Assessment the Safety of CyclASol compared with Vehicle and Commercially Available 0.05% Cyclosporine in Dry Eye Disease: A Systematic Review and Meta-analysis

Abstract

Introduction

To compare the safety of 0.05% and 0.1% water-free cyclosporine formulation (CyclASol) with vehicle and 0.05% cyclosporine (CsA) in patients with dry eye disease (DED).

Methods

A systematic review with meta-analysis, reporting on the safety of CyclASol in patients with DED in three databases (PubMed, Scopus, and Web of Science until 4 April 2025), was performed according to the PRISMA statement.

Results

Four randomized controlled trials (RCTs) were included, encompassing 1575 eyes from 1575 patients. The meta-analysis revealed no significant difference in the likelihood of experiencing treatment-emergent adverse events (TEAEs) between CyclASol and control groups (risk ratio [RR]: 0.98; 95% confidence interval [CI] 0.85–1.12; P = 0.72; I² = 43%) (rate CyclASol: 30.3% [240 eyes]; rate controls: 30.9% [243 eyes]; rate difference: –0.6%). Similar results were observed for ocular TEAEs (RR: 1.00; 95% CI 0.78–1.30; P = 0.97; I² = 0%) (rate CyclASol: 3.6% [95 eyes]; rate controls: 3.7% [93 eyes]; rate difference: –0.1%). Regarding sensitivity analyses, no significant difference in the likelihood of TEAEs was observed between CyclASol and vehicle groups (RR: 1.02; 95% CI 0.88–1.18; P = 0.83; I² = 44%) (rate CyclASol: 32.5% [240 eyes]; rate vehicle: 30.3% [222 eyes]; rate difference: 2.2%). Comparable results were found for ocular TEAEs (RR: 1.07; 95% CI 0.81–1.41; P = 0.65; I² = 0%) (rate CyclASol: 4.1% [95 eyes]; rate vehicle: 3.6% [85 eyes]; rate difference: 0.5%). Similarly, no statistically significant differences in TEAEs were observed when comparing CyclASol with 0.05% CsA (RR: 0.74; 95% CI 0.51–1.09; P = 0.13; I² = 5%) (rate CyclASol: 29.4% [30 eyes]; rate CsA: 39.6% [21 eyes]; rate difference: –10.2%). Ocular TEAEs also remained comparable between groups (RR: 0.67; 95% CI 0.32–1.41; P = 0.29; I² = 0%) (rate CyclASol: 2.8% [10 eyes]; rate CsA: 3.7% [8 eyes]; rate difference: –0.9%).

Conclusions

Based on the data presented in the meta-analysis, CyclASol is a safe treatment for patients with DED. However, the comparable likelihood of experiencing TEAEs and ocular TEAEs between CyclASol and 0.05% CsA suggests that there is not sufficient evidence to indicate a superior safety profile of CyclASol over commercially available CsA.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40123-025-01217-9.

Key Summary Points

Why carry out this study?

CyclASol is water-free cyclosporine formulation developed using the EyeSol technology, which employs semi-fluorinated alkanes to enhance ocular tolerability compared with commercially available cyclosporine. However, the existing literature has not specifically addressed its safety through a focused analysis of pooled data on treatment-emergent adverse events (TEAEs) and ocular TEAEs.

What was learned from this study?

CyclASol is a safe treatment for patients with moderate-to-severe dry eye disease (DED).

The risk ratio (RR) of TEAEs and ocular TEAEs was comparable between CyclASol and vehicle.

The RR of TEAEs and ocular TEAEs was also similar between CyclASol and 0.05% CsA.

There is not sufficient evidence to indicate a superior safety profile of CyclASol over 0.05% CsA.

Introduction

Topical cyclosporine A (CsA) is an anti-inflammatory agent with immunomodulatory properties widely used in the management of moderate-to-severe dry eye disease (DED) [1]. As a calcineurin inhibitor, CsA modulates T-cell activity by preventing their infiltration, activation, and the release of inflammatory cytokines [2, 3]. Furthermore, CsA inhibits apoptosis in conjunctival epithelial cells while promoting apoptosis in activated T cells, which contribute to its therapeutic effects in DED [3, 4].

Although the safety and efficacy of commercially available CsA—Restasis® (0.05% CsA, Allergan, CA, USA) and Ikervis® (0.1% CsA, Santen Pharmaceutical, CA, USA) in the USA, and Cequa® (0.09%, Sun Pharmaceutical, Mumbai, India) and Zirun® (0.05%, Sinqi Pharmaceutical, Shenyang, China) in Asia—have been demonstrated in several clinical trials for the treatment of DED [5–8], its topical administration remains challenging [9, 10]. This is due to the highly hydrophobic nature of CsA, which prevents the use of common aqueous ophthalmic vehicles [9, 10]. To address this limitation, the aforementioned medications utilize oil-in-water or nano-sized micellar formulations with surfactants and preservatives to deliver CsA to the ocular surface [9–11]. However, these formulations are often associated with a high incidence of treatment-emergent adverse events (TEAEs), ocular burning, redness, eye pain, instillation site pain, and blurred vision [12–16], which can impact tolerability and adherence to treatment [13]. Therefore, there remains a need for innovative delivery approaches to address these challenges.

