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. 2022 Dec 31;100(2):164–169. doi: 10.1097/OPX.0000000000001986

Does Dry Eye Disease Severity Impact Efficacy of Varenicline Solution Nasal Spray on Sign and Symptom Treatment Outcomes?

John D Sheppard 1, Leslie E O'Dell 2, Paul M Karpecki 3, Michael B Raizman 4, Walter O Whitley 5, Gretchen Blemker 6, Mandy Hemphill 6, Laura H Hendrix 6, Andrea Gibson 6,∗, Marian Macsai 6
PMCID: PMC9970014  PMID: 36728653

SIGNIFICANCE

There is a clinical necessity for dry eye disease treatments that perform across a broad range of presenting patient severities. Varenicline solution nasal spray (VNS), a unique cholinergic agonist ocular surface–sparing nasal spray therapy, demonstrated significant improvement in both signs and symptoms of dry eye disease in subjects with mild, moderate, and severe symptoms as the clinical studies enrolled a more real-world patient population.

PURPOSE

This study evaluated efficacy outcomes for VNS in patients with mild-moderate and severe dry eye disease.

METHODS

An analysis of integrated data from two randomized clinical trials, ONSET-1 (NCT03636061) and ONSET-2 (NCT04036292) (vehicle control [VC], n = 294; VNS 0.03 mg, n = 308), was performed. Adults 22 years or older with dry eye disease, Ocular Surface Disease Index score of ≥23, corneal fluorescein staining score of ≥2 in ≥1 regions/≥4 all regions, and Schirmer Test Score (STS) of ≤10 mm (no restrictions on Eye Dryness Score [EDS]) were included in this study. Efficacy was evaluated using analysis of covariance among pre-specified subgroups of mild-moderate and severe baseline disease severity defined by STS (≤5 vs. >5) and EDS (<60 vs. ≥60). Consistency of effect was evaluated by interaction tests.

RESULTS

No treatment-subgroup interactions were observed for all end points (P > .05). The odds of achieving a ≥10-mm improvement in STS for VNS versus VC for patients with baseline STS ≤5 and >5 were 3.4(95% confidence interval, 2.0 to 5.6) and 2.3(1.3 to 4.0) and for EDS of <60 and ≥60 were 3.4(1.9 to 6.1) and 2.5(1.5 to 4.0). Least-squares mean treatment/VC differences in change from baseline in EDS for patients with baseline STS ≤5 or >5 were −7.4(95% confidence interval, −12.5 to −2.4) and −2.8(−8.7 to 3.1); EDS of <60 and ≥60 were −2.9(−8.3 to 2.5) and −8.1(−13.6 to −2.6).

CONCLUSIONS

Compared with VC, VNS improved tear production and patient-reported symptoms in patients with dry eye disease, demonstrating consistency of effect regardless of initial presenting severity.

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Varenicline solution nasal spray (TYRVAYA [varenicline solution] 0.03 mg; Oyster Point Pharma Inc., Princeton, NJ) was recently approved by the U.S. Food and Drug Administration for the treatment of the signs and symptoms of dry eye disease.1 Administered once into each nostril twice daily, this new therapeutic approach provides an alternative route of administration and mechanism of action for the estimated >20 million adults in the United States with dry eye disease.2

After administration, the varenicline molecule binds to nicotinic acetylcholine receptors on the terminal branches of the trigeminal nerve in the nasal cavity,3,4 activating the parasympathetic pathway to stimulate the Meibomian glands, lacrimal glands, and goblet cells of the lacrimal functional unit to produce natural tear film.5,6 Varenicline solution nasal spray is unique among approved treatments for dry eye disease because: (1) the therapy targets the nasal mucosa7; (2) the active component, varenicline, is a nicotinic acetylcholine receptor agonist; (3) the route of administration is via the nasal cavity; (4) the therapeutic benefit includes the endogenously expressed bioactive components (such as anti-inflammatory and antimicrobial proteins) secreted onto the ocular surface from the patient's own natural tear film8,9; and (5) the nasal spray avoids known issues with topical ophthalmic drug administration, such as dexterity for ocular application, poor compliance of multiple topicals, tip trauma, and potential stinging or toxicity on the ocular surface.

