Efficacy of bilateral OC-01 (varenicline solution) nasal spray in alleviating signs and symptoms of dry eye disease: a systematic review

Contact Lens and Anterior Eye 47 (2024) 102097 Available online 8 December 2023 1367-0484/© 2023 The Author(s). Published by Elsevier Ltd on behalf of British Contact Lens Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Review article Efficacy of bilateral OC-01 (varenicline solution) nasal spray in alleviating signs and symptoms of dry eye disease: A systematic review Antonio Ballesteros-S´ anchez a , b , * , Davide Borroni c , d , Concepci´ on De-Hita-Cantalejo a , María Carmen S´ anchez-Gonz´ alez a , Serafin Sanchez-Gomez e , Carlos Rocha-de-Lossada f , g , h , i , Jos´ e-María S´ anchez-Gonz´ alez a a Department of Physics of Condensed Matter, Optics Area, University of Seville, Seville, Spain b Department of Ophthalmology, Clínica Novovisi´ on, Murcia, Spain c Department of Doctoral Studies, Riga Stradins University, LV-1007 Riga, Latvia d Advalia Vision, Cornea Research Unit, 20145 Milan, Italy e Servicio de Otorrinolaringología, Hospital Universitario Virgen Macarena, 41009 Seville, Spain f Ophthalmology Department, VITHAS Malaga, 29016 Malaga, Spain g Regional University Hospital of Malaga, Hospital Civil Square, 29009 Malaga, Spain h Qvision, Ophthalmology Department, VITHAS Almeria Hospital, 04120 Almeria, Spain i Surgery Department, Ophthalmology Area, University of Seville, Doctor Fedriani, 41009 Seville, Spain ARTICLE INFO Keywords: OC-01 varenicline nasal spray Dry eye disease Goblet cells Meibomian gland dysfunction ABSTRACT Purpose: To comprehensively review the efficacy and safety of OC-01 varenicline nasal spray versus vehicle nasal spray (VNS) in the treatment in dry eye disease (DED). Methods: A systematic review that included full-length randomized controlled studies (RCTs), as well as post hoc analyses of RCTs reporting new findings on OC-01 VNS treatment in three databases, PubMed, Scopus and Web of Science, was performed according to the PRISMA statement. The search period included studies published between December 2021 and September 2023. The Cochrane risk of bias tool was used to analyze the quality of the studies selected. Results: A total of 8 studies were included in this systematic review. OC-01 VNS treatment achieved higher improvement than vehicle in all reported variables. The mean differences between both groups were in favor of OC-01 VNS treatment and were as follow: eye dryness score base on a visual analogue scale (EDS-VAS) of −7.5 ±2.2 points [-11.6 to −5.6], Schirmer test (ST) with anesthesia of 6.6 ±2.3 mm [4.9 to 11.8] and total corneal fluorescein staining (tCFS) of −1.2 ±0.01 points [-1.2 to −1.1]. Similar improvements were reported with OC01 VNS 0.03 mg and 0.06 mg. Adverse events (AEs) were 15.5 ±19.4 % [-13 to 80.5] higher in the OC-01 VNS group with an overall adherence >93 %. Conclusions: OC-01 VNS improves dry eye symptoms and signs with a satisfactory tolerability. Therefore, OC-01 VNS seems to be a safe and effective treatment that could be recommended in patients with DED. This new treatment could be particularly useful in those patients who have difficulties with the administration of traditional topical therapies. 1. Introduction Dry eye disease (DED) is a prevalent and multifactorial condition characterized by an unstable and deficient tear film, resulting in discomfort, visual impairment, ocular surface epitheliopathy, inflammation, and neurosensory abnormalities [1,2]. The impact of DED on patients is substantial, affecting their visual function and quality of life [3,4]. Despite the existing therapeutic options, there remains a need for treatments that target the underlying pathophysiology rather than provide temporary symptom relief [5]. The autonomic nervous system, particularly the efferent parasympathetic and sympathetic nerves, plays a vital role in maintaining the ocular surface and tear film stability [6,7]. Activation of the trigeminal afferent nerves in the cornea, conjunctiva and