CyclASol (VEVYE®, Novaliq GmbH, Heidelberg, Germany) is a water-free formulation that utilizes the EyeSol ocular drug delivery technology, which is based on the semifluorinated alkane perfluorobutylpentane [17, 18]. This vehicle is a colorless liquid, free of oils, surfactants, and preservatives [19], designed to enhance ocular tolerability [17, 18]. Owing to its low surface tension, CyclASol spreads rapidly over the ocular surface, while its refractive index—similar to that of water—helps minimize visual disturbances compared with commercially available oil-based CsA formulations [17, 18]. Moreover, ex vivo studies have demonstrated that CyclASol achieves greater corneal barrier penetration than oil-based CsA formulations, supporting its potential for improved bioavailability [20, 21].

To date, the phase II [17], phase IIB/3 (ESSENCE-1) [18], and phase III (ESSENCE-2) [19, 22] trials have reported that CyclASol is a safe and effective treatment for DED with an excellent tolerability profile. Despite this, to the best of our knowledge, no review articles specifically addressing its safety—with particular focus on TEAEs and ocular TEAEs such as reduced visual acuity (VA), blurred vision, eye pain, and instillation site pain—have been published. Therefore, the aim of this systematic review and meta-analysis was to thoroughly assess the safety of CyclASol in comparison with vehicle and commercially available CsA.

Methods

Data Sources and Search Strategy

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [23, 24]. The study was registered in PROSPERO (ID: CRD420251014331) to promote transparency, help reduce potential for bias, and serves to avoid unintended duplication of reviews. The search strategy was guided by the following PICO framework: Is CyclASol safer than vehicle and commercially available CsA formulations for patients with DED?

To address this question, a comprehensive literature search was conducted across PubMed, Scopus, and Web of Science using the following Boolean operators: (water-free cyclosporine solution OR cyclASol solution OR VEVYE cyclosporine solution) AND (dry eye disease OR DED OR evaporative dry eye OR EDE OR aqueous-deficient dry eye OR ADDE OR meibomian gland dysfunction OR MGD). This search identified a total of 25 relevant articles published before 4 April 2025.

Study Selection

All 25 articles identified through the search strategy were considered. Duplicated records were removed using Mendeley Reference Manager, version 2.128.0 (Elsevier Ltd., Amsterdam, Netherlands) [25]. The remaining studies underwent a multistep screening process, including title, abstract, and full-text evaluation. Studies unrelated to the topic were exluded on the basis of title and abstract screening. Full-text screening was conducted by two investigators (A.B.S. and S.L.V.), who selected studies on the basis of predefined inclusion and exclusion criteria. The inclusion criteria encompassed full-length prospective randomized controlled trials (RCTs) conducted in human subjects, specifically evaluating the safety of CyclASol in patients with DED. Exclusion criteria included studies published in languages other than English and/or those appearing in non-indexed journals. No restrictions were placed regarding study location, follow-up duration, sample size, or study outcomes. The study selection process of this systematic review is presented with a flowchart diagram in Fig. 1.

Fig. 1.

Flowchart of study selection process according to the PRISMA statement

Data Extraction and Quality Assessment

The data from each study were independently extracted and summarized in tables created by a single researcher (S.L.V.). The following information was gathered from each article: (1) author and date of publication (year); (2) study design; (3) mean follow-up of all patients in the whole procedure (expressed in months); (4) number of patients; (5) mean age of the patients (expressed in years); (6) patient sex (male/female); (7) number of eyes involved; (8) inclusion criteria of the studies; (9) intervention; (10) control; and (11) conflicts of interest. Regarding the results of the studies, the following safety data were collected: (1) TEAEs; and (2) ocular TEAEs, including (2.1) reduced VA, (2.2) blurred vision, (2.3) eye pain, and (2.4) instillation site pain.

The studies that remained after the full-text screening were further evaluated to determine their quality. To assess the risk of bias, two investigators (C.R.D.L. and J.M.S.G.) summarized the quality using the Cochrane Risk of Bias 2 (RoB 2) tool [26]. This tool assesses the methodological quality of RCTs across the following domains: (1) bias arising from the randomization process, (2) bias due to deviations from intended intervention, (3) bias due to missing outcome data, (4) bias in measurement of the outcome, and (5) bias in selection of the reported result. Each domain consists of one or more signaling questions designed to guide the assessment of bias risk. These judgments are categorized as “yes”, “probably yes,” “probably no,” “no,” and “no information.” RoB 2 utilizes algorithms that link responses to these signaling questions with a risk of bias judgment for each domain, classified as “low risk of bias,” “some concerns,”or “high risk of bias.” The overall risk of bias for each study was determined by the highest risk of bias identified in any domain. However, if a study is assessed as having “some concerns” across multiple domains, it may be classified as having a high overall risk of bias. In cases of disagreement between the two investigators (C.R.D.L. and J.M.S.G.). A third non-masked investigator (D.B.) decided the quality of the studies.

