen-4-ol (2.5%) and hyaluronic acid (0.2%) cleansing wipe. Clin Ophthalmol. 2019;13:1043–54. 10.2147/OPTH.S198585. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Fromstein SR, Harthan JS, Patel J, Opitz DL. Demodex blepharitis: clinical perspectives. Clin Optom (Auckl). 2018;10:57–63. 10.2147/OPTO.S142708. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Luo X, Li J, Chen C, Tseng S, Liang L. Ocular demodicosis as a potential cause of ocular surface inflammation. Cornea. 2017;36 Suppl 1(Suppl 1):S9–14. 10.1097/ICO.0000000000001361. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Rhee MK, Yeu E, Barnett M, et al. Demodex blepharitis: a comprehensive review of the disease, current management, and emerging therapies. Eye Contact Lens. 2023;49(8):311–8. 10.1097/ICL.0000000000001003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Savla K, Le JT, Pucker AD. Tea tree oil for Demodex blepharitis. Cochrane Database Syst Rev. 2020;6(6):CD013333. 10.1002/14651858.CD013333.pub2. [DOI] [PMC free article] [PubMed]
- 10.Salem DA, El-Shazly A, Nabih N, El-Bayoumy Y, Saleh S. Evaluation of the efficacy of oral ivermectin in comparison with ivermectin-metronidazole combined therapy in the treatment of ocular and skin lesions of Demodex folliculorum. Int J Infect Dis. 2013;17(5):e343–7. 10.1016/j.ijid.2012.11.022. [DOI] [PubMed] [Google Scholar]
- 11.Filho PA, Hazarbassanov RM, Grisolia AB, et al. The efficacy of oral ivermectin for the treatment of chronic blepharitis in patients tested positive for Demodex spp. Br J Ophthalmol. 2011;95(6):893–5. 10.1136/bjo.2010.201194. [DOI] [PubMed] [Google Scholar]
- 12.Frame K, Cheung IMY, Wang MTM, et al. Comparing the in vitro effects of MGO() Manuka honey and tea tree oil on ocular Demodex viability. Cont Lens Anterior Eye. 2018;41(6):527–30. 10.1016/j.clae.2018.06.006. [DOI] [PubMed] [Google Scholar]
- 13.Farid M, Ayres BD, Donnenfeld E, et al. Delphi panel consensus regarding current clinical practice management options for Demodex blepharitis. Clin Ophthalmol. 2023;17:667–679. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Gonzalez-Salinas R, Karpecki P, Yeu E, et al. Safety and efficacy of lotilaner ophthalmic solution, 0.25% for the treatment of blepharitis due to Demodex infestation: a randomized, controlled, double-masked clinical trial. Cont Lens Anterior Eye. 2022;45(4):101492. [DOI] [PubMed] [Google Scholar]
- 15.Gonzalez-Salinas R, Yeu E, Holdbrook M, et al. Safety and efficacy of topical lotilaner ophthalmic solution 0.25% for the treatment of Demodex blepharitis: a pilot study. J Ophthalmol. 2021. 10.1155/2021/3862684. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Gonzalez-Salinas R, Yeu E, Holdbrook M, et al. Collarette elimination and Demodex mite eradication with topical lotilaner ophthalmic solution, 0.25. J Ocul Pharmacol Ther. 2021;37(8):479–84. 10.1089/jop.2021.0011. [DOI] [PubMed] [Google Scholar]
- 17.Yeu E, Holdbrook M, Baba SN, et al. Treatment of Demodex blepharitis: a prospective, randomized, controlled, double-masked clinical trial comparing topical lotilaner ophthalmic solution, 0.25% eyedrops to vehicle. Ocul Immunol Inflamm. 2022. 10.1080/09273948.2022.2093755. [DOI] [PubMed] [Google Scholar]
