
==== Front
Ophthalmol Ther
Ophthalmol Ther
Ophthalmology and Therapy
2193-8245
2193-6528
Springer Healthcare Cheshire

39133376
1013
10.1007/s40123-024-01013-x
Original Research
Real-Life Study on the Efficacy and Tolerance of a Preservative-Free Surfactant-Free Latanoprost Eye Drop in Patients with Glaucoma
http://orcid.org/0009-0004-3916-6478
Chauchat Laure laure.chauchat@horus-pharma.com

1
Guerin Camille 1
Rebika Hayette 12
Sahyoun Marwan 1
Collignon Nathalie 3
1 Laboratoires Horus Pharma, 22 Allée Camille Muffat, 06200 Nice, France
2 https://ror.org/02tcf7a68 grid.411163.0 0000 0004 0639 4151 Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France
3 https://ror.org/044s61914 grid.411374.4 0000 0000 8607 6858 Centre Hospitalier Universitaire de Liège, Liège, Belgium
12 8 2024
12 8 2024
10 2024
13 10 26612677
26 6 2024
25 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Introduction

The purpose of this study is to assess the real-life efficacy and tolerance of a new preservative-free, surfactant-free latanoprost (PFSF-LAT) formulation.

Methods

Retrospective, multicentre, non-comparative, observational study in patients with ocular hypertension or open angle glaucoma, naïve or non-naïve to previous intraocular pressure (IOP)-lowering treatment, and treated for at least 3 months with the study eye drop. IOP for worse eye, ocular signs and symptoms, and concomitant use of artificial tears were collected at study drug initiation and at last visit under treatment. Reasons for discontinuing the study eye drop (if relevant) and investigators’ satisfaction were also assessed.

Results

In the per protocol population (103 eyes; 63 naïve, 39 switched, 1 not classified because of missing data), IOP decreased significantly (p < 0.001) from 21.6 ± 5.0 mmHg at baseline to 16.1 ± 3.5 mmHg at the end of the study (mean reduction of − 5.5 ± 4.6 mmHg; − 25.5%). IOP in naïve patients was significantly improved, with a mean reduction of 7.1 mmHg (− 30.7%), which was within expected latanoprost IOP-lowering effect. Interestingly, in previously treated patients, switching to PFSF-LAT also allowed for a further 2.9 mmHg decrease in IOP (p < 0.001). The incidence of ocular side effects at study initiation was significantly (p < 0.001) reduced from 31.1% to 11.3% in the overall population, and from 65.0% to 7.5% in switched patients. This included conjunctival hyperaemia and superficial punctate keratitis (from 42.5% to 2.5% and from 37.5% to 2.5% in switched patients, respectively). According to investigators, tolerance and efficacy of the study eye drop were satisfactory or very satisfactory in 98.1% and 83.2% of patients, respectively.

Conclusion

PFSF-LAT is an efficient treatment for patients with glaucoma with an improved tolerance profile. It can be considered as initial therapy in naïve patients or in patients with poor ocular tolerance to previous IOP-lowering eye drops.

Keywords

Adherence
Efficacy
Glaucoma
Intraocular pressure
Latanoprost
Preservative-free
Real-life study
Surfactant-free
Tolerance
Laboratoires Horus Pharmaissue-copyright-statement© Springer Healthcare Ltd., part of Springer Nature 2024
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pmcKey Summary Points

Why carry out this study?	
Prostaglandin analogue eye drops are considered a first-line treatment in the management of glaucoma.	
Both preservatives and high concentrations of surfactants in eye drop formulations increase corneal toxicity; poor ocular tolerance can adversely affect patients’ adherence and, consequently, treatment efficacy.	
The aim of this study was to assess the real-life efficacy and tolerance of a preservative-free, surfactant-free latanoprost eye drop among patients with glaucoma.	
What was learned from the study?	
In routine clinical practice, this new preservative-free and surfactant-free latanoprost formulation was effective in lowering the intraocular pressure and was well tolerated by both naïve and switched patients with glaucoma.	
In switched patients, the study latanoprost eye drop was better tolerated than prior treatments and provided better intraocular pressure control.	
By reducing intraocular pressure and improving ocular tolerance, this new formulation can improve adherence to treatment and disease control, which is crucial for chronic conditions like glaucoma.	