Data Synthesis and Analysis

The data were categorized into the section “RCTs comparing the safety of CyclASol versus controls,” which was further divided into “CyclASol formulated at 0.05%” and “CyclASol formulated at 0.1%.” In terms of study outcome measures, intra-group and inter-group safety outcomes were reported. Intra-group safety outcomes were presented as frequencies (n) and percentages (%), while inter-group safety outcomes were calculated as the difference in TEAES and ocular TEAEs between the two groups: “TEAEs_(CyclASol) – TEAEs_(control)” and “ocular TEAEs_(CyclASol) – ocular TEAEs_(Control).”

A meta-analysis was conducted to synthesize the inter-group safety outcomes using Review Manager Web (RevMan Web), version 5.7 (The Cochrane Collaboration, Oxford, UK) [27]. The Mantel–Haenszel test was used to provide pooled risk ratios (RRs). The absolute value was interpreted together with the P value and 95% confidence intervals (CI) presented on forest plots. P < 0.05 was considered statistically significant. Heterogeneity of the included studies was analyzed together with the Cochrane Q-statistics chi-squared (chi²) test and I-square (I²) test, which was graded as low (I² < 50%) [28]. If there was any significant heterogeneity between studies (I²  ≥ 50% or chi² with a P < 0.05) a random effects model was performed to pool the data, otherwise a fixed effects model was conducted [29, 30]. A sensitivity analysis was also conducted to further assess the safety outcomes of CyclASol compared with the control group in greater detail, evaluating the robustness and stability of the results obtained in the meta-analysis [30]. This analysis focused on two comparisons: “safety of CyclASol versus vehicle” and “safety of CyclASol versus 0.05% CsA.” More detailed information on the data synthesis and analysis is provided in Fig. 2.

Fig. 2.

Flowchart of data synthesis and analysis

Results

Study Characteristics

This systematic review included four RCTs published between 2019 and 2024, comprising 1575 eyes from 1575 patients with a mean age of 59.4 ± 12.7 years. The sex distribution was 1182 females (75%) and 393 males (25%). Patient follow-up ranged from 1 to 4 months, with a mean follow-up of 2.3 ± 1.3 months. Regarding the interventions, one study evaluated both 0.05% and 0.1% CyclASol [17], while the remaining studies administered only 0.1% CyclASol [18, 19, 22]. In terms of control groups, one study included both vehicle and 0.05% CsA (Restasis®) [17], whereas all other studies used vehicle [18, 19, 22]. The dosage regimen was twice daily across all studies. Conflicts of interest were reported in all studies, attributed to affiliations with the manufacturer responsible for distributing the product under investigation (Novaliq GmbH, Heidelberg, Germany). A more detailed description of the study characteristics is provided in Table 1.

Table 1.

Summary of included RCTs

Author (date)	Design	F/Ua	Patients (TG/CG)	Ageb (TG/CG)	Sex (F/M)	Eyes	Inclusion criteria	Intervention	Control	CoI
Wirta et al. [17] 2019 (A)	DM MT	4	103 (51/52)	62.8 ± 10.6 (64.3 ± 10.7/61.3 ± 10.5)	77/26	103	(1) VAS dryness ≥ 40 points; (2) ST ≥ 2 and ≤ 8 mm; (3) tCFS ≥ 6 points; (4) tCS ≥ 2 points	0.05% CyclAsol (Twice daily)	Vehicle (Twice daily)	Yes
Wirta et al. [17] 2019 (B)	DM MT	4	103 (51/52)	61.2 ± 11.4 (61.1 ± 12.3/61.3 ± 10.5)	75/28	103	(1) VAS dryness ≥ 40 points; (2) ST ≥ 2 and ≤ 8 mm; (3) tCFS ≥ 6 points; (4) tCS ≥ 2 points	0.1% CyclAsol (Twice daily)	Vehicle (Twice daily)	Yes
Wirta et al. [17] 2019 (C)	DM MT	4	104 (51/53)	63.5 ± 11.3 (64.3 ± 10.7/62.8 ± 11.9)	78/26	104	(1) VAS dryness ≥ 40 points; (2) ST ≥ 2 and ≤ 8 mm; (3) tCFS ≥ 6 points; (4) tCS ≥ 2 points	0.05% CyclAsol (Twice daily)	0.05% cyclosporine (Twice daily)	Yes
Wirta et al. [17] 2019 (D)	DM MT	4	104 (51/53)	61.9 ± 12.1 (61.1 ± 12.3/62.8 ± 11.9)	76/28	104	(1) VAS dryness ≥ 40 points; (2) ST ≥ 2 and ≤ 8 mm; (3) tCFS ≥ 6 points; (4) tCS ≥ 2 points	0.1% CyclAsol (Twice daily)	0.05% cyclosporine (Twice daily)	Yes
Sheppard et al. [18] 2021	DM MT	3	328 (162/166)	61.4 ± 13.1 (61.5 ± 13.6/61.3 ± 12.7)	235/93	328	(1) OSDI score ≥ 20 points; (2) ST ≥ 1 and ≤ 10 mm; (3) tCFS ≥ 10 points; (4) tCS ≥ 2 points	0.1% CyclAsol (Twice daily)	Vehicle (Twice daily)	Yes
Akpek et al. [22] 2023	DM MT	1	834 (423/411)	57.1 ± 15.9 (57.6 ± 15.4/56.6 ± 16.3)	609/225	834	(1) VAS dryness ≥ 50 points; (2) ST ≥ 1 and ≤ 10 mm; (3) tCFS ≥ 10 points; (4) tCS ≥ 2 points	0.1% CyclAsol (Twice daily)	Vehicle (Twice daily)	Yes
Peng et al. [19] 2024	DM MT	3	206 (103/103)	47.8 ± 14.3 (46.7 ± 14.1/48.9 ± 14.4)	185/21	206	(1) VAS dryness ≥ 50 points; (2) ST ≥ 1 and ≤ 10 mm; (3) tCFS ≥ 10 points; (4) tCS ≥ 2 points	0.1% CyclAsol (Twice daily)	Vehicle (Twice daily)	Yes