The efficacy and safety of 0.03 mg varenicline solution nasal spray were investigated in more than 600 patients with dry eye disease in two pivotal randomized, vehicle-controlled trials, ONSET-1 and ONSET-2. These trials demonstrated that varenicline solution nasal spray improved both tear production and patient-reported symptoms as compared with vehicle.10,11 Although the topline data reports inform on overall treatment outcomes in the study population, there remains an unmet need/data gap to inform clinicians managing a spectrum of dry eye disease (mild, moderate, and severe), as patients often present in the “real-world” setting with a broad range of disease severity.2 Clinical trials across therapeutic areas share a common phenomenon by which disease severity at baseline impacts the magnitude of change with an intervention.12–14 For example, enrolled patients in a clinical trial with mild disease may have little room to demonstrate a treatment effect,13 or enrolled patients with severe disease may potentially drive the totality of a therapeutic benefit (because they have more room to improve). Interestingly, some previous dry eye disease pivotal study designs restricted enrollment criteria to include more severe disease subjects, and outcomes must be interpreted with caution if applying results to a broad patient population under management with eye care clinicians.15–17

Accordingly, the aim of this analysis is to explore whether baseline disease severity played a role in the treatment effect of varenicline solution nasal spray compared with vehicle control in subjects with dry eye disease. The efficacy of varenicline solution nasal spray in patients with both mild-moderate and severe dry eye disease integrated data has not previously been evaluated. Herein, integrated ONSET-1 and ONSET-2 data were used to assess consistency of the effect of varenicline solution nasal spray among subgroups pre-specified by measures of baseline dry eye disease severity.

METHODS

Study Designs

Data for this integrated analysis were obtained from two randomized clinical trials: ONSET-1 (ClinicalTrials.gov NCT03636061) and ONSET-2 (NCT04036292). For both studies, institutional review board and/or ethics committee approval was obtained, and the studies were conducted in compliance with the ethical principles of the Declaration of Helsinki and International Council for Harmonization Good Clinical Practice. All patients provided written informed consent before participation. Individual study methods and safety and efficacy results have been previously reported.10,11 Briefly, the ONSET-1 (phase 2b) and ONSET-2 (phase 3) studies were both 4-week multicenter, randomized, vehicle-controlled trials in adults in the United States to evaluate the efficacy and safety of varenicline solution nasal spray. For both studies, patients were eligible if they had a physician's diagnosis of dry eye disease, an Ocular Surface Disease Index score of at least 23 with up to three responses of “Not Applicable,” corneal fluorescein staining score of at least 2 in at least one corneal region or at least 4 for all corneal regions (using the National Eye Institute scale), baseline Schirmer Test Score of 10 mm/5 minutes or lower, and Schirmer Test Score of at least 7 mm greater in the same eye after nasal stimulation. The study eye was defined as the eye that met all the inclusion criteria. Eligibility was not restricted by Eye Dryness Score (patient-rated ocular dryness symptoms from 0 [none] to 100 [maximal]). The efficacy end points of these pivotal studies included the percentage of patients who achieved a ≥10-mm improvement in the study eye in Schirmer Test Score from baseline to week 4 and the mean change in Schirmer Test Score and Eye Dryness Score from baseline to week 4.

Statistical Analysis

Efficacy assessments were conducted using data from ONSET-1 and ONSET-2 for varenicline solution nasal spray (0.03 mg) twice daily (the approved dose) versus vehicle control. Post hoc analyses evaluated the following end points: (1) the percentage of patients who achieved a ≥10-mm improvement in the study eye in anesthetized Schirmer Test Score from baseline to week 47; (2) the mean change in Schirmer Test Score from baseline to week 4; and (3) the mean change in patient-reported Eye Dryness Score from baseline to week 4.

Prespecified severity subgroups for mild-moderate versus severe dry eye disease were defined in ONSET-2 by baseline ocular assessments and included Schirmer Test Score (pre-procedure anesthetized; >5 vs. ≤5 mm) and Eye Dryness Score (<60 vs. ≥60). Severity status for mild-moderate versus severe dry eye disease at clinical presentation was primarily defined by Eye Dryness Score subgroup category.