the nasal cavity leads to stimulation of the efferent sympathetic and * Corresponding author at: University of Seville, Reina Mercedes Street, Seville, Spain. E-mail address: [email protected] (A. Ballesteros-S´ anchez). Contents lists available at ScienceDirect Contact Lens and Anterior Eye journal homepage: www.elsevier.com/locate/clae https://doi.org/10.1016/j.clae.2023.102097 Received 15 October 2023; Received in revised form 13 November 2023; Accepted 27 November 2023 Contact Lens and Anterior Eye 47 (2024) 102097 2 parasympathetic nerves in the facial nerve [8,9], as well as the trigeminal efferent parasympathetic nerves that innervate the lacrimal functional unit (LFU) [10,11]. Varenicline, a small-molecule nicotinic acetylcholine receptor (nAChR) agonist, has recently been approved as a preservative-free nasal spray (OC-01 VNS) for DED treatment [12]. When administered, OC-01 VNS binds to nAChRs, which are located on the free nerve endings of the nasociliary and maxillary branches of the trigeminal nerve in the nasal mucosa [13,14]. This binding leads to the activation of ligandgated ion channels and depolarization of the nerve that innervates the LFU, thereby stimulating tear film production [14,15]. However, although some studies have demonstrated the effectiveness of OC-01 VNS in inducing the production of the aqueous component of the tear film [16–23], its impact on goblet cells and meibomian gland function is still unclear. Therefore, the objective of this systematic review is to evaluate the efficacy and safety of OC-01 VNS treatment in patients with DED, as well as its potential influence on goblet cells and meibomian gland function. Through this review, a comprehensive overview of the current evidence on OC-01 VNS is provided, enabling evidence-based decision making and guiding future research directions. 2. Methods 2.1. Data sources and search strategy This systematic review (PROSPERO ID: CRD42023469618) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [24,25]. Fifty-six articles published before September 9, 2023, through the following databases: PubMed, Scopus and Web of science were identified. The data search strategy with Boolean operators was as follows: (varenicline solution OR varenicline nasal spray OR tyrvaya) AND (dry eye disease OR DED OR evaporative dry eye OR EDE OR aqueous deficient dry eye OR ADDE OR meibomian gland dysfunction). The references of the retrieved articles were reviewed to identify other related studies if they met the inclusion criteria. Fig. 1. Flowchart study selection process according to the PRISMA statement. Table 1 Summary of included studies. Author (date) Design F/ U a Patients (TG/CG) Age b (TG/ CG) Sex (F/M) Eyes Inclusion criteria Intervention Control Posology c CoI Wirta et al. [16] 2021ª MT DM 1 139 / 43 65.5 ± 10.8 137 / 45 182 OSDI ≥23 points tCFS ≥2 points ST ≤10 mm OC-01 VNS (0.006 mg / 0.03 mg / 0.06 mg) Vehicle nasal spray (Phosphatebuffered saline) 12 Yes Quiroz-Mercado et al. [17] 2021 MT DM 3 82 / 41 53.8 ± 12.8 100 / 23 123 tCFS ≥2 points ST ≤10 mm OC-01 VNS (0.03 mg / 0.06 mg) Vehicle nasal spray (Phosphatebuffered saline) 12 Yes Wirta et al. [18] 2021b MT DM 1 506 / 252 58.8 ± 13 576 / 182 758 OSDI ≥23 points tCFS ≥2 points ST ≤10 mm OC-01 VNS (0.03 mg / 0.06 mg) Vehicle nasal spray (Phosphatebuffered saline) 12 Yes Dieckmann et al. [19] 2022 MN DM – 12 / 6 61.4 ± 13.4 14 / 4 18 OSDI ≥23 points tCFS ≥2 points ST ≤12 mm OC-01 VNS (0.06 mg) Vehicle nasal spray (Phosphatebuffered saline) 12 Yes Katz et al. [20] 2022 MT DM 1 597 / 294 59.9 ± 12.8 676 / 215 1782 OSDI ≥23 points ST ≤10 mm OC-01 VNS (0.03 mg / 0.06 mg) Vehicle nasal spray (Phosphatebuffered saline) 12 Yes Nijm et al. [21] 2022 MT DM 1 222 / 227 59.6 ± 11.6 449 / 0 449 Menopausal status OSDI ≥23 points ST ≤10 mm OC-01 VNS (0.03 mg) Vehicle nasal spray (Phosphatebuffered saline) 12 Yes Sheppard et al. [22] 2022 MT DM 1 308 / 294 59.9 ± 12.7 521 / 81 602 OSDI ≥23 points tCFS ≥2 points ST ≤10 mm OC-01 VNS (0.03 mg) Vehicle nasal spray (Phosphatebuffered saline) 