Introduction

Glaucoma is a degenerative disease of the optic nerve head leading progressively to visual field loss and potentially blindness. Optic nerve damage in patients with glaucoma is irreversible, but lowering intraocular pressure (IOP) with glaucoma medications, laser trabeculoplasty and/or ocular surgery is effective in slowing down the progression of the disease [1]. Elevated IOP results from a homeostatic disequilibrium between the production and drainage of aqueous humour. Ocular hypotensive eye drops are the mainstay of glaucoma therapy. There is currently a large choice of IOP-lowering eye drops including prostaglandin analogues (PGAs), beta-blockers, carbonic anhydrase inhibitors, alpha-2 adrenergic agonists, and parasympathomimetic drugs [2]. These medications primarily act by reducing the production of aqueous humour by the ciliary body and/or by decreasing the outflow resistance through the uveoscleral or trabecular meshwork pathways.

PGAs, such as latanoprost, travoprost, and tafluprost, are recommended as the first-line therapeutic class for the medical treatment of glaucoma. They are favoured owing to their 24-h IOP-lowering efficacy with just once-daily dosing, as well as their favourable systemic and ocular adverse effect profiles [3]. PGAs are particularly effective, reducing IOP by 25–35%, and they have a comparable impact on visual field progression in patients with open angle glaucoma (OAG) [2–5]. Latanoprost 50 µg/mL was the first PGA to be granted marketing authorization for OAG or ocular hypertension (OHT), and still accounts for the majority of prescriptions [6]. The original latanoprost formulation (Xalatan®, Pfizer, New York, USA) contains benzalkonium chloride (BAK) as a preservative. BAK is a polyquaternium ammonium compound that can disrupt the tear film with each instillation, leading to ocular surface inflammation and ocular surface disease (OSD) over time [7]. This can result in poor local tolerance and, in some cases, compromise the outcome of filtering surgery in patients with glaucoma [8]. BAK-preserved eye drops have also been shown to exacerbate the ocular signs and symptoms of dry eye disease, a common condition in both the elderly and glaucomatous patients [9]. Overall, many patients on preserved glaucoma medications experience moderate to severe signs and symptoms of OSD, which can be challenging as this affects adherence to treatment and compromises its efficacy [10, 11]. In cross-sectional studies, logistic regression analysis showed that the number of antiglaucoma medications and the duration of therapy were key predictors of significant ocular signs and symptoms in patients with glaucoma [12, 13]. Thus, OSD frequently coexists with glaucoma and may be initiated or exacerbated by topical glaucoma medications [14].

To improve tolerance, preservative-free (PF) latanoprost eye drops have been developed and should be preferred in patients with OSD [3]. Switching to PF-latanoprost provides similar IOP-reduction with better tolerance and patient satisfaction, thereby improving compliance [15–19]. While preservatives are widely recognized for causing ocular toxicity, other non-active ingredients, such as surfactants, receive less attention. However, high concentrations of surfactants compromise cell membrane integrity and induce latent ocular inflammation in in vitro and ex vivo animal models [20–23]. A new PF and surfactant-free formulation of latanoprost 0.005% (Xalof/Xiop®, Horus Pharma, France) has been available in several European countries for a few years. Our study aimed to retrospectively evaluate the efficacy and ocular tolerance of this medication in patients with OHT or OAG who were treated for at least 3 months.

Methods

This retrospective, multicentre, open-label, non-comparative, observational study was performed at 11 clinical sites (5 hospital centres and 6 private practices) in Belgium. Patient selection occurred from May to September 2022. Eligibility criteria included being male or female, at least 18 years old, diagnosed with OAG or OHT in one or both eyes, under the care of the investigator for at least 3 months prior to data collection, treated with monotherapy using the study eye drop (Xalof/Xiop®, Horus Pharma, Nice, France) according to the Summary of Product Characteristics (once daily at night) for at least 3 months, with IOP measurements taken at least 3 months after starting the study drug, and providing informed consent. Patients could have been either treatment-naïve before starting the study eye drop or previously treated for OHT or OAG before switching to the study medication. Concomitant IOP-lowering medications in one or both eyes during treatment with the study drug were not allowed. Patients with insufficient documented data, those suffering from secondary acquired glaucoma, or those who underwent ocular surgery and/or laser trabeculoplasty during follow-up were excluded.