Summary statistics and analysis included observed measurements and a last observation carried forward imputation for missing data. Mean change from baseline in study eye Schirmer Test Score and Eye Dryness Score in the treatment group versus vehicle control was evaluated using an analysis of covariance model, and percentage of patients achieving ≥10-mm change from baseline in Schirmer Test Score in the treated group versus vehicle control was evaluated using Cochrane-Mantel-Haenszel tests. Both analysis of covariance models and Cochrane-Mantel-Haenszel tests included treatment, study, site, baseline Schirmer Test Score, and baseline Eye Dryness Score as covariates. Results from analysis of covariance models are presented as least-squares mean treatment minus vehicle difference with 95% confidence intervals (CI).18 P values are reported for the overall data only (Fig. 1), as subgroups were not powered to evaluate statistical significance (Figs. 2–4). Results from Cochrane-Mantel-Haenszel tests are presented as percentage of patients achieving ≥10-mm change from baseline in Schirmer Test Score; treatment/vehicle control comparisons were presented as odds ratios with 95% CI.

FIGURE 1.

FIGURE 1

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Overall (A) percentage of patients who achieved ≥10-mm improvement in STS from baseline to week 4, (B) LS mean change from baseline to week 4 in STS, and (C) LS mean change from baseline to week 4 in EDS. Last observation carried forward. CI = confidence interval; EDS = Eye Dryness Score; LS = least-squares; SE = standard error; STS = Schirmer Test Score; VNS = varenicline solution nasal spray.

FIGURE 2.

FIGURE 2

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Forest plot of the percentage of patients who achieved ≥10-mm improvement in STS from baseline to week 4 stratified by disease severity. Mild-moderate versus severe: STS of >5 (n = 123, 137 for vehicle, VNS) versus ≤5 (n = 171, 171 for vehicle, VNS); EDS of <60 (n = 131, 134 for vehicle, VNS) versus ≥60 (n = 163, 174 for vehicle, VNS). Last observation carried forward. CI = confidence interval; EDS = Eye Dryness Score; STS = Schirmer Test Score; VNS = varenicline solution nasal spray.

FIGURE 4.

FIGURE 4

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Forest plot of LS mean change in EDS from baseline to week 4 stratified by disease severity. Mild-moderate versus severe: STS of >5 (n = 123, 134 for vehicle, VNS) versus ≤5 (n = 168, 167 for vehicle, VNS); EDS of <60 (n = 131, 132 for vehicle, VNS) versus ≥60 (n = 160, 169 for vehicle, VNS). Last observation carried forward. CI = confidence interval; EDS = Eye Dryness Score; LS = least-squares; SD = standard deviation; STS = Schirmer Test Score; VNS = varenicline solution nasal spray.

To evaluate the consistency of the treatment effect within subgroups, treatment-subgroup interaction terms were included in models and tests with overall data. Interaction was considered statistically significant at P > .05. For purposes of interpretation, the term no interaction may be defined as follows: no statistically significant (P > .05) difference in the treatment effect, that is, OC-01 (varenicline solution) nasal spray (0.03 mg) treatment outcome minus vehicle control outcome, between the respective subgroups (i.e., Schirmer Test Score anesthetized; >5 vs. ≤5 mm) and Eye Dryness Score (<60 vs. ≥60). Differences among exploratory post hoc subgroups are not evaluated for statistical significance.

RESULTS

Demographic and Baseline Clinical Characteristics

The integrated population for efficacy assessments included 602 patients—294 assigned to vehicle and 308 assigned to 0.03 mg of varenicline solution nasal spray (Table 1). Overall, the mean age of the treatment population was 60.7 years, and patients were predominantly female (74.0%) and White (83.8%). The baseline ocular assessments were balanced across treatment assignments (Table 1).

TABLE 1.

