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Varenicline Nasal Spray (OC-01) for the Treatment of Dry Eye Disease: The ONSET-2 Study

  • Oculus Research, Inc.


ONSET-2 is a Phase 3 clinical trial to evaluate the efficacy and safety of OC-01 nasal spray vs. placebo (vehicle) for the treatment of signs and symptoms of dry eye disease.
Patrick M. Vollmer1,2 Carol A. Aune3,4 Alan G. Kabat5,6
1Vita Eye Clinic, Shelby, NC; 2Core (Clinical Ophthalmic Research Exploration), Shelby, NC; 3Oculus Research, Raleigh, NC; 4eyecarecenter, Raleigh, NC; 5Oyster Point Pharma, Inc., Princeton, NJ; 6Pennsylvania College of Optometry at Salus University, Elkins Park, PA.
Dry eye disease is a common ocular disorder affecting tens of millions of people in the
United States alone.1A recent global consensus paper, published in December of 2020,
redefined dry eye disease as follows:
Multiple definitions of dry eye disease have been suggested by previous authors.
Unfortunately, the range of definitions has contributed to confusion and a lack of
consistent diagnosis of this condition across the globe. Criteria for the clinical definition
of dry eye has varied considerably, including such elements as tear deficiency,
symptoms of discomfort, ocular surface damage, tear hyperosmolarity, inflammation of
the ocular surface, tear film instability, loss of homeostasis and neurosensory
abnormalities.1-4 According to the new 2020 global consensus definition of dry eye
disease by Tsubota et al.,2tear film stability is a sensitive measure of tear dysfunction
that can be easily determined, making it a clinically practical and reproducible marker of
tear dysfunction, and “it should be the key criterion in a clinical definition of dry eye
OC-01 (varenicline) nasal spray contains a small-molecule nicotinic acetylcholine
receptor agonist. OC-01 has been proposed as a treatment for dry eye disease due to its
ability to increase natural tear production via the trigeminal parasympathetic pathway, as
seen in preclinical and clinical studies.5ONSET-2 is a Phase 3 clinical trial to evaluate
the efficacy and safety of OC-01 nasal spray vs. placebo (vehicle) for the treatment of
signs and symptoms of dry eye disease.
758 subjects (aged 22 years) across 22 clinical sites were randomized in a 1:1:1 fashion
to receive either 0.6 mg/mL OC-01 nasal spray (N=260), 1.2 mg/mL OC-01 nasal spray
(N=246), or placebo (vehicle) nasal spray (N=252). Subjects in all three groups received
the nasal spray BID for 28 days. The primary efficacy measure involved the percent of
subjects achieving 10 mm improvement in Schirmer's Test Score (STS) from baseline at
Day 28. Secondary efficacy measures included: mean change from baseline in STS at
Day 28; mean change from baseline in Eye Dryness Score (EDS) by visual analog scale
(0-100)in the Controlled Adverse Environment (CAE®) Chamber at Day 28; mean change
from baseline in EDS through Day 28;and mean change from baseline in corneal
fluorescein staining at Day 28. Self-reported adverse events (AEs) were also monitored
and recorded throughout the study.
Subjects in both the 0.6 mg/mL and the 1.2 mg/mL OC-01 groups showed statistically
significant improvement compared with placebo, as indicated by a gain in STS of 10
mm from baseline at Day 28. This effect was seen in 47.3% and 49.2% of subjects
respectively, vs.27.8% of those in the placebo group (ITT population, LOCF) [Figure #1].
The mean change from baseline in STS was 11.3 mm and 11.5 mm, respectively, vs. 6.3
mm for the placebo group [Figure #2]. No significant changes were seen in mean change
from baseline in EDS in the CAE®chamber at Day 28 [Figure #3], however a (nominally)
significant reduction in EDS from baseline was demonstrated in the clinic in both the 0.6
mg/mL and 1.2 mg/mL groups as compared to placebo at both Day 14 and Day 28
[Figure #4].