Data were collected retrospectively from medical charts. The study was approved for each of the 11 clinical sites by four correspondent ethics committees (C.H. Bois de l’Abbaye, Seraing, 21/02/2022, reference number 2022/02; Clinique Sainte-Elisabeth C.H.U. UCL Namur, Namur, 01/03/2022, reference number 05-22; C.H.U. de Liège, Liège, 01/04/2022, reference number 2022/34; and C.H.U. Saint-Pierre, Bruxelles, 07/04/2022, reference number CE/22-04-02) and was conducted in accordance with all applicable regulatory requirements and the Helsinki Declaration of 1964 and its later amendments (Version 64th, World Medical Association, Fortaleza, Brazil, 2013). The data used in this study were de-identified to ensure the confidentiality and anonymity of the participants. No information that could directly identify individuals was included in the datasets analysed. Patients were pre-selected for participation and were contacted by the investigators or their delegated staff, who orally informed them about the study. Data were collected by the investigator or their delegated site staff and entered into the case report forms.

The following information was collected: age and sex; detailed diagnosis; significant systemic medical history (hypertension, diabetes, others) and ocular medical history; ocular medications (IOP-lowering treatments, artificial tears or lubricants, steroids, others) and systemic medications (antidepressants, diuretics, retinoids, antihypertensives, others); dates of OHT/OAG diagnosis and initiation of IOP-lowering therapy (if applicable); date of initiation of the study eye drop; equipment used to measure IOP (Goldmann applanation tonometry, pneumotonometer, or other); time of day (morning or afternoon) of IOP measurement; IOP value at initiation of the study eye drop and the last available IOP value on study drug; reason for switching to the study eye drop (if applicable); previous IOP-lowering treatments (if applicable); reason for discontinuation of the study eye drop (if applicable); signs and symptoms of ocular tolerance before the initiation of the study drug and during treatment with the study eye drop; and investigator satisfaction (assessed as very satisfactory, satisfactory, neutral, not satisfactory, or very dissatisfactory).

Study Outcomes

IOP was determined in each eye at initiation and after at least 3 months of treatment with the study eye drop (last available measurement following initiation). When both eyes were treated, the eye with the highest IOP at treatment initiation was defined as the “worse eye” and included in further statistical analysis. If both eyes had the same IOP, the right eye was randomly assigned as the worse eye. Safety outcomes included ocular signs (e.g. conjunctival hyperaemia, superficial punctate keratitis [SPK]) and symptoms (e.g. stinging on instillation, foreign body sensation, itching, tearing). The concomitant use of artificial tears/lubricants was also recorded, as well as the investigator’s satisfaction regarding the drug’s efficacy and tolerance at the end of the follow-up.

Statistical Analysis

Statistical analyses were performed using SPSS v29.0 and RStudio v4.3.2. Study outcomes were determined overall and separately in naïve and non-naïve patients. Changes in IOP were primarily assessed in the per protocol (PP) population (patients with at least 3 months of treatment with the study drug) and tested using a paired t test. Ocular tolerance was investigated in the overall population and in the subgroup of patients who switched to the study eye drop because of poor ocular tolerance to their previous treatment. Comparisons before and during treatment with the study drug were performed using a Wilcoxon signed ranks test (artificial tears usage, number of ocular signs, number of ocular symptoms). The percentages of patients with ocular signs or symptoms before and at the end of follow-up were compared using a binomial two-sided exact McNemar test. All comparisons were two-sided at 0.05 level.

Results

As shown in the trial inclusion flow chart (Fig. 1), 109 patients were selected by the investigators, and 107 were included in the overall population. Two patients were excluded because of insufficient data available in their records and undergoing ocular surgery during treatment with the study drug. In the overall study population, patients were treated with the study drug for a mean duration of 9.4 ± 6.5 months (median 7.0 months) before inclusion. Four (3.7%) patients had a treatment follow-up with the study drug of less than 3 months and were therefore excluded from the PP population (N = 103; 63 naïve patients, 39 switched patients, and 1 not classified because of missing data).Fig. 1 Trial inclusion flow chart. N stands for number

The main characteristics of the overall study population at the initiation of the study drug are summarized in Table 1. Sixty-six (61.7%) patients were naïve, and 40 (37.4%) were previously treated with IOP-lowering therapy; one patient could not be classified because of missing data. The mean total duration of previous IOP-lowering treatments was 2.9 ± 3.8 years (ranging from 0 to 21 years). At the time of inclusion, 24 (22.4%) patients had been treated with artificial tears for an average duration of 14.6 ± 10.6 months.Table 1 Patients’ characteristics at study drug initiation (overall study population)