CG control group, CoI conflict of interest, DED dry eye disease, DM double-masked, F female, F/U follow-up, M male, MT multicentric, OSDI ocular surface disease index, RCTs Randomized controlled trials, TG treatment group, ST Schirmer test, tCFS total corneal fluorescein staining, tCS total conjunctival staining, VAS visual analog scale

^a Expressed as months

^b Expressed as mean ± SD (standard deviation)

RCTs Comparing the Safety of CyclASol versus Controls

Intra-group and inter-group safety outcomes are presented in Table 2. All studies reported no significant changes from baseline in intraocular pressure, slit-lamp biomicroscopy, or dilated fundoscopy in both groups.

Table 2.

Intra-group and inter-group safety outcomes of CyclASol versus control

Author (date)	CyclASol					Control					Inter-group differences
	TEAE (0–100, %)	Ocular TEAE (0–100, %)				TEAE (0–100, %)	Ocular TEAE (0–100, %)				TEAE (0–100, %)	Ocular TEAE (0–100, %)
		Reduced VA	Blurred vision	Eye pain	Instillation site pain		Reduced VA	Blurred vision	Eye pain	Instillation site pain		Reduced VA	Blurred vision	Eye pain	Instillation site pain
Wirta et al. [17] 2019 (A)b	18 (35.3)	2 (3.9)	0 (0)	1 (2)	1 (2)	14 (26.9)	1 (1.9)	0 (0)	1 (1.9)	1 (1.9)	8.4	2	0	0.1	0.1
Wirta et al. [17] 2019 (B)c	12 (23.5)	4 (7.8)	1 (2)	0 (0)	1 (2)	14 (26.9)	1 (1.9)	0 (0)	1 (1.9)	1 (1.9)	−3.4	5.9	2	−1.9	0.1
Wirta et al. [17] 2019 (C)d	18 (35.3)	2 (3.9)	0 (0)	1 (2)	1 (2)	21 (39.6)	4 (7.5)	2 (3.8)	0 (0)	2 (3.8)	−4.3	−3.6	−3.8	2	−1.8
Wirta et al. [17] 2019 (D)e	12 (23.5)	4 (7.8)	1 (2)	0 (0)	1 (2)	21 (39.6)	4 (7.5)	2 (3.8)	0 (0)	2 (3.8)	−16.1	0.3	−1.8	0	−1.8
Sheppard et al. [18] 2021c	72 (44.4)	5 (3.1)	2 (1.2)	NR	4 (2.5)	71 (42.7)	3 (1.8)	4 (2.4)	NR	2 (1.2)	1.7	1.3	−1.2	NR	1.3
Akpek et al. [22] 2023c	82 (19.4)	7 (1.7)	2 (0.5)	NR	43 (10.1)	96 (23.4)	13 (3.2)	2 (0.5)	NR	36 (8.7)	−4	−1.5	0	NR	1.4
Peng et al. [19] 2024c	56 (54.4)	13 (12.6)	3 (2.9)	3 (2.9)	3 (2.9)	41 (39.8)	18 (17.5)	2 (1.9)	2 (1.9)	0 (0)	14.6	−4.9	1	1	2.9

CsA Cyclosporine, NR Not reported, TEAE Treatment-emergent adverse event, VA Visual acuity

^aDefined as “CyclASol group–Vehicle group”

^b0.05% CyclASol Vs. Vehicle

^c0.1% CyclASol Vs. Vehicle

^d0.05% CyclASol Vs. 0.05% CsA (Restasis®)

^e0.1% CyclASol Vs. 0.05% CsA (Restasis®)

CyclASol Formulated at 0.05%

CyclASol versus vehicle: Wirta et al. (A) [17] reported that TEAEs occurred in 35.3% of patients treated with CyclASol compared with 26.9% in the vehicle group. Regarding ocular TEAEs, reduced VA was observed in 3.9% of patients in the CyclASol group versus 1.9% in the vehicle group. Eye pain was comparable between groups, reported by 2% of patients in the CyclASol group and 1.9% in the vehicle group. Similarly, instillation site pain occurred in 2% and 1.9% of patients in the CyclASol and vehicle groups, respectively. No cases of blurred vision were reported in either group.