12 Yes Schallhorn et al. [23] 2023 MT DM 1 597 / 294 60.1 ± 11.9 676 / 215 891 Autoimmune disease OSDI ≥23 points ST ≤10 mm OC-01 VNS (0.03 mg / 0.06 mg) Vehicle nasal spray (Phosphatebuffered saline) 12 Yes CG =Control group; CoI =Conflict of interest; DM =Double-masked; DED =Dry eye disease; F =Female; F/U =Follow-up; M =Male; MN =Monocentric; MT = Multicenter; OSDI =Ocular surface disease index; OC-01 VNS =Varenicline nasal spray; SM =Single-masked; ST =Schirmer test; tCFS =Total corneal fluorescein staining; TG =Treatment group. a Expressed as months. b Expressed as mean ±SD, years. c Varenicline administration in each nostril expressed as hours per day. A. Ballesteros-S´ anchez et al. Contact Lens and Anterior Eye 47 (2024) 102097 3 2.2. Study selection All those 56 articles identified through the search strategy were considered and analyzed. Duplicate studies were removed by DistillerSR software (DistillerSR Inc., Ottawa, Canada) [26]. The remaining studies underwent additional screening stages, which included title screening, abstract screening, and full-text screening. Studies unrelated to the topic were excluded from the review during title and abstract screening. Fulltext screening studies that did not include OC-01 VNS treatment were also excluded from the review. These studies were reviewed by two investigators (ABS and JMSG) who selected them according to the inclusion and exclusion criteria. The inclusion criteria were as follows: prospective randomized controlled trials (RCTs), as well as post hoc analyses of RCTs comparing the safety and efficacy of OC-01 VNS treatment with vehicle nasal spray. The exclusion criteria included nonEnglish publications and unindexed journals. There were no restrictions placed on the country in which the study was performed, the follow-up period, the sample size, the age of the participants and the results of the studies. 2.3. Quality assessment and data extraction The data from each study were collected and summarized independently in tables designed by two researchers (ABS and JMSG). The following information was obtained from each article: (1) author and date of publication (year), (2) study design, (3) mean follow-up of all Table 2 Intra-group and inter-group differences outcomes. Author (Date) OC-01 VNS group Vehicle group Inter-group differences a F / A EDS (0–100) ST, mm tCFS (0–15) EDS (0–100) ST, mm tCFS (0–15) EDS (0–100) ST, mm tCFS (0–15) Wirta et al. [16] 2021a Baseline 60.9 ±20.3 5.1 ± 2.9 6.7 ±2 65.2 ± 17.7 4.5 ± 2.9 6.7 ± 2.4 ¡11.6* 7.6* ¡1.1 F Last visit 43.7 ±21.3 16.4 ± 4.3 7.9 ± 2.5 59.6 ± 18.1 8.2 ± 3.9 9 ±3.2 Difference LV-B ¡17.2* 11.3* 1.2 ¡5.6 3.7 2.3 Quiroz-Mercado et al. [17] 2021 Baseline NR 5.5 ± 2.4 5.3 ± 2.6 NR 5.3 ±2 5.8 ± 3.8 – 4.9* – F Last visit NR 16.4 ± 3.3 NR NR 11.3 ± 3.5 NR Difference LV-B – 10.9* – – 6 – Wirta et al. [18] 2021b Baseline 58.9 ±22.4 5.3 ± 2.9 6.4 ± 2.2 58.1 ± 22.4 4.9 ± 2.9 6.2 ± 2.1 ¡5.6* 5.1* ¡1.2 F Last visit 37.9 ±20.4 16.7 ± 3.7 5.6 ± 2.8 42.7 ± 22.6 11.2 ± 3 5.8 ± 2.8 Difference LV-B ¡21* 11.4* ¡0.8 ¡15.4 6.3 ¡0.4 Dieckmann et al. [19] 2022 Baseline 58.8 ±26.7 6.6 ± 4.4 NR 66.3 ± 17.4 4.5 ± 3.9 NR – – – F Last visit NR NR NR NR NR NR Difference LV-B – – – – – – Katz et al. [20] 2022 Baseline 58.8 ±22.1 7.8 ± 5.1 6.3 ± 2.4 59.1 ± 21.8 7.4 ± 5.6 6.1 ± 2.3 ¡6.5* 6.1* – F Last visit 43.3 ±23.2 16.6 ± 5.5 NR 50.1 ± 19.4 10.1 NR Difference LV-B ¡15.5* 8.8* – ¡9 2.7 – Nijm et al. [21] 2022 Baseline 61.8 ±20.6 4.5 ± 2.9 NR 58.8 ± 21.7 4.6 ± 2.9 NR ¡6.4* 5.1* – F Last visit 40.7 ±19.2 15.1 ± 4.4 NR 44.1 ± 22.1 10.1 ± 2.5 NR Difference LV-B ¡21.1* 10.6* – ¡14.7 5.5 – Sheppard et al. [22] 2022 Baseline 59.3 ±21.6 5.1 ± 2.9 6.5 ± 2.2 59.1 ± 21.8 4.8 ± 2.9 6.2 ± 2.2 ¡5.7* 5.5* – F Last visit 44.9 ±20.5 15.5 ± 5 NR 50.1 ± 20.3 9.7 ± 3.6 NR Difference LV-B ¡14.7* 10.4* – ¡9 4.9 – Schallhorn et al. [23] 2023 Baseline 59.2 ±26.1 5.6 ± 2.8 NR 52.7 ± 24.4 4.2 ± 3.4 NR ¡9.3* 11.8* – F Last visit 39.6 ±24.2 19.2 ± 4.8 NR 42.4 ± 23.6 6 ±3.1 NR Difference LV-B ¡19.6* 13.6* – ¡10.3 1.8 – Mean ± SD ¡18.2 ± 2.5 b 11 ± 1.3 b 0.2 ± 1 b ¡10.6 ± 3.4 b 4.4 ± 1.6 b 1.4 ± 0.9 b ¡7.5 ± 2.2 c 6.6 ± 2.3 c ¡1.2 ± 0.01 c B =Baseline; EDS = a Defined as (OC-01 VNS group Last visit - Baseline ) – (Vehicle group Last visit - Baseline ). b Mean ± SD values of the difference LV-B for each variable. c Mean ± SD values of the inter-group difference for each variable. *p <0.05. A. Ballesteros-S´ anchez et al. Contact Lens and Anterior Eye 47 (2024) 102097 4 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) study group intervention, (9) control group intervention, (10) OC-01 VNS posology and (11) conflicts of interest. Regarding the results of the studies, the following date were collected: (12) eye dryness score based on a visual analog scale (EDSVAS, values from 0 to 100); (13) Schirmer test with anesthesia (ST, expressed in millimeters, mm) [27]; (14) total corneal fluorescein staining (tCFS), which was defined as the sum of fluorescein staining in 5 areas (inferior, superior, central, nasal and temporal) with a maximum score of 15 points [28]. Fluorescein staining in each area was assessed with the National Eye Institute scale from grade 0 (no staining) to grade 3 (heavy staining) [29]; (15) ocular and non-ocular adverse events (AEs) (expressed as percentages); and finally (16) authors judgment expressed by commenting in favor or against of OC-01 VNS treatment. Data synthesis was performed according to the Cochrane guideline for synthesis without meta-analysis (SWiM) [30]. Baseline and last visit values for all these variables were collected in the OC-01 VNS and vehicle groups. Intra-group clinical outcomes were defined as “Last visit (LV) – Baseline (B) differences”. Inter-group clinical outcomes were defined as “OC-01 VNS (LV–B) – vehicle group (LV–B) differences”. Mean ±SD, were calculated to report intra-group and inter-group clinical outcomes. The literature that remained after full-text screening was examined to assess the quality of the studies. To avoid the risk of bias, two dependable authors created a synopsis based on the Cochrane risk of bias tool [31], which includes the following items: (1) random sequence generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective reporting and (7) other sources of bias. A third nonblinded assessor decided the quality of the studies when disagreements occurred between the two assessors. 3. Results 3.1. Study characteristics The study selection process of this systematic review is presented with a flowchart diagram in Fig. 1. The design of the included studies was prospective RCTs published between 2021 and 2023. This systematic review included 1972 eyes from 1081 patients with a mean age of 59.9 ±3 years. The sex distribution was 827 females (76.5 %) and 254 males (23.5 %). Patient follow-up, expressed in months, ranged from 1 month [16,18,20–23] to 3 months [17], with a mean follow-up of 1.3 ± 0.7 months. Regarding study and control group intervention, all studies used OC-01 VNS (Oyster Point Pharma Inc., Princeton, USA) and vehicle nasal spray, respectively [16–18,20–23]. In addition, all studies also had conflicts of interest by the authors (Oyster Point Pharma Inc., Princeton, USA) [16–18,20–23]. More detailed study characteristics and nasal spray composition are presented in Table 1. 3.2. Outcomes Regarding efficacy outcomes, 6 studies reported dry eye symptom outcomes using the EDS-VAS [16,18,20–23]. Seven studies also reported dry eye sign outcomes [16–18,20–23], of which all evaluated ST [16–18,20–23], while only 2 studies assessed tCFS [16,18] Regarding safety outcomes, 3 studies reported ocular AEs [16,17,19], while nonocular AEs was reported by 5 studies [16–20]. Intra-group and inter-group clinical outcomes are presented in Table 2. Regarding OC-01 VNS group, EDS-VAS and ST achieved an improvement of −18.2 ±2.5 points and 11 ±1.3 mm, respectively. However, tCFS remained unchanged with a value of 0.2 ±1 points. Inferior improvements were achieved in the vehicle group with an EDSVAS and ST of −10.6 ±3.4 points and 4.4 ±1.6 mm, respectively. In