Patients’ characteristics	Results (N = 107)	
Age, years	
 Mean (SD)	64.3 (11.9)	
 Min–max	28.0–98.0	
Sex, n (%)	
 Male	55 (51.4%)	
 Female	52 (48.6%)	
Relevant systemic pathologies, n (%)	
 None	73 (68.2%)	
 Diabetes	9 (8.4%)	
 Systemic hypertension	19 (17.8%)	
 Other	15 (14.0%)	
Type of glaucoma, n (%)	
 Ocular hypertension	41 (38.3%)	
 Primary open angle glaucoma	63 (58.9%)	
 Pigmentary glaucoma	1 (0.9%)	
 Othera	4 (3.7%)	
Time since diagnosis, years	
 Mean (SD)	3.4 (4.4)	
 Median	1.0	
 Min–max	0.0–24.0	
Previous IOP-lowering therapy, n (%)	
 Missing	1	
 Naïve patients	66 (61.7%)	
 Switched patients	40 (37.4%)	
 From previous prostaglandin analogue monotherapy	24 (22.4%)	
 From previous beta-blocker monotherapy	7 (6.5%)	
 From previous carbonic anhydrase inhibitor monotherapy	1 (0.9%)	
 From previous bitherapy	8 (7.4%)	
Duration of previous IOP-lowering therapy in switched patients, years	
 Mean (SD)	2.9 (3.8)	
 Min–max	0.0–21.0	
Unilateral/bilateral treatment, n (%)	
 Bilateral	97 (90.7%)	
 Unilateral	10 (9.3%)	
Relevant ocular treatments, n (%)	
 Lubricants	24 (22.4%)	
 Indometacin	2 (1.9%)	
 Diclofenac	1 (0.9%)	
 Steroids	1 (0.9%)	
 Cromolyn	1 (0.9%)	
 Punctal plugs	1 (0.9%)	
Relevant systemic treatments, n (%)	
 Systemic antihypertensive	19 (17.8%)	
 Antidepressants	5 (4.7%)	
 Diuretics	1 (0.9%)	
IOP intraocular pressure, max maximum, min minimum, n number, OAG open angle glaucoma, SD standard deviation

aNormal tension glaucoma (1 patient); iris plateau (1 patient); mixed primary OAG (1 patient); primary narrow angle glaucoma (1 patient)

As summarized in Table 2, most non-naïve patients were switched to the study drug because of poor ocular tolerance (24/40, 60.0%) or insufficient IOP control (11/40, 27.5%).Table 2 Reasons for study drug initiation

	Overall population (N = 107)	Switched patients (N = 40)	
Initiation of preservative-free drug, n (%)	28 (26.2%)	13 (32.5%)	
Poor tolerance, n (%)	24 (22.4%)	24 (60.0%)	
Poor IOP control, n (%)	11 (10.3%)	11 (27.5%)	
Contraindication, n (%)	1 (0.9%)	1 (2.5%)	
Other, n (%)	6 (5.6%)	4 (10.0%)	
Not applicable, n (%)	57 (53.3%)	–	
Several responses possible

n number, IOP intraocular pressure

Among the 107 included patients, 100 (93.5%) were still using the study drug at the end of follow-up; 7 (6.5%) patients (5 naïve and 2 switched patients) discontinued the study drug because of insufficient IOP control. This included 5 (4.5%) patients (4 naïve and 1 switched) who switched to a fixed antiglaucoma combination, 1 (0.9%) patient (switched) as a result of poor tolerance and insufficient IOP control, and 1 (0.9%) patient (naïve) who requested to switch to multidose container eye drops.

Efficacy Results

Figure 2 shows the mean IOP values for the worse eye at initiation and during treatment with the study drug in the PP population (N = 103 eyes) for naïve patients, switched patients, and the overall group. Overall, the mean IOP was significantly (p < 0.001) reduced from 21.6 ± 5.0 mmHg at initiation of the study drug to 16.1 ± 3.5 mmHg at last available measurement (mean reduction of − 5.5 ± 4.6 mmHg; − 25.5%). In naïve patients, the IOP was significantly (p < 0.001) reduced from 23.1 ± 4.3 to 16.0 ± 3.6 mmHg (mean reduction of − 7.1 ± 4.4 mmHg; − 30.7%). In switched patients, the IOP was also significantly (p < 0.001) reduced from 19.3 ± 5.1 to 16.4 ± 3.4 mmHg (mean reduction of − 2.9 ± 3.8 mmHg; − 15.0%). Details of changes in IOP according to prior treatment of non-naïve patients are summarized in Table 3.Fig. 2 Changes in IOP between initiation of the study eye drop and end of follow-up in the per protocol population. IOP was determined before and after at least 3 months of treatment with the study drug in the worse eye in the PP population (103 eyes) (*p < 0.001, paired t test). IOP intraocular pressure, N number, PP per protocol