CyclASol versus 0.05% CsA: Wirta et al. (C) [17] reported that TEAEs occurred in 35.3% of patients treated with CyclASol compared with 39.6% in the 0.05% CsA group. Regarding ocular TEAEs, reduced VA was observed in 3.9% of patients in the CyclASol group versus 7.5% in the 0.05% CsA group. No cases of blurred vision were reported in the CyclASol group, whereas 3.8% of patients in the 0.05% CsA group experienced this symptom. Instillation site pain was reported in 2% of patients in the CyclASol group, increasing to 3.8% in the 0.05% CsA group. Conversely, whereas 2% of patients in the CyclASol group reported eye pain, no cases were documented in the 0.05% CsA group.

CyclASol Formulated at 0.1%

CyclASol versus vehicle: Wirta et al. (B) [17], Sheppard et al. [18], Akpek et al. [22], and Peng et al. [19] reported that TEAEs occurred in 23.5%, 44.4%, 19.4%, and 54.4% of patients treated with CyclASol compared with 26.9%, 42.7%, 23.4%, and 39.8% in the vehicle group, respectively. Regarding ocular TEAEs, Wirta et al. (B) [17] and Sheppard et al. [18] reported reduced VA in 7.8% and 3.1% of patients in the CyclASol group compared with 1.9% and 1.8% in the vehicle group, respectively. In contrast, Akpek et al. [22] and Peng et al. [19] found lower rates of reduced VA in the CyclASol group, reported by 1.7% and 12.6% of patients compared with 3.2% and 17.5% of patients in the vehicle group. For blurred vision, Wirta et al. (B) [17] and Peng et al. [19] reported rates of 2% and 2.9% in the CyclASol group, while the vehicle group showed lower frequencies, with rates of 0% and 1.9%, respectively. Conversely, Sheppard et al. [18] found that blurred vision was less frequent in the CyclASol group, reported by 1.2% of patients compared with 2.4% of patients in the vehicle group. Akpek et al. [22] observed similar rates of blurred vision in both groups, with 0.5% of patients in each group reporting this symptom. Regarding eye pain, Wirta et al. (B), [17] reported no cases in the CyclASol group, while 1.9% of patients in the vehicle group experienced it. However, both groups reported similar rates of instillation site pain, with 2% and 1.9%, respectively. Sheppard et al. [18] found that eye pain was more frequent in the CyclASol group, reported by 2.9% of patients compared with 1.9% of patients in the vehicle group. This trend continued for instillation site pain, with 2.5% of patients in the CyclASol group and 1.2% in the vehicle group reporting this symptom. Similarly, Akpek et al. [22] and Peng et al. [19] observed that instillation site pain was more frequent in the CyclASol group, with rates of 10.1% and 2.9% compared with 2.9% and 0% in the vehicle group, respectively.

CyclASol versus 0.05% CsA: Wirta et al. (D) [17] reported that TEAEs occurred in 23.3% of patients treated with CyclASol compared with 39.6% in the 0.05% CsA group. Regarding ocular TEAEs, reduced VA was similar between the CyclASol and 0.05% CsA groups, reported by 7.8% and 7.5% of patients, respectively. Blurred vision was reported in 2% of patients in the CyclASol group, rising to 3.8% in the 0.05% CsA group. Similarly, instillation site pain was reported in 2% of patients in the CyclASol group, increasing to 3.8% in the 0.05% CsA group. However, no cases of eye pain were reported in either group.

Meta-analysis

CyclASol versus controls: forest plots illustrating the results of the meta-analyses for TEAEs and ocular TEAEs are presented in Figs. 3 and 4, respectively. The overall likelihood of experiencing TEAEs was similar between CyclASol (rate: 30.3% [240 eyes]) and controls (rate: 30.9% [243 eyes]), with a rate difference of –0.6%. The pooled RR was 0.98 (95% CI 0.85–1.12; P = 0.72; I² = 43%), indicating no statistically significant difference between groups. The overall likelihood of experiencing ocular TEAEs was also comparable between CyclASol (rate: 3.6% [95 eyes]) and controls (rate: 3.7% [93 eyes]), with a rate difference of –0.1%. The pooled RR was 1.00 (95% CI: 0.78–1.30; P = 0.97; I² = 0%), revealing no statistically significant difference. Moreover, no statistically significant differences were observed for specific ocular TEAEs, including reduced VA (RR: 0.84; 95% CI 0.56–1.28; P = 0.43; I² = 0%), blurred vision (RR: 0.78; 95% CI: 0.34–1.77; P = 0.55; I² = 0%), eye pain (RR: 1.22; 95% CI 0.38–3.94; P = 0.74; I² = 0%), and instillation site pain (RR: 1.20; 95% CI 0.82–0.76; P = 0.34; I² = 0%).