The data from ONSET-2 also demonstrate that OC-01 nasal spray was safe and well-
tolerated at both the 0.6 mg/mL and the 1.2 mg/mL concentrations. The most commonly
reported AEs in all groups (>5%) were non-ocular in nature, and included transient
sneezing, cough, throat irritation and instillation site irritation related to the administration
of the drug [Table #1]. The vast majority of AEs were reported as mild. No serious drug-
related adverse events were reported.
1. Craig JP, Nelson JD, Azar DT, Belmonte C, Bron AJ, Chauhan SK, de Paiva CS, Gomes JAP, Hammitt KM, Jones L, Nichols JJ, Nichols KK, Novack
GD, Stapleton FJ, Willcox MDP, Wolffsohn JS, Sullivan DA. TFOS DEWS II Report Executive Summary. Ocul Surf. 2017 Oct;15(4):802-812.
2. Tsubota K, Pflugfelder SC, Liu Z, Baudouin C, Kim HM, Messmer EM, Kruse F, Liang L, Carreno-Galeano JT, Rolando M, Yokoi N, Kinoshita S, Dana R.
Defining Dry Eye from a Clinical Perspective. Int J Mol Sci. 2020 Dec 4;21(23):9271.
3. Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. CLAO J. 1995 Oct;21(4):221-32.
4. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop
(2007). Ocul Surf. 2007 Apr;5(2):75-92.
5. Keiger CJ, Case LD, Kendal-Reed M, Jones KR, Drake AF, Walker JC. Nicotinic cholinergic receptor expression in the human nasal mucosa. Ann Otol
Rhinol Laryngol. 2003 Jan;112(1):77-84.
6. Paulsen AJ, Cruickshanks KJ, Fischer ME, Huang GH, Klein BE, Klein R, Dalton DS. Dry eye in the beaver dam offspring study: prevalence, risk
factors, and health-related quality of life. Am J Ophthalmol. 2014 Apr;157(4):799-806.
7. Perry HD, Donnenfeld ED. Topical 0.05% cyclosporin in the treatment of dry eye. Expert Opin Pharmacother. 2004 Oct;5(10):2099-107.
8. Friedman NJ, Butron K, Robledo N, Loudin J, Baba SN, Chayet A. A nonrandomized, open-label study to evaluate the effect of nasal stimulation on tear
production in subjects with dry eye disease. Clin Ophthalmol. 2016 May 4;10:795-804.
9. Gumus K, Schuetzle KL, Pflugfelder SC. Randomized Controlled Crossover Trial Comparing the Impact of Sham or Intranasal Tear Neurostimulation on
Conjunctival Goblet Cell Degranulation. Am J Ophthalmol. 2017 May;177:159-168.
10. Pondelis N, Dieckmann GM, Jamali A, Kataguiri P, Senchyna M, Hamrah P. Infrared meibography allows detection of dimensional changes in
meibomian glands following intranasal neurostimulation. Ocul Surf. 2020 Jul;18(3):511-516.
11. Sheppard JD, Torkildsen GL, Geffin JA, Dao J, Evans DG, Ousler GW, Wilson J, Baba SN, Senchyna M, Holland EJ. Characterization of tear
production in subjects with dry eye disease during intranasal tear neurostimulation: Results from two pivotal clinical trials. Ocul Surf. 2019
12. Dieckmann G, Cox SM, Lopez MJ, Ozmen MC, Yavouz-Saricay L, Byraktutar BN, Binotti WW, Nau J, Hamrah P. OC-01 (Varenicline) Nasal Spray
Induces Goblet Cell Alterations in Patients with Dry Eye Disease. Poster presented at the American Academy of Ophthalmology Virtual Annual Meeting,
November 13,2020.