- 18.Yeu E, Wirta DL, Karpecki P, Baba SN, Holdbrook M. Lotilaner ophthalmic solution, 025%, for the treatment of Demodex blepharitis: results of a prospective, randomized, vehicle-controlled, double-masked, pivotal trial (Saturn-1). Cornea. 2023;42(4):435. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Gaddie IB, Donnenfeld ED, Karpecki P, et al. Lotilaner ophthalmic solution 0.25% for Demodex blepharitis: randomized, vehicle-controlled, multicenter, phase 3 trial (Saturn-2). Ophthalmology. 2023;130(10):1015–1023. [DOI] [PubMed] [Google Scholar]
- 20.Muhammad Akhtar S, Fareed A, Sohaib Asghar M, Mumtaz M, Kaur S. Efficacy and safety of lotilaner ophthalmic solution 02.5% for the treatment of Demodex blepharitis: a meta-analysis of randomized controlled trials. Cont Lens Anterior Eye. 2024;47(3):102148. 10.1016/j.clae.2024.102148. [DOI] [PubMed] [Google Scholar]
- 21.Talha M, Haris Ali M, Fatima E, et al. Efficacy and safety of lotilaner ophthalmic solution (0.25%) for the treatment of Demodex blepharitis: a GRADE assessed systematic review and meta-analysis of observational & experimental studies. Am J Ophthalmol. 2024;264:8–16. 10.1016/j.ajo.2024.03.019. [DOI] [PubMed] [Google Scholar]
- 22.Awan B, Elsaigh M, Tariq A, et al. A systematic review and meta-analysis of the safety and efficacy of 0.25% lotilaner ophthalmic solution in the treatment of Demodex blepharitis. Cureus. 2024;16(1):e52664. 10.7759/cureus.52664. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Coston TO. Demodex folliculorum blepharitis. Trans Am Ophthalmol Soc. 1967;65:361–92. [PMC free article] [PubMed] [Google Scholar]
- 24.English FP. Demodex folliculorum and oedema of the eyelash. Br J Ophthalmol. 1971;55(11):742–6. 10.1136/bjo.55.11.742. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Gao Y-Y, Di Pascuale MA, Li W, et al. High prevalence of Demodex in eyelashes with cylindrical dandruff. Invest Ophthalmol Vis Sci. 2005;46(9):3089–94. [DOI] [PubMed] [Google Scholar]
- 26.Jabbehdari S, Memar OM, Caughlin B, Djalilian AR. Update on the pathogenesis and management of ocular rosacea: an interdisciplinary review. Eur J Ophthalmol. 2021;31(1):22–33. 10.1177/1120672120937252. [DOI] [PubMed] [Google Scholar]
- 27.Sadri E, Paauw JD, Ciolino JB, et al. Long-term outcomes of 6-week treatment of lotilaner ophthalmic solution, 0.25% for Demodex blepharitis: A non-interventional extension study. Cornea. 2024. (in press). [DOI] [PubMed]
- 28.O’Dell L, Dierker DS, Devries DK, et al. Psychosocial impact of Demodex blepharitis. Clin Ophthalmol. 2022;16:2979–87. 10.2147/OPTH.S374530. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Barnett M, Simmons B, Vollmer P, et al. The impact of Demodex blepharitis on patient symptoms and daily life. Optom Vis Sci. 2024;101(3):151–6. 10.1097/OPX.0000000000002111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Wesolowska M, Knysz B, Reich A, et al. Prevalence of Demodex spp. in eyelash follicles in different populations. Arch Med Sci. 2014;10(2):319–24. 10.5114/aoms.2014.42585. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Cheng S, Zhang M, Chen H, Fan W, Huang Y. The correlation between the microstructure of meibomian glands and ocular Demodex infestation: a retrospective case-control study in a Chinese population. Medicine. 2019;98(19): e15595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Bhandari V, Reddy JK. Blepharitis: always remember: Demodex. Middle East Afr J Ophthalmol. 2014;21(4):317–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Siong RLB, Angelito B-dV, Ruben L-BS. Demodex sp. infestation in anterior blepharitis, meibomian-gland dysfunction, and mixed blepharitis. Philipp J Ophthalmol. 2011;36:15–22. [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.