Table 3 Comparison of intraocular pressure between initiation of the study eye drops and end of follow-up based on the prior treatment in the switched population (N = 39 eyes)

	Number	IOP (mmHg) at the initiation of the study eye drops, mean ± SD	IOP (mmHg) at the end of follow-up, mean ± SD	IOP change (mmHg)	
Previous monotherapy with prostaglandin	23	18.8 ± 5.2	16.5 ± 3.0	− 2.3	
 Preserved	10	17.4 ± 5.5	15.7 ± 3.0	− 1.7	
 Preservative-free	13	19.8 ± 4.9	17.1 ± 3.0	− 2.8	
Previous monotherapy with beta-blocker	7	19.7 ± 2.7	16.1 ± 1.9	− 3.6	
 Preserved	2	22.5 ± 0.7	17.0 ± 1.4	− 5.5	
 Preservative-free	5	18.6 ± 2.3	15.8 ± 2.0	− 2.8	
Previous monotherapy with carbonic anhydrase inhibitor	1	16.0	15.0	− 1.0	
Previous bitherapy	8	20.7 ± 6.7	16.2 ± 5.0	− 4.5	
Total	39	19.3 ± 4.1	16.3 ± 3.2	− 2.9	
SD standard deviation, IOP intraocular pressure

Tolerance Results

Overall, 33 (31.1%) patients complained of at least one ocular side effect at study drug initiation versus 12 (11.3%) at the end of follow-up (p < 0.001). At initiation, 31 (29.0%) patients had at least one ocular sign and 26 (24.3%) had at least one ocular, compared to 9 (8.4%) and 11 (10.3%) patients, respectively, at the end of follow-up. The prevalence of conjunctival hyperaemia was reduced from 18.7% (20 patients) at initiation to 3.7% (4 patients) at the end of follow-up, SPK from 14.0% (15 patients) to 4.7% (5 patients), and other signs from 8.4% (9 patients) to 1.9% (2 patients) (Fig. 3A). Stinging upon instillation decreased from 15.9% (17 patients) to 5.6% (6 patients), foreign body sensation from 11.2% (12 patients) to 2.8% (3 patients), and itching from 9.3% (10 patients) to none (Fig. 3B).Fig. 3 Ocular signs and symptoms in the overall study population (N = 107). Ocular signs (A) and ocular symptoms (B) were determined before and after the study drug initiation. The percentage of patients with at least one sign or one symptom was compared before and after the study drug initiation. (*p < 0.001, Wilcoxon signed ranks test). N number

In switched patients (Fig. 4), 28 (70.0%) patients complained of at least one ocular side effect at study drug initiation versus 4 (10.0%) patients at the end of follow-up. At initiation, 26 (65.0%) patients had at least one ocular sign and 21 (52.5%) had at least one ocular symptom, compared to 3 (7.5%) and 4 (10%) patients, respectively, at the end of follow-up.Fig. 4 Ocular signs and symptoms in the switched patients (N = 40). Ocular signs (A) and ocular symptoms (B) were determined before and after the study drug initiation. The percentage of switched patients with at least one sign or one symptom was compared before and after the study drug initiation. (*p < 0.001, Wilcoxon signed ranks test). N number

Among the 24 non-naïve patients who switched to the study drug because of poor tolerance, 21 (87.5%) reported at least one ocular sign at initiation, including 12 (50.0%) with conjunctival hyperaemia, 13 (54.2%) with SPK, and 6 (25.0%) with other signs (morning eyelid crusts, hypertrichosis, blepharitis, dry eye). Additionally, 15 (62.5%) reported at least one ocular symptom, mainly stinging at instillation (11 patients, 45.8%), foreign body sensation (7 patients, 29.2%), and itching (5 patients, 20.8%). By comparison, at the end of follow-up, only 2 (8.3%) patients had ocular signs and 3 (12.5%) had ocular symptoms. No patient had conjunctival hyperaemia, 1 (4.2%) patient had SPK, and 1 (4.2%) patient had blepharitis, swelling of the eyelids, and tingling. Overall, ocular side effects in patients with poor tolerance at initiation resolved in 21 (87.5%) patients after initiation of the study drug (p < 0.001).