Though dry eye disease is estimated to affect more than 30 million American adults, the
condition continues to be both underdiagnosed and undermanaged.6,7 Most current
treatments target downstream disease sequelae, such as ocular surface inflammation,
while expert consensus continues to recommend therapies that restore tear film stability
and homeostasis.1,2 A relatively recent therapeutic strategy for the management of dry
eye disease involves activation of the parasympathetic trigeminal pathway. Friedman
and associates demonstrated the efficacy of an intranasal, electrical neurostimulation
device for increasing tear production and reducing symptoms of dry eye disease.8
Further studies with this device revealed its ability to stimulate complete, natural tear
production, including goblet cell degranulation (mucin) and meibomian gland expression
(lipid) in addition to aqueous tear secretion.9-11 OC-01 (varenicline) nasal spray targets
this same trigeminal parasympathetic pathway via pharmacologic stimulation, with
similar complete, natural tear production.12 It is postulated that, by augmenting the
natural tear film rather than addressing downstream inflammatory sequelae, OC-01 may
potentially target the core mechanism of dry eye disease more directly, alleviating tear
film instability and restoring homeostasis to the ocular surface environment.
In this multicenter, randomized, masked, placebo-controlled clinical trial of subjects with
dry eye disease, OC-01 nasal spray was shown to stimulate tear production as reflected
by a statistically significant increase in patients with 10 mm or greater change in
Schirmer's Test Score from baseline versus placebo at 28 days. Additionally, the data
reflect that patients receiving OC-01 had (nominally) statistically significant improvement
in Eye Dryness Scores from baseline at 14 and 28 days, as compared to placebo. The
most common adverse events related to OC-01 were mild, transient sneezing, cough,
throat irritation and instillation site irritation following administration of the nasal spray.
Dry eye is a multifactorial disease characterized by a persistently unstable and/or
deficient tear film causing discomfort and/or visual impairment, accompanied by
variable degrees of ocular surface epitheliopathy, inflammation and neurosensory
This study was funded and supported by Oyster Point Pharma, Inc. (Princeton, NJ, USA) Presented at the New Technologies and Treatments in Eye Care Conference. March 19-20, 2021 & June11-12, 2021.
Most Frequent Adverse Events in >5% of Subjects
Reported Adverse Event
OC-01 0.6 mg/mL
n (%)
OC-01 1.2 mg/mL
n (%)
n (%)
Sneezing 247 (95.0) 237 (96.7) 73 (29.1)
Cough 49 (18.8) 53 (21.6) 5 (2.0)
Throat irritation
35 (13.5) 44 (18.0) 5 (2.0)
Instillation Site Irritation
19 (7.3) 35 (14.3) 3 (1.2)
Table #1
PMV Clinical Investigator, Oyster Point Pharma, Inc.
CAA Clinical Investigator, Oyster Point Pharma, Inc.
AGK Full-time employee (Medical Director), Oyster Point Pharma, Inc.
Mean Change in Baseline Eye Dryness Score at Week 1, 2, & 4
* Controlled Adverse Environment (CAE®)is a registered trademark of Ora, Inc.
Figure #3
Mean Change in Baseline Eye Dryness Score in
the Controlled Adverse Environment (CAE®)
Mean Change From Baseline in Schirmer's Score
(mm) @ Week 4
% Subjects with ≥10 mm Change from Baseline in
Schirmer's Score (mm) @ Week 4
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Over the past decades, the number of patients with dry eye disease (DED) has increased dramatically. The incidence of DED is higher in Asia than in Europe and North America, suggesting the involvement of cultural or racial factors in DED etiology. Although many definitions of DED have been used, discrepancies exist between the various definitions of dry eye disease (DED) used across the globe. This article presents a clinical consensus on the definition of DED, as formulated in four meetings with global DED experts. The proposed new definition is as follows: “Dry eye is a multifactorial disease characterized by a persistently unstable and/or deficient tear film (TF) causing discomfort and/or visual impairment, accompanied by variable degrees of ocular surface epitheliopathy, inflammation and neurosensory abnormalities.” The key criteria for the diagnosis of DED are unstable TF, inflammation, ocular discomfort and visual impairment. This definition also recommends the assessment of ocular surface epitheliopathy and neurosensory abnormalities in each patient with suspected DED. It is easily applicable in clinical practice and should help practitioners diagnose DED consistently. This consensus definition of DED should also help to guide research and clinical trials that, to date, have been hampered by the lack of an established surrogate endpoint.