Fig. 3.

Meta-analysis: overall safety of CyclASol compared with controls for treatment-emergent adverse events (TEAEs). Forest plot showing the risk ratio (RR), 95% confidence intervals (CI), and P-value. A fixed effects model was performed, revealing no statistically significant difference between both groups

Fig. 4.

Meta-analysis: overall safety of CyclASol compared with controls for ocular treatment-emergent adverse events (TEAEs). Forest plot showing the risk ratio (RR), 95% confidence intervals (CI), and P-value. A fixed effects model was performed, revealing no statistically significant difference between both groups. In addition, no statistically significant differences were observed in reduced visual acuity (VA), blurred vision, eye pain, and instillation site pain between the two groups

Sensitivity Analysis

CyclASol versus vehicle: forest plot showing the results of these analyses are presented in Supplementary Material 1 and 2. The overall likelihood of experiencing TEAEs was comparable between CyclASol (rate: 32.5% [240 eyes]) and vehicle (rate: 30.3% [222 eyes]), with a rate difference of 2.2%. The pooled RR was 1.02 (95% CI 0.88–1.18; P = 0.83; I² = 44%), showing no statistically significant difference between groups. The overall likelihood of experiencing ocular TEAEs was also similar between CyclASol (rate: 4.1% [95 eyes]) and vehicle (rate: 3.6% [85 eyes]), with a rate difference of 0.5%. The pooled RR was 1.07 (95% CI 0.81–1.41; P = 0.65; I² = 0%), indicating no statistically significant difference. Moreover, no statistically significant differences were found for specific ocular TEAEs, including reduced VA (RR: 0.86; 95% CI 0.54–1.36; P = 0.52; I² = 17%), blurred vision (RR: 1.00; 95% CI 0.39–2.58; P = 0.99; I² = 0%), eye pain (RR: 1.01; 95% CI 0.28–3.68; P = 0.99; I² = 0%), and instillation site pain (RR: 1.27; 95% CI: 0.86–1.88; P = 0.24; I² = 0%).

CyclASol versus 0.05% CsA: forest plots displaying the results of these analyses are presented in Supplementary Material 3 and 4. The overall likelihood of experiencing TEAEs was lower in CyclASol (rate: 29.4% [30 eyes]) compared with 0.05% CsA (rate: 39.6% [21 eyes]), with a rate difference of –10.2%. However, the pooled RR was 0.74 (95% CI: 0.51–1.09; P = 0.13; I² = 5%), revealing no statistically significant difference between groups. The likelihood of experiencing ocular TEAEs was comparable between CyclASol (rate: 2.8% [10 eyes]) and 0.05% CsA (rate: 3.7% [8 eyes]), with a rate difference of –0.9%. The pooled RR was 0.67 (95% CI 0.32–1.41; P = 0.29; I² = 0%), revealing no statistically significant difference. Moreover, no statistically significant differences were reported for specific ocular TEAEs, including reduced VA (RR: 0.78; 95% CI 0.28–2.17; P = 0.63; I² = 0%), blurred vision (RR: 0.35; 95% CI 0.06–2.16; P = 0.26; I² = 0%), eye pain (RR: 3.12; 95% CI 0.13–74.76; P = 0.48; I² not applicable), and instillation site pain (RR: 0.52; 95% CI 0.10–2.78; P = 0.44; I² = 0%).

Risk of Bias

The risk of bias summary for the RCTs is presented in Fig. 5A. The risk of bias assessment was categorized into three evidence levels: (1) studies with a low risk of bias (Akpek et al. [22] and Peng et al. [19]), (2) studies with some concerns (Wirta et al. [17] and Sheppard et al. [18]), and (3) studies with a high risk of bias (none). The overall summary of the risk of bias across the domains assessed in each study is shown in Fig. 5B. The items used to evaluate the risk of bias indicated that 50% of the cases were classified as having a low risk of bias, while the remaining 50% were deemed to have some concerns.

Fig. 5.

Risk of bias assessment. A Risk of bias summary of the included studies with traffic light plot. The traffic lights represent the author’s risk of bias judgment in each domain (D) used to assess the quality of the studies. B Overall risk of bias summary of the domains in a bar plot. Bars represent the overall author’s risk of bias judgment in each domain, presented as percentages

Discussion

This study analyzes and compares the safety of CyclASol with vehicle and 0.05% CsA in patients with moderate-to-severe DED. Overall, the analyses showed RR close to 1 for TEAEs (0.91 ± 0.21) and ocular TEAEs (0.91 ± 0.22), suggesting no differences in the likelihood of experiencing TEAEs and ocular TEAEs between patients treated with cyclASol and those who received vehicle, or between CyclASol and commercially available CsA. Moreover, this finding was supported by non-statistically significant P-values accompanied by narrow 95% CIs, which suggest the reliability of the results.