Baseline demographic characteristics and ocular assessments

Patient characteristic Vehicle control
(n = 294)		 VNS 0.03 mg
(n = 308)
Age (y) 59.2 (13.0) 60.7 (12.5)
Female, n (%) 233 (79.3) 288 (74.0)
Race, n (%)
 White 250 (85.0) 258 (83.8)
 Black or African American 29 (9.9) 31 (10.1)
 Other 15 (5.1) 19 (6.2)
Ocular assessments
 Schirmer Test Score (mm) 4.8 (2.9) 5.1 (2.9)
 Cotton swab Schirmer Test Score (mm)* 27.5 (8.0) 27.8 (8.2)
 Eye Dryness Score (mm) 59.1 (21.8) 59.3 (21.6)
 Best-corrected visual acuity (logMAR) 0.124 (0.154) 0.112 (0.144)
 Ora Calibra Ocular Discomfort Scale (grade) 2.8 (1.0) 2.8 (0.9)
 Ocular Surface Disease Index 51.1 (18.5) 51.1 (18.9)
 Corneal fluorescein staining (total score) 6.2 (2.1) 6.5 (2.2)
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Mean (standard deviation) unless stated. *Vehicle, n = 248; VNS 0.03 mg, n = 257. VNS = varenicline solution nasal spray.

Efficacy Outcomes, Integrated Population

Overall, patients who received varenicline solution nasal spray demonstrated statistically significant improvements in tear film production and patient-reported eye dryness symptoms compared with vehicle control. The percentage of patients achieving a ≥10-mm improvement in Schirmer Test Score was greater in the varenicline solution nasal spray group (48.1%) compared with vehicle control (25.9%; P < .001) (Fig. 1A); least-squares mean change from baseline in Schirmer Test Score was greater in the varenicline solution nasal spray group (10.4 mm) compared with vehicle control (4.9 mm; P < .001) (Fig. 1B); least-squares mean change from baseline in Eye Dryness Score was greater in the varenicline solution nasal spray group (−14.7) compared with vehicle control (−9.0; P = .003) (Fig. 1C).

Efficacy Outcomes by Severity of Dry Eye Disease

In the subgroup analyses, improvements in tear production and patient-reported eye dryness symptoms were greater for varenicline solution nasal spray than for vehicle control in patients with mild-moderate or severe dry eye disease, regardless of whether severity of dry eye disease was classified by Schirmer Test Score or Eye Dryness Score.

The odds of achieving a ≥10-mm improvement in Schirmer Test Score for varenicline solution nasal spray versus vehicle control for patients with baseline Schirmer Test Score of ≤5 and >5 mm were 3.4 (95% CI, 2.0 to 5.6) and 2.3 (1.3 to 4.0), respectively. For patients with baseline Eye Dryness Score of <60 and ≥60, odds ratios were 3.4 (1.9 to 6.1) and 2.5 (1.5 to 4.0), respectively (Fig. 2). Least-squares mean treatment-vehicle control differences in change from baseline Schirmer Test Score for patients with baseline Schirmer Test Score of ≤5 or >5 mm were 5.7 (95% CI, 3.9 to 7.6) and 5.2 mm (2.9 to 7.6), respectively, and for patients with baseline Eye Dryness Score of <60 and ≥60 were 6.5 (4.2 to 8.8) and 4.8 mm (2.9 to 6.7), respectively (Fig. 3). Least-squares mean treatment-vehicle control differences in change from baseline in Eye Dryness Score for patients with baseline Schirmer Test Score of ≤5 or >5 mm were −7.4 (95% CI, −12.5 to −2.4) and −2.8 (−8.7 to 3.1), respectively, and those for patients with baseline Eye Dryness Score of <60 and ≥60 were −2.9 (−8.3 to 2.5) and −8.1 (−13.6 to −2.6), respectively (Fig. 4).

FIGURE 3.

FIGURE 3

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Forest plot of LS mean change in STS from baseline to week 4 stratified by disease severity. Mild-moderate versus severe: STS of >5 (n = 123, 132 for vehicle, VNS) versus ≤5 (n = 168, 165 for vehicle, VNS); EDS of <60 (n = 131, 130 for vehicle, VNS) versus ≥60 (n = 160, 167 for vehicle, VNS). Last observation carried forward. CI = confidence interval; EDS = Eye Dryness Score; LS = least-squares; SD = standard deviation; STS = Schirmer Test Score; VNS = varenicline solution nasal spray.

Models evaluating treatment effect across subgroups did not demonstrate any statistically significant treatment-subgroup interactions for all baseline stratification factors of Schirmer Test Score and Eye Dryness Score (all interaction terms, P > .05), thereby demonstrating the consistency of the treatment effect for Schirmer Test Score and Eye Dryness Score end points assessed across these subgroups.