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Purpose: The intranasal tear neurostimulator (ITN) activates the nasolacrimal pathway, which is involved with basal and bolus tear secretion. These studies characterized the acute and long-term effectiveness of the ITN in stimulating tear production in subjects with dry eye disease (DED). Methods: Study 1: Randomized, double-masked, dual-controlled, 1-day crossover. Study 2: Single-arm, open-label, 180-day prospective cohort. Eligible subjects had basal unstimulated Schirmer test (with anesthesia) ≤10 mm and intranasal cotton swab-stimulated Schirmer test at least 7 mm greater in the same eye, and Ocular Surface Disease Index® ≥13 and ≥ 23, in Studies 1 and 2, respectively. Study 1: Subjects (n = 48) received three randomized test applications: active intranasal, extranasal (active control), and sham intranasal (inactive control) stimulation, 3 min/application with 1-hour minimum between applications. Primary outcome measure was the difference in Schirmer test scores during active intranasal and control applications. Study 2: Subjects (n = 97) performed intranasal neurostimulation for ≤3 min/application, 2-10 times/day. Primary outcome measure was the difference in Schirmer scores (stimulated minus unstimulated) at day 180. Both studies recorded device-related adverse events (AEs). Results: Study 1: Schirmer scores (mean ± SEM) were significantly greater (p < 0.0001) with active intranasal (25.3 ± 1.5 mm) vs extranasal (9.5 ± 1.2 mm) and sham (9.2 ± 1.1 mm) applications. Study 2: Schirmer scores were significantly greater (p < 0.0001) with ITN stimulation vs unstimulated at day 180 (17.3 ± 1.3 mm vs 7.9 ± 0.7 mm). No serious device-related AEs were reported in either study. Conclusion: The ITN was well-tolerated and effective in stimulating tear production with acute and long-term use in DED. CLINICALTRIALS. Gov identifier: NCT02680158 and NCT02526290.
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Purpose: The aim of the study was to investigate the effects of the Oculeve Intranasal Lacrimal Neurostimulator (ILN) on conjunctival goblet cell degranulation. Design: A randomized, double-masked, placebo-controlled crossover trial METHODS: A total of 15 subjects (5 normal and 10 dry eye) were enrolled in a three-visit study consisting of one screening and two separate randomized-masked ILN treatments (sham extranasal or intranasal). Tear meniscus height (TMH) was measured by AS-OCT before and after applications. Impression cytology (IC) was taken from the bulbar conjunctiva of the right eye for PAS staining and from the left eye for MUC5AC mucin immunostaining at baseline and after each treatment. The ratio of degranulated to non-degranulated GCs was measured as a marker of secretion. Results: In all participants, both IB and TB cytology specimens stained for MUC5AC revealed a significantly higher ratio of degranulated to non-degranulated GCs after the ILN (IB: 2.28 ± 1.27 and TB: 1.81 ± 1.01) compared to baseline (IB: 0.56 ± 0.55, p= 0.015) (TB: 0.56 ± 0.32, p= 0.003) and extranasal sham application (IB: 0.37 ± 0.29, p= 0.001) (TB: 0.39 ± 0.33, p= 0.001). When the same analysis was repeated in the dry eye or control groups, the ratio was significantly higher after ILN than the baseline ratio and ratio after extranasal application in both groups (p< 0.05). Moreover, while control subjects had higher ratio of degranulated to non-degranulated GCs at baseline (0.75 ± 0.52) compared to the dry eye group (0.41 ± 0.27); the ratio became slightly higher in dry eye (2.04 ± 1.12 vs. 1.99 ± 1.21 in control) after the ILN application. There was no significant difference between the IB or TB conjunctiva locations in terms of the effectiveness of the ILN application on conjunctival goblet cell secretory response. Conclusions: These preliminary results document that the Oculeve ILN can stimulate degranulation of goblet cells in the conjunctiva, which is a promising new approach for the management of dry eye. • This study protocol was registered on (#NCT02385292).