To date, commercially available CsA have demonstrated efficacy and safety in the treatment of DED [5–8]. However, the European panel of experts on the management of inflammation in DED states that one of the main reasons for nonadherence, lack of persistence, or discontinuation of CsA is treatment intolerance [31]. This intolerance is primarily attributed to oil-in-water or nano-sized micellar formulations containing surfactants and preservatives designed to improve CsA delivery to the ocular surface [9–11]. Furthermore, evidence from clinical trials and real-world settings indicates that these formulations are associated with mild-to-moderate ocular TEAEs, such as ocular burning, redness, eye pain, instillation site pain, and blurred vision [12–16]. In this context, CyclASol has emerged as a novel CsA formulation that could potentially reduce the ocular TEAEs reported with commercially available CsA [17, 18]. This is owing to the use of perfluorobutylpentane as a vehicle, which is a colorless liquid free of oils, surfactants, and preservatives [19]. However, while the results of this systematic review with meta-analysis indicate that CyclASol is a safe treatment, no evidence suggests superior safety over commercially available CsA. Recently, the long-term safety and tolerability of 0.1% CyclASol were evaluated in the ESSENCE-2 OLE trial [32]. This study included a total of 202 patients who had been randomized to receive 0.1% CyclASol during the ESSENCE-2 trial and continued treatment in ESSENCE-2 OLE, and 102 who had initially received vehicle in ESSENCE-2 but were switched to 0.1% CyclASol during ESSENCE-2 OLE. Although 0.1% CyclASol was found to be safe and well tolerated after 1 year of treatment, it would have been interesting to include a comparator group of patients receiving long-term treatment with commercially available CsA. Therefore, this aspect should be thoroughly investigated in future RCTs.

In line with this, Wirta et al. [17] conducted the first phase II clinical trial to evaluate the efficacy and safety of CyclASol at different concentrations compared with vehicle and commercially available CsA in patients with DED. This study reported a consistent reduction in total corneal fluorescein staining (tCFS), central corneal fluorescein staining (cCFS), and total lissamine-green staining (tCS) following treatment with 0.05% and 0.1% CyclASol compared with both the vehicle and the commercially available CsA, along with satisfactory safety and tolerability. Although this study did not directly compare the efficacy and safety between the 0.05% and 0.1% CyclASol concentrations, the ESSENCE-1 and ESSENCE-2 trials selected the 0.1% concentration owing to its reported trend toward a greater effect on DED symptoms, as reported by Wirta et al. [17]. These studies indicated that 0.1% CyclASol is effective in treating the signs and symptoms of DED, providing early therapeutic effects on the ocular surface compared with the vehicle. In addition, 0.1% CyclASol demonstrated a clinically meaningful effect in 71.6% of patients with moderate-to-severe DED, with a favorable safety profile and good tolerability.

To further investigate these findings, two pooled analyses from the ESSENCE-1 and ESSENCE-2 trials have been performed. Kaercher et al. [33] evaluated the treatment effects of 0.1% CyclASol in the overall population of patients with DED, as well as in patient subgroups defined by age, sex, and severity. Their analyses confirmed that 0.1% CyclASol is effective in reducing tCFS after 2 weeks of treatment, achieving clinically relevant improvements in more than 50% of patients across both the overall population and subgroups. Building on this evidence, Akpek et al. [34] evaluated the efficacy of 0.1% CyclASol specifically in patients with coexisting cataracts and DED, suggesting that 0.1% CyclASol is a promising candidate for preoperative management of tCFS in patients with DED undergoing cataract surgery. Despite these studies, a detailed observation of the figures reported by Wirta et al. [17] reveals that while 0.1% CyclASol achieved a greater reduction from baseline ocular surface disease index (OSDI) compared with 0.05% cyclASol at week 16, the 0.05% concentration appears to produce a greater reduction from baseline in tCFS, cCFS, and tCS at the same follow-up visit. However, it remains unclear whether there were statistically significant differences in these signs between the two CyclASol concentrations. Therefore, further RCTs with longer follow-up periods are needed to thoroughly compare the efficacy and safety of CyclASol at 0.05% and 0.1% concentrations, and subsequently analyze its effects on the ocular surface, TEAEs, and tolerability in comparison with other commercially available CsA, such as Ikervis®, Cequa®, and Zirun®.

Strengths and Limitations

To the best of our knowledge, this is the first systematic review with meta-analyses registered in PROSPERO that evaluates the safety of CyclASol from a broader perspective. It includes both 0.05% and 0.1% formulations, comparing them with vehicle and commercially available CsA, with a particular focus on TEAEs and ocular TEAEs, such as reduced VA, blurred vision, eye pain, and instillation site pain.