DISCUSSION

Patients with dry eye disease present in “real-world” clinical settings with a broad range of severities, and notably, 92% of participants in a survey self-reported their symptoms as mild or moderate.2 Given this heterogeneity of the disease, it is important to consider a treatment approach that could benefit patients across a range of disease severities at clinical presentation. In this post hoc integrated analysis, varenicline solution nasal spray improved the signs and symptoms of dry eye disease for patients with either mild-moderate or severe dry eye disease. Compared with vehicle control at 4 weeks, varenicline solution nasal spray treatment effect results support consistency in increasing both tear production (by the percentage of patients achieving a ≥10-mm improvement in Schirmer Test Score and the least-squares mean change in [anesthetized] Schirmer Test Score) and decreased patient-reported symptoms (as measured by the least-squares mean change in Eye Dryness Score) in patients with mild-moderate or severe dry eye disease (defined by pre-specified baseline measures of Schirmer Test Score or Eye Dryness Score). In addition, the integrated analysis found that varenicline solution nasal spray was well tolerated (data not shown), with safety outcomes similar to previous studies.10,11 Overall, safety findings were consistent with those identified in the primary ONSET-1 and ONSET-2 trials, with no new findings identified.10,11 These results confirm that varenicline solution nasal spray will benefit patients with a broad range of disease severities, regardless of their disease severity status at initial clinical presentation.

Although a number of prescription therapies are approved for the treatment for the signs and symptoms of dry eye disease,19 an unmet need still exists.20 Importantly, the Tear Film and Ocular Surface Society Dry Eye Workshop II recommends individualized management of dry eye disease based on patient characteristics, disease etiology, and symptom severity.21 The most common prescription medications for dry eye disease are approved for all patients,7,22 but primary clinical trial reports for these drugs restricted participants to those with more severe dry eye disease by Eye Dryness Score of ≥4017,23–25 or by Schirmer Test Score of ≤5 mm,16 which may limit interpretation of outcomes in patients with mild-moderate disease. Furthermore, a recent pooled analysis report found that the impact of treatment varied greatly based on baseline disease severity, and treatment benefits demonstrated were limited to subjects categorized as having more moderate to severe dry eye disease at clinical presentation.18 In contrast, participant eligibility for ONSET-1 and ONSET-2 was not restricted by Eye Dryness Score,10,11 so we were able to assess a broader range of patients. These data better elucidate the outcomes of increasing natural tear production in more mild-moderate and severe presenting dry eye disease patients as a potential initial treatment strategy (and per consideration of the benefits of endogenously expressed bioactive growth factors, proteins, anti-inflammatory components within human tears).8,9

This analysis was limited by the constraints of post hoc analyses; however, subgroups assessed were based on pre-specified baseline stratification factors accounted for at randomization, which provided similar subgroup sizes for comparisons, and tests for treatment-subgroup interaction indicated no differences in treatment effect among subgroups. Our findings are also limited by the study designs for the primary studies. However, given the mechanism of action of varenicline solution nasal spray, which aims to increase basal tear production, the use of Schirmer Test Score as the primary end point is supported by the Tear Film and Ocular Surface Society Dry Eye Workshop II report recommendation that study outcomes measured should align with the mechanism of action, be objective, and be minimally invasive.26 We used integrated data from our pivotal studies to increase overall subgroup sample size for more robust interpretation of outcomes and followed the most appropriate methodology to explore the consistency of effect (interaction testing) outcomes in subgroups from clinical trials,27 although subgroup analyses should be interpreted with caution. Another strength of the study is that we used both a direct clinical dry eye disease sign measure and a patient-reported outcome to define the severity status of dry eye disease at baseline, which may provide complementary information on response to treatment, especially as markers of dry eye disease severity can be variable in consistency, repeatability, and utilization.28–30

In conclusion, our analysis of integrated ONSET-1 and ONSET-2 data found that varenicline solution nasal spray improved tear production and decreased patient-reported symptoms in subjects with dry eye disease, regardless of mild-moderate or severe disease at clinical presentation. In an indirect comparison which matched subjects using varenicline solution nasal spray to those using two Food and Drug Administration–approved dry eye disease therapies by baseline disease severity, varenicline solution nasal spray showed greater sign and symptom improvements than comparison therapies whose study populations had worse baseline disease.31,32 These data demonstrate the potential for varenicline solution nasal spray to be beneficial for a broad range of presenting patient disease severities. Our data may further inform clinicians' decision-making regarding initiating pharmacologic neuroactivation of natural tear production improvements earlier in the treatment course and in managing the complexity of treatment approach considerations for this challenging disorder.