addition, tCFS showed an increase of 1.4 ±0.9 points. Regarding intergroup clinical outcomes, all outcomes were in favor of the OC-01 VNS group with an EDS-VAS, ST and tCFS of −7.5 ±2.2 points, 6.6 ±2.3 mm Table 3 Intra-group and inter-group differences outcomes at different Varenicline concentrations. Author (Date) OC-01 VNS group Inter-group differences a OC-01 VNS 0.03 mg OC-01 VNS 0.06 mg EDS(0–100) ST, mm tCFS (0–15) EDS (0–100) ST, mm tCFS (0–15) EDS (0–100) ST, mm tCFS (0–15) Wirta et al. [16] 2021a Baseline 63.7 ±18.4 4.8 ±2.7 6.7 ±2.1 53.5 ± 22.4 5.5 ±3 6.9 ±2.4 ¡3.6 0.3 ¡0.8 Last visit 44.7 ±17.6 16.2 ±4 7.5 ±1.9 38.1 ± 19.5 16.6 ±4.7 8.5 ±2.2 Difference LVB ¡19* 11.4* 0.8 ¡15.4 11.1* 1.6 Quiroz-Mercado et al. [17] 2021 Baseline NR 5.5 ±2.4 4.6 ±1.9 NR 5.4 ±2.4 6 ±3.3 – ¡0.2 – Last visit NR 16.3 ±4.3 NR NR 16.4 ±3.8 NR Difference LVB – 10.8* – – 11* – Wirta et al. [18]2021b Baseline 58.5 ±22.1 5.1 ±3 6.4 ±2.2 59.3 ± 22.6 5.4 ±2.9 6.3 ±2.2 2.4 ¡0.2 0.3 Last visit 38.7 ±20.3 16.4 ±5 5.8 ±2.4 37.1 16.9 ±3.5 5.4 ±2.8 Difference LVB ¡19.8* 11.3* ¡0.6 –22.2* 11.5* ¡0.9 Katz et al. [20]2022 Baseline 59.3 ±21.6 7.2 ±5 6.4 ±2.3 58.4 ± 22.6 8.3 ±5.2 6.2 ±2.5 1.5 ¡0.1 – Last visit 44.6 ±22.5 15.9 ±4.8 NR 42.2 17.1 ±4.3 NR Difference LVB ¡14.7* 8.7* – ¡16.2* 8.8* – Mean ± SD ¡17.8 ± 2.2 b 10.5 ± 1.1 b 0.1 ± 0.7 b ¡17.9 ± 3 b 10.6 ± 1.1 b 0.4 ± 1.3 b 0.1 ± 2.6 c ¡0.1 ± 0.2 c ¡0,3 ± 0.6 c a Defined as (OC-01 VNS 0.03 mg Last visit - Baseline ) – (OC-01 VNS 0.06 mg Last visit - Baseline ). b Mean ± SD values of the difference LV-B for each variable. c Mean ± SD values of the inter-group difference for each variable. *p <0.05. A. Ballesteros-S´ anchez et al. Contact Lens and Anterior Eye 47 (2024) 102097 5 and −1.2 ±0.01 points, respectively. Intra-group and inter-group clinical outcomes of OC-01 VNS at different concentrations are presented in Table 3. Regarding OC-01 VNS 0.03 mg group, EDS-VAS and ST achieved an improvement of −17.8 ± 2.2 points and 10.5 ±1.1 mm, respectively. However, tCFS remained unchanged with a value of 0.1 ±0.7 points. Similar results were reported in the OC-01 VNS 0.06 mg with an EDS-VAS, ST and tCFS of −17.9 ±3 points, 10.6 ±1.1 mm and 0.4 ±1.3 points, respectively. Regarding inter-group clinical outcomes, all outcomes were in favor of both OC-01 VNS concentrations with minimal EDS-VAS, ST and tCFS differences of 0.1 ±2.6 points, −0.1 ±0.2 mm and −0,3 ±0.6 points, respectively. Ocular and non-ocular AEs are presented in Table 4. The most common ocular and non-ocular AEs in both groups were blurred vision and sneeze, occurring in 2.9 ±3.4 % and 43.4 ±36.7 %, respectively. In addition, the OC-01 VNS group reported that ocular AEs was 3.9 ±6.4 % lower than the vehicle group. However, non-ocular AEs was 34.9 ±28 % higher in the OC-01 VNS group compared to the vehicle group. Overall, adherence to OC-01 VNS treatment was >93 %. 3.3. Risk of bias The risk of bias summary of the included studies is presented in Fig. 2. Risk of bias assessment was classified into three evidence level groups: (1) studies with a low risk of bias (Wirta et al. 2021a [16], Wirta et al. 2021b [18], Katz et al. [20], Nijm et al. [21], Sheppard et al. [22] and Schallhorn et al. [23]), (2) studies with an unclear risk of bias (Quiroz-Mercado et al. [17]) and (3) studies with a high risk of bias (Dieckmann et al. [19]). The overall risk of bias summary of the domains used in each study is presented in Fig. 3. The items used to assess the risk of bias showed an overall low risk of bias, which was 75 %. Therefore, no study was excluded due to risk of bias. The Robvis tool (NIHR, Bristol, UK) was used to create risk of bias assessment figures [32]. 4. Discussion This systematic review of the literature demonstrated that OC-01 VNS treatment achieved a higher reduction in the symptoms and signs of DED compared to vehicle nasal spray, reporting AEs that were well tolerated. 