Concomitant Use of Artificial Tears

Among the 40 switched patients, there was no statistically significant difference (p = 1.000) in the number of patients using artificial tears before and after initiation of the study drug (N = 18, 45.0%). However, the frequency of instillation was significantly reduced (p = 0.034) with half of the patients instilling ≤ 2 drops per day (Fig. 5).Fig. 5 Frequency of artificial tears/lubricants in switched patients. In switched patients who used artificial tears/lubricants (N = 18), the frequency of artificial tears (number of instillations per day) was compared before and after the study drug initiation and showed a significant reduction after the study drug initiation (p = 0.034, Wilcoxon signed rank test). N number

In the 66 naïve patients, the percentage of those who used artificial tears increased from 6 (9.1%) at initiation to 14 (21.2%) at last follow-up (p = 0.008). The frequency of instillation remained similar (p = 0.785).

Investigators’ Satisfaction

As shown in Fig. 6, the investigators rated the efficacy of the study drug as satisfactory or very satisfactory for 89 out of 107 patients (83.2%)—75.0% of switched patients and 88.4% of naïve patients. Tolerance was rated similarly in 105 out of 107 patients (98.1%)—100% of switched patients and 97.0% of naïve patients. Overall, the study drug was deemed satisfactory or very satisfactory in 101 out of 107 patients (94.4%)—92.5% of switched patients and 97.0% of naïve patients.Fig. 6 Investigator’s satisfaction in the overall study population

Discussion

This is the first study to report the efficacy and tolerance of a PF, surfactant-free latanoprost 0.005% formulation in patients with OHT or OAG. The formulation led to a significant reduction in IOP in both naïve and switched patients and was very well tolerated, showing a significant reduction in ocular signs and symptoms, even among patients who had previously been intolerant to other hypotensive eye drops.

Naïve Patients

In naïve patients, the mean IOP was reduced by 30.7% after at least 3 months of treatment which is in line with the expected IOP-lowering effect (between 25% and 35%) of PGAs [2, 24]. This reduction is consistent with the level of IOP decrease required to delay or halt the progression of glaucoma [25, 26].

No significant ocular intolerance was observed in naïve patients following a mean treatment duration of over 9 months.

In our cohort, most enrolled patients (62%) had not previously received hypotensive treatment, and less than 10% had pre-existing OSD. Despite this, their treating physicians opted to prescribe PF hypotensive eye drops, reflecting ongoing discussions about the benefits of such formulations for treatment-naïve patients without pre-existing OSD [27, 28]. Ophthalmologists likely anticipate the potential adverse effects of preservatives on the ocular surface, which could compromise long-term treatment adherence, IOP control, and surgical outcomes [29]. Initiating PF glaucoma therapy may act as a preventive measure for patients at risk of developing dry eye disease. This includes older patients, female patients, those taking antidepressants or antihistamines, individuals with thyroid abnormalities or hypertension, those working in air-conditioned environments, and frequent users of electronic screens [30]. Collectively, these factors affect a significant proportion of patients with glaucoma [27]. In fact, OSD is often underestimated [31]. Initiating PF glaucoma eye drops ensures long-term tolerance, adherence, and efficacy and enhances the likelihood of successful surgical outcomes [32]. This practice is in line with findings from a previous European survey, where 58% of ophthalmologists prescribed PF glaucoma eye drops for newly diagnosed patients, increasing to 70% for those with pre-existing OSD [33].

In contrast, a retrospective multinational study conducted in the Netherlands, Germany, and Spain, which involved 1541 patients who initiated PF-latanoprost for at least 3 months [15], found that 24% of these patients were previously untreated. Our study also showed that the occurrence of ocular adverse events in treatment-naïve patients did not differ significantly after starting the study drug (p = 0.1306). There was a slight increase in the use of tear substitutes, possibly due to the onset of new dry eye disease. It is well recognized that individuals with glaucoma are more prone to ocular surface impairment compared to those without glaucoma [9].

Overall, the tolerance of the study drug was rated as satisfactory or very satisfactory by investigators for all (100%) naïve patients. None of these patients discontinued treatment because of intolerance, underscoring the clear benefit of initiating the study PF latanoprost formulation in treatment-naïve individuals.

Switched Patients

Switched patients showed improved tolerance and better IOP control with the study’s latanoprost eye drop compared to their previous medication. After at least 3 months of treatment, the mean IOP was reduced by 15.0%, which is less than the reduction observed in naïve patients. This difference can be attributed to the absence of a washout period and the lower baseline IOP.

When the previous treatment was beta-blocker monotherapy, the mean IOP reduction was estimated at − 3.6 mmHg, which reflects the generally lower efficacy of beta-blockers in reducing IOP compared to PGAs [3, 34].

Switching from a preserved PGA to the PF study eye drop resulted in an additional IOP decrease, consistent with findings from existing literature [35–39]. This additional reduction is likely due to decreased cellular damage in the trabecular meshwork caused by BAK and improved ocular tolerance, which enhance treatment adherence. In 60% of cases, poor tolerance was the primary reason for switching to the study drug, in line with previous studies [15, 39]. When hypotensive eye drops are poorly tolerated, switching to a PF medication is often recommended [40, 41].

The switch to the study PF-latanoprost formulation was deemed successful, with 87.5% of patients who initially experienced poor ocular tolerance reporting no further clinical signs or symptoms by the end of the follow-up period. Our study demonstrated that switching from a poorly tolerated hypotensive eye drop (with or without preservatives) significantly reduced ocular signs (such as hyperaemia and SPK) and symptoms (including stinging upon instillation or foreign bodies sensation). This finding aligns with numerous studies showing that transitioning from poorly tolerated glaucoma eye drops to PF latanoprost can markedly improve ocular signs and symptoms while maintaining or even enhancing IOP control [39, 42–44]. The accumulating scientific evidence suggests that these adverse effects are primarily attributable to preservatives, particularly BAK.

The question of why switching from a previous PF prostaglandin to the study PF latanoprost led to better IOP control remains. One possible explanation is that newly treated patients may exhibit better compliance, which could account for the improved efficacy observed. Tolerance issues are a major cause of non-compliance [45] and can persist even with PF formulations [23]. Although PF eye drops are generally associated with lower prevalence of OSD signs and symptoms compared to preserved drops [24], similar issues can still occur. Additionally, some PF medications can have deleterious effects on the ocular surface [23, 39]. For instance, a recent French multicentre cross-sectional observational study found that 78.2% of patients treated with PF PGA monotherapy (N = 271) had at least one clinical or functional sign of dry eye disease [32]. It was suggested that certain excipients, such as non-ionic surfactants at high concentration (e.g. MGHS40 at 5%), may negatively impact the ocular surface [20–23] and compromise adherence to treatment. The formulation-related pharmacokinetics might also play a role. Research indicates that non-ionic surfactants can result in lower and slower ocular penetration compared to preserved or PF surfactant-free formulations [46]. Further clinical studies are needed to compare the study’s PF surfactant-free latanoprost formulation with other PF latanoprost.

In cases where the previous treatment was a dual therapy, the mean IOP reduction was estimated at − 4.5 mmHg. This finding supports Baudouin et al.’s concept of the subtractive strategy [47], where discontinuation of harmful compounds, whether active or inactive ingredients [48], has been shown to be effective in improving ocular surface conditions and lowering IOP [10, 11]. This effect is potentially due to a reduction in inflammation within the trabecular meshwork.

Treatment adherence is essential for maintaining IOP control over time and slowing the progression of visual impairment in patients with glaucoma [49]. Although non-adherence is influenced by multiple factors, patients who experience ocular side effects are often more likely to be non-adherent compared to those without side effects. Similarly, patients using preserved medications tend to be more non-adherent than those using PF-medications [50, 51].

Improving patient satisfaction with medication is essential for ensuring adherence. Research has shown that patient satisfaction with antiglaucoma eye drops is closely linked to the presence of ocular symptoms [40], and patients who switch to PF-latanoprost have reported better satisfaction compared to their previous treatments [15]. Therefore, it is plausible that the study’s PF and surfactant-free latanoprost eye drops provide adherence benefits. However, further research is needed to confirm this potential advantage.

The study has several limitations. Firstly, as a result of its retrospective design, only patients who had at least 3 months of treatment with the study latanoprost formulation were included. This could have excluded patients who discontinued treatment before reaching the 3-month mark. However, a 3-month period is generally considered the minimum required to assess the efficacy and tolerance of hypotensive medications in clinical practice. The retrospective nature of the study does not introduce significant information bias because all data were recorded in patient charts. All enrolled patients had comprehensive documentation of IOP and ocular signs and symptoms before and after treatment with the study drug; only one patient with insufficient information was excluded.