Footnotes

Funding/Support: None of the authors have reported funding/support.

Conflict of Interest Disclosure: AG, corresponding author, is an employee of and shareholder in Oyster Point Pharma, Inc., the sponsor of this study.

The authors report the following conflicts of interest: JDS has consulted for the following companies: AbbVie, Alcon, Aldeyra, Allergan, Alphaeon, ArcScan, Avedro, Bausch & Lomb, BioLayer, Bio-Tissue, Bruder Healthcare, Clearside, Clearview, Clementia Pharma, Dompe, Eleven, Eyedetec, EyeGate Research, EyeRx Research, Eyevance, Glaukos, Hovione, Imprimis Pharma, InSite Vision Inc., Inspire/Merck Pharmaceuticals, Isis Pharmaceuticals, Johnson & Johnson/TearScience/Vistakon, Kala Pharmaceuticals, Kowa, LacriSciences, LayerBio, Lenstatin, Lumenis, Lux Biosciences, Mallinckrodt, Mati Therapeutics, MioTech, Neomedix, NicOx, NovaBay, Novaliq, Novartis, Noveome Biotherapeutics, OcuCure, Ocular Therapeutix, Oculis, Okogen, Omeros, Oyster Point, Parion, Pfizer, Portage, Quidel, Rapid Pathogen Screening, Rutech, Santen, Science Based Health, Senju, Shire, Sun Pharmaceuticals, Surrozen, Synedgen, Takeda, Talia Technology, Tear Solutions, TearLab, Topcon, TopiVert, and Xoma/Servier. LEO, PMK, and WOW are speakers and consultants for Oyster Point Pharma, Inc. GB, MH, LHH, AG, and MM are employees of and shareholders in Oyster Point Pharma, Inc.

Study Registration Information: This study represents a subanalysis from two previous clinical trials (both published): ONSET-1 (ClinicalTrials.gov, NCT03636061) and ONSET-2 (ClinicalTrials.gov, NCT04036292).

Author Contributions and Acknowledgments: Conceptualization: AG; Data Curation: LHH; Formal Analysis: GB, MH, LHH, AG, MM; Methodology: LHH, AG; Supervision: MM; Validation: JDS, LEO, PMK, MBR, WOW, GB, MH, LHH, AG, MM; Visualization: GB, MH, AG; Writing – Original Draft: JDS, LEO, PMK, MBR, WOW, GB, MH, LHH, AG, MM; Writing – Review & Editing: JDS, LEO, PMK, MBR, WOW, GB, MH, LHH, AG, MM.

Statistical analysis assistance was provided by Eugenia Henry, PhD, and Kuei Hsun Chiu, MS, of Firma Clinical Research and was funded by Oyster Point Pharma, Inc. Medical writing assistance was provided by Nikolas Vann, PhD, and Janelle Keys, PhD, CMPP, of Envision Pharma Group and was funded by Oyster Point Pharma, Inc. Envision Pharma Group's services complied with international guidelines for Good Publication Practice (GPP3). Portions of these data were presented at the American Academy of Optometry Meeting, Boston, MA, November 3 to 6, 2021, and the American Academy of Ophthalmology Meeting, New Orleans, LA, November 13 to 14, 2021.

Contributor Information

John D. Sheppard, Email: jsheppard@cvphealth.com.

Leslie E. O'Dell, Email: drodell@medodamerica.com.

Paul M. Karpecki, Email: karpecki@karpecki.com.

Michael B. Raizman, Email: mbraizman@eyeboston.com.

Walter O. Whitley, Email: wwhitley@cvphealth.com.

Gretchen Blemker, Email: gblemker@oysterpointrx.com.

Mandy Hemphill, Email: mancran@mac.com.

Laura H. Hendrix, Email: lhendrix@oysterpointrx.com.

Marian Macsai, Email: mmacsai@oysterpointrx.com.

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