In general, this study included a substantial number of patients from various countries and ethnicities, with a sensitivity analysis showing consistent results. Although these aspects may enhance the generalizability of the findings, several limitations should be acknowledged. One of the main limitations of this study is the moderate heterogeneity observed for TEAEs, which may be attributed to the following methodological differences among the included studies: (1) varying follow-up periods (ranging from 1 to 4 months); (2) differences in patient age (ranging from 46.7 to 64.3 years); (3) the use of different tests to assess DED symptoms (OSDI and VAS dryness), along with varying cutoff values for inclusion—VAS dryness (≥ 40 or ≥ 50 points), ST (≥ 2 to ≤ 8 mm or ≥ 1 to ≤ 10 mm), and tCFS (≥ 6 or ≥ 10 points); and (4) the application of different versions of the Medical Dictionary for Regulatory Activities (MedDRA) to code adverse events (version 18.1 or 20.1). These methodological differences may have influenced the detection, classification, and frequency of TEAEs across studies. Longer follow-up periods may increase the likelihood of detecting TEAEs, while older populations are more likely to present with comorbidities, potentially confounding the attribution of TEAEs to CsA formulations. Variability in inclusion criteria among studies may have led to differences in baseline DED severity, thus affecting safety and tolerability profiles. In addition, the use of different versions of the MedDRA could have introduced inconsistencies in the classification of TEAEs. Another limitation is the repeated inclusion of the Wirta et al. [17] study in both the meta-analysis and sensitivity analyses, owing to the presence of multiple treatment comparisons—0.05% or 0.1% CyclASol versus vehicle, and 0.05% or 0.1% CyclASol versus 0.05% CsA. Although each comparison is distinct, their inclusion may have resulted in patient duplication, potentially introducing bias into the overall results. In contrast, recently published studies such as the ESSENCE-2 OLE trial [32] and the pooled analyses of ESSENCE-1 and ESSENCE-2 trials [33, 34] were excluded from this review to minimize the risk of overrepresentation and improper weighting of data across studies.

Finally, it is also important to mention that all the included studies had conflicts of interest with the manufacturer responsible for distributing CyclASol. In line with this, it is important to mention that the purpose of this study was initially to evaluate both the safety and efficacy of CyclASol. However, efficacy results at the end of the follow-up period could not be extracted from half of the studies included in this systematic review with meta-analysis. Wirta et al. [17] established the primary endpoints as the change from baseline in tCFS and visual analog scale (VAS) dryness in the worse eye after 16 weeks of treatment with CyclASol. However, the results were mainly reported in week 4 of follow-up, while the results in week 16 could not be extracted from the main text or the figures. Similarly, Sheppard et al. [18] determined the primary endpoints as the change from baseline in tCFS and OSDI after 4 weeks of treatment with CyclASol. Although the follow-up continued until week 12, the results from this visit could not be extracted from the main text or the figures either. As a result, the manufacturer responsible for distributing CyclASol was contacted to kindly request the efficacy results at the end of the follow-up period for these studies. However, despite efforts, these data could not be obtained. This situation may influence the conduct of systematic reviews with meta-analyses on CyclASol. In a recent systematic review with meta-analysis, Rehan et al. [35] evaluated the efficacy and safety of 0.1% CyclASol compared with vehicle in patients with DED. Regarding efficacy results, only the tCFS and dryness symptoms from these studies in week 4 could be included. However, for safety results, TEAEs from these studies were reported at the end of the follow-up period, enabling them to be incorporated into the meta-analysis. This discrepancy in reporting efficacy and safety results at different follow-up periods within the same study complicates the appropriate integration of data when performing the systematic review. In addition, this may impact on the overall interpretation of meta-analysis, limiting the ability to assess the sustained effects of CyclASol and to coherently compare efficacy and safety results. Therefore, it would be interesting for the previously published RCTs on CyclASol to provide efficacy and safety results at the same follow-up period. Overall, these limitations, along with the limited number of studies included, suggest that the findings of this systematic review and meta-analysis should be interpreted with caution.

Conclusions

Based on the data analyzed, CyclASol is a safe treatment for patients with moderate-to-severe DED. Specifically, the likelihood of experiencing TEAEs and ocular TEAEs was similar between patients treated with CyclASol and those who received vehicle, or between CyclASol and 0.05% CsA. This last finding suggests that there is not sufficient evidence to indicate a superior safety profile of CyclASol over commercially available CsA. Further RCTs are needed to confirm these findings, including comparative evaluations of CyclASol at 0.05% and 0.1% concentrations, and to assess its efficacy and safety relative to other commercially available CsA treatments, such as Ikervis®, Cequa®, and Zirun®.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Antonio Ballesteros-Sánchez: Conceptualization, methodology, formal analysis, investigation, and writing—original draft preparation. Sara Llort-Vilaró: Data curation and writing—review and editing. José-María Sánchez-González: Data curation and writing—review and editing. Davide Borroni: Data curation and writing—review and editing. Carlos Rocha-de-Lossada: Data curation and writing—review and editing.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations

Conflict of Interest

Antonio Ballesteros-Sánchez, José-María Sánchez-González, Davide Borroni, and Carlos Rocha-de-Lossada are Editorial Board members of Ophthalmology and Therapy. They were not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Sara Llort-Vilaró has no conflicts of interest to declare.

Ethical Approval

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study was registered in PROSPERO (ID: CRD420251014331) to promotes transparency, helps reduce potential for bias and serves to avoid unintended duplication of reviews.

Scale Permission

This study did not employ any proprietary or copyrighted assessment tools or scales that require special permissions for use. All methodologies and measurement instruments used are either original to this study or fall within the public domain.