Secondly, the open-label design introduces potential performance and expectation biases, as both participants and physicians were aware of the treatment, which could influence perceptions and outcome assessments. However, IOP is an objective measure assessed with standardized instruments, which helps mitigate these potential biases.

Thirdly, while drug administration was planned in the evening at 8 pm, the specific time of IOP measurement was not recorded, which could affect the results because of diurnal IOP variation. The equipment used for tonometry varied among practices, though most measurements were performed using Goldmann applanation tonometry (82.2%). There were no adjustments for the type of equipment used or the time of day for IOP measurement.

Additionally, as a non-comparative study, it does not allow conclusions regarding the benefits of the study latanoprost formulation compared to other PF-latanoprost or PF-PGAs. Comparative studies are needed to address this. Furthermore, while many patients had ocular side effects at initiation, the intensity of these signs and symptoms was not documented, and mild effects may have been overlooked or resolved spontaneously.

Lastly, since ocular tolerance may be influenced by the cumulative effect of topical medication, the long-term tolerance of the study latanoprost formulation cannot be predicted from this study alone. Future research with longer follow-up periods is necessary to determine if the efficacy and tolerability of the study formulation are sustained over time.

Conclusion

Real-life studies are crucial for evaluating patient benefits and reinforcing treatment efficacy. Our results demonstrated that the PF and surfactant-free latanoprost formulation led to improved IOP control and enhanced ocular tolerance in patients with OAG/OHT. This formulation proves to be a safe and effective treatment option for patients with glaucoma. By reducing IOP and improving ocular tolerance, this new formulation has the potential to enhance treatment adherence and disease control, which are essential for managing chronic conditions such as glaucoma.

Acknowledgements

The authors knowledge all the investigators involved in this study: Pr Collignon (CHU Liège), Dr Tek (Centre Hospitalier Bois de L’Abbaye, CHBA, Waremme), Dr Van de Veire (CHU Bruges), Dr Feron (Private practice, Remicourt), Dr Lizin (Private practice, Eupen), Dr Clotuche (Private practice, Fléron), Dr Chapelle (CHU UCL Namur), Dr Lampe (Private practice, Fauvillers), Dr Van Elmbt (Private practice, Waremme), Dr Bogdan (CHC MontLégia, Liège), Dr Dieryck (Private practice, Hasselt), and Thierry Radeau (Epinay-sous-Sénart, France) for medical writing support. We also thank the participants for accepting to participate in this study. We would like to extend our gratitude to Steve Ravelingien for his assistance with investigator recruitment, result analysis, and manuscript revision.

Medical Writing/Editorial Assistance

Medical writing in the preparation of this article was provided by Thierry Radeau, through his sole proprietorship located in Epinay-Sous-Senart, France. Support for this assistance was funded by Horus Pharma.

Author Contributions

Laure Chauchat, Camille Guerin and Hayette Rebika contributed to study conception, design, result discussion, and article outlines. Marwan Sahyoun contributed to result discussion and article outlines. Nathalie Collignon was the principal investigator of this study and contributed to result discussion. All authors reviewed and approved the manuscript. All 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. The study was sponsored by Horus Pharma (Nice, France).

Funding

Sponsorship for this study and the journal’s Rapid Service Fee were funded by Laboratoires Horus Pharma, Pharmaceutical Company (Nice, France).

Data Availability

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

Declarations

Conflict of Interest

Laure Chauchat, Camille Guerin, Hayette Rebika and Marwan Sahyoun were employed by Horus Pharma Company. Nathalie Collignon have nothing to disclose.

Ethical Approval

The study was approved for each of the 11 clinical sites by four correspondent ethics committees (C.H. Bois de l’Abbaye, Seraing, 21/02/2022, reference number 2022/02; Clinique Sainte-Elisabeth C.H.U. UCL Namur, Namur, 01/03/2022, reference number 05-22; C.H.U. de Liège, Liège, 01/04/2022, reference number 2022/34; and C.H.U. Saint-Pierre, Bruxelles, 07/04/2022, reference number CE/22-04-02) and was conducted in accordance with all applicable regulatory requirements and the Helsinki Declaration of 1964 and its later amendments (Version 64th, World Medical Association, Fortaleza, Brazil, 2013). The data used in this study were de-identified to ensure the confidentiality and anonymity of the participants. No information that could directly identify individuals was included in the datasets analysed.

Prior Presentation: The data included in this manuscript was presented as a poster at the annual meeting of The Association for Research in Vision and Ophthalmology (ARVO), New Orleans, Louisiana, USA, 2023.
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