4.1. OC-01 VNS efficacy All studies included in this systematic review that evaluated dry eye symptoms used the EDS-VAS. This questionnaire is based on a visual analog scale that quantifies both the severity and frequency of dry eye symptoms and it is significant correlated with OSDI score [35,36]. Although EDS-VAS has a high degree of sensitivity and discriminating capacity, the minimal clinically important difference has been defined recently by Pattar et al. [37], concluding that intra-group changes in EDS-VAS >13 points would be clinically meaningful. Wirta et al. (2021a) [16], Wirta et al. (2021b) [18], Katz et al. [20], Nijm et al. [21], Sheppard et al. [22] and Schallhorn et al. [23] reported that patients who received OC-01 VNS treatment achieved significant EDS-VAS improvement of −18.2 ±2.5 points, while the vehicle group achieved non-significant EDS-VAS improvement of −10.6 ±3.4 points. However, although these results may suggest that OC-01 VNS treatment seems to improve DED symptoms to a clinically meaningful degree compared to vehicle, the benefit of taking OC-01 VNS treatment compared to the vehicle is just 7.6 points, which could be argued to be not clinically significant. Therefore, the effects of OC-01 VNS treatment on DED symptoms should be carefully interpreted. The effect of OC-01 VNS on tear volume was evaluated by the ST with topical anesthesia, which is more objective and reliable in DED detection [27,38]. Wirta et al. (2021a) [16], Quiroz-Mercado et al. [17], Wirta et al. (2021b) [18], Katz et al. [20], Nijm et al. [21], Sheppard et al. [22] and Schallhorn et al. [23] reported that patients who received OC-01 VNS treatment achieved anesthetized ST improvement of 11 ± 1.3 mm compared to the 4.4 ±1.6 mm achieved in the vehicle group. This difference between both groups may be considered large enough for patients to move to “normal” tear production, reducing DED severity [1]. Regarding ST long-term efficacy, Quiroz-Mercado et al. [17] was the only study to report ST long-term outcomes with OC-01 VNS treatment. Their results may be compared with long-term outcomes of other DED therapies such as topical cyclosporine and lifitegrast. Topical cyclosporine studies have shown that anesthetized ST improvements of 2.5 mm may take up 6 months to manifest in patients with DED [34,39,40]. Similar results were reported by topical lifitegrast studies, with anesthetized ST improvements <2 mm at 3-months follow-up [41–43]. However, Quiroz-Mercado et al. [17] reported anesthetized ST improvement of 10.9 mm at 3-months follow-up, which suggest a rapid initial response to OC-01 VNS treatment. The OC-01 VNS effects in EDSVAS and ST were also evaluated in populations with high DED Table 4 AEs inter-group differences. Author (Date) Varenicline group Vehicle group Inter-group Differences a Wirta et al. [16] 2021a Ocular AEs, % 3 16 ¡13 Nonocular AEs, % 92.5 12 80.5 Quiroz-Mercado et al. [17] 2021 Ocular AEs, % 10.9 9.8 1.1 Nonocular AEs, % 14.6 22 ¡7.4 Wirta et al. [18] 2021b Ocular AEs, % NR NR – Nonocular AEs, % 98.3 57 41.3 Dieckmann et al. [19] 2022 Ocular AEs, % 0 0 0 Nonocular AEs, % 50 16.7 33.6 Katz et al. [20] 2022 Ocular AEs, % NR NR – Nonocular AEs, % 33.3 6.6 26.7 Nijm et al. [21] 2022 Ocular AEs, % NR NR – Nonocular AEs, % NR NR – Sheppard et al. [22] 2022 Ocular AEs, % NR NR – Nonocular AEs, % NR NR – Schallhorn et al. [23] 2023 Ocular AEs, % NR NR – Nonocular AEs, % NR NR – AEs, Adverse events. a Defined as (Varenicline group) – (Vehicle group). A. Ballesteros-S´ anchez et al. Contact Lens and Anterior Eye 47 (2024) 102097 6 prevalence, such as patients with autoimmune diseases [44] and menopausal women [45,46]. Schallhorn et al. [23] reported that patients with autoimmune diseases who received OC-01 VNS treatment achieved significant EDS-VAS and ST improvements of −9.3 points and 11.8 mm compared to those who received vehicle, respectively. Similar results were achieved by Nijm et al. [21] reporting that menopausal women who received OC-01 VNS treatment achieved significant EDSVAS and ST improvements of −6.4 points and 5.1 mm compared to those who received vehicle, respectively. In addition, Sheppard et