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Background: Dry eye disease (DED), a chronic disorder affecting the tear film and lacrimal functional unit, is a widely prevalent condition associated with significant burden and unmet treatment needs. Since specific neural circuits play an important role in maintaining ocular surface health, microelectrical stimulation of these pathways could present a promising new approach to treating DED. This study evaluated the efficacy and safety of nasal electrical stimulation in patients with DED. Methods: This prospective, open-label, single-arm, nonrandomized pilot study included 40 patients with mild to severe DED. After undergoing two screening visits, enrolled subjects were provided with a nasal stimulation device and instructed to use it at home four times daily (or more often as needed). Follow-up assessments were conducted up to day 180. The primary efficacy endpoint was the difference between unstimulated and stimulated tear production quantified by Schirmer scores. Additional efficacy endpoints included change from baseline in corneal and conjunctival staining, symptoms evaluated on a Visual Analog Scale, and Ocular Surface Disease Index scores. Safety parameters included adverse event (AE) rates, visual acuity, intraocular pressure, slit-lamp biomicroscopy, indirect ophthalmoscopy, and endoscopic nasal examinations. Results: Mean stimulated Schirmer scores were significantly higher than the unstimulated scores at all visits, and corneal and conjunctival staining and symptom scores from baseline to day 180 were significantly reduced. No serious device-related AEs and nine nonserious AEs (three device-related) were reported. Intraocular pressure remained stable and most subjects showed little or no change in visual acuity at days 30 and 180. No significant findings from other clinical examinations were noted. Conclusion: Neurostimulation of the nasolacrimal pathway is a safe and effective means of increasing tear production and reducing symptoms of dry eye in patients with DED.
Purpose Patients with dry eye disease (DED) may suffer from decreased tear break-up time due to meibomian gland (MG) dysfunction. Infrared meibography (IR Meibography) uses infrared wavelength light to visualize meibomian glands in vivo. We aimed to explore the feasibility of using serial IR Meibography imaging to assess morphological changes in MGs as an indirect measure of functionality, following intranasal neurostimulation (ITN). Methods Fifteen DED subjects were prospectively enrolled in a single-center, single-arm study. Changes in MGs were captured using IR meibography (RTVUE-XR, Optovue, Inc. Fremont, CA, USA) on the lower eyelids before and after 3 minutes of ITN (TrueTear®, Allergan, Dublin, Ireland) use that delivers a microcurrent to sensory neurons of the nasal cavity. The same MGs were selected pre- and post-stimulation, and MG area and perimeter were analyzed by two masked observers. Results Mean (±SD) pre- and post-stimulation MG areas were 2,187.60±635.88 μm² and 1,933.20±538.55 μm², respectively. The mean change in area, 254.49 μm², representing an 11.6% reduction following ITN use, was statistically significant (p=0.001). Mean (±SD) pre- and post-stimulation MG perimeters were 235.9±51.38 μm and 222.2±47.72μm, respectively. The mean change in perimeter, 13.7 μm, representing a 5.81% reduction following ITN use, was statistically significant (p=0.012). Conclusions Our study shows that IR meibography can be used to detect immediate changes in gland area and perimeter, an indirect measure of MG activity following intervention by ITN.
To estimate dry eye prevalence in the Beaver Dam Offspring Study (BOSS), including a young adult population, and investigate associated risk factors and impact on health-related quality of life. Cohort study. The BOSS (2005-2008) is a study of aging in the adult offspring of the population-based Epidemiology of Hearing Loss Study cohort. Questionnaire data on health history, medication use, risk factors, and quality of life were available for 3275 participants. Dry eye was determined by self-report of