al. [22] demonstrated that OC-01 VNS treatment significantly improves EDS-VAS and ST in patients with different DED severity. Therefore, these results suggest the potential efficacy of OC-01 VNS for DED regardless of the study population. Regarding ocular surface staining, Wirta et al. (2021a) [16] and Wirta et al. (2021b) [18] reported that patients who received OC-01 VNS treatment achieved tCFS improvement of −1.2 ±0.01 mm compared to the vehicle group. Although these results suggest that OC-01 VNS treatment could reduce corneal damage due to DED, interpretation could be limited by the anesthesia used for ST evaluation, which may increase corneal staining [47]. This is consistent with the non-significant tCFS slight increase of 1.2 points reported by Wirta et al. (2021a) [16] in the OC-01 VNS group. It is important to emphasize that in these studies the type of dry eye was not specified, which would have been of interest to determine in which type of dry eye the OC-01 VNS treatment is more effective. The clinical effects on EDS-VAS, ST and tCFS may be explained by the mechanism of action of OC-01 VNS. This agent is a cholinergic agonist with high affinity and selectivity at human α 3β4, α 3 α 5β4, α 4β2, α 4 α 6β2 and α 7 nAChRs [13,14], which are present on the trigeminal nerve Fig. 2. 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. Fig. 3. Overall risk of bias summary of the domains with bar plot. Bars represent the overall author’s risk of bias judgment in each domain presented as percentages. A. Ballesteros-S´ anchez et al. Contact Lens and Anterior Eye 47 (2024) 102097 7 within the nasal cavity throughout the nasal mucosa [14]. Tear film production occurs when OC-01 VNS binds to nAChRs that open ligandgated ion channels and depolarizes the nerve that innervates the LFU [19]. To the best of our knowledge, Dieckmann et al. [19] is the only study to analyze changes in goblet cells and meibomian glands after OC01 VNS treatment. Regarding goblet cells, significantly reduced goblet cells area and perimeter were reported 10 min after OC-01 VNS administration. These changes induce goblet cells degranulation which results in the release of mucin onto the ocular surface that plays a key role in restoring tear film homeostasis [48,49]. Regarding meibomian glands, no significant changes in meibomian glands area were reported 10 min after OC-01 VNS administration. This may be due to the possibility that OC-01 VNS treatment only influences meibomian gland function [50], but further studies are needed. Overall, is hypothesized that OC-01 VNS induce TTP stimulation through nAChRs present in the nasal mucosa, which mediate afferent signals that may innervate the lacrimal functional upregulating all 3 layers of the tear film [14,19], and consequently ameliorate DED symptoms and signs [16–18]. 4.2. OC-01 VNS safety Wirta et al. (2021a) [16], Quiroz-Mercado et al. [17], Wirta et al. (2021b). [18], Dieckmann et al. [19] and Katz et al. [20] reported AEs after OC-01 VNS treatment. Non-ocular AEs were more common than ocular AEs after OC-01 VNS treatment, which may be expected due its nasal route of administration. Sneeze and blurred vision were the most reported non-ocular and ocular AEs, respectively. However, both were mild and transient, occurring immediately after OC-01 VNS administration. In addition, sneeze reflex from trigeminal nerve stimulation is well documented [51,52]. Therefore, it seems that the AEs of OC-01 VNS treatment do not influence its tolerability, which favors high adherence. OC-01 VNS safety may be put in context with other DED therapies. Topical cyclosporine and lifitegrast studies have shown that burning after instillation is the most common ocular AEs, reporting an overall discontinuation of 19.8 %[34,39,40] and 8.9 % [41–43], respectively. However, no case of burning occurred after OC-01 VNS administration with an overall discontinuation of 4.6 % [16–18], which included patients who stopped taking the treatment due to improvement in their DED symptoms and signs, as well as patients who did not tolerate the non-ocular AEs. In addition, the nasal route of administration of OC-01 VNS offers the following advantages over traditional topical therapies, which also contribute to increase adherence: (1) reduce the common patient-reported complains of eye drops, (2) can be administered to contact lens wearers and (3) provide a potentially easier delivery method for patients with tremors, neck deformities, and overall difficulty with the administration of eye drops [16–18]. This suggests OC-01 VNS as a potentially safe treatment option in patients with DED. 4.3. Strengths and limitations The main strength of this systematic review is high quality of reported results since all studies included were RCTs or post hoc analysis of RCTs with an overall low risk of bias. The interventions in both groups, as well as the doses applied per day were essentially the same between the studies; therefore, the methodologies of all of them were substantially similar. In addition, this study provides an update on the topic, including new RCTs and evaluating other variables, such as EDSVAS and tCFS compared to other systematic reviews [53]. However, there are limitations that may have influenced the results. First, a metaanalysis was not performed, which may influence the interpretation of the results. Second, the included studies had a short follow-up period. Therefore, there is a needed for larger, well-designed, strictly blinded, multicenter RCTs evaluating the long-term effect of OC-01 VNS on the LFU at different concentrations, particularly in patients with Sjogren’s syndrome (SS) and meibomian gland dysfunction (MGD), which are the main cause of aqueous-deficient dry eye (ADDE) and evaporative dry eye (EDE) [33,54], respectively. In addition, it would also be interesting to compare OC-01 VNS with other preservative-free nasal sprays, such as simpinicline (OC-02 SNS), which has been shown to significantly increase tear production and improve dry eye symptoms [55]. Third, the influence of anesthetized TS on the interpretation of tCFS results. Thus, further studies analyzing tear volume by objective and non-invasive tests, such as tear meniscus height (TMH) and tear meniscus area (TMA) are needed to avoid the influence of traditional tests on tCFS. Fourth, the studies included in this systematic review have not considered a nasal endoscopic evaluation to establish as exclusion criteria the absence of nasal pathologies that could alter the administration or absorption of OC-01 VNS. Fifth, although OC-01 VNS 0.03 mg and 0.06 mg have shown to achieve similar results, tear production was only assessed at the time of OC-01 VNS administration. Consequently, it would be interesting to determine the duration of increased tear production after OC-01 VNS treatment at different concentrations. This information could be useful to establish the effective daily dose and concentration of OC-01 VNS. Finally, it is important to mention that all studies included in this systematic review were supported by Oyster Point Pharma; hence, there is an unmet need of further non-industry funded studies. 5. Conclusions In conclusion, this systematic review has demonstrated that OC-01 VNS treatment achieves better results than vehicle. Despite the AEs, its tolerability is satisfactory, reporting high adherence. OC-01 VNS treatment reduces the symptoms and signs of DED, such as EDS, anesthetized ST and tCFS. Therefore, OC-01 VNS seems to be an effective and safe treatment that may be recommended for patients with DED. In addition, OC-01 VNS may be represented as a novel candidate to treat DED due to its nasal mode of administration, acting on the nerves that innervate the LFU without the commonly AEs of topical ocular application modalities, but further RCTs are needed. Conflicts of interest disclosures The authors have no financial/non-financial competing interest. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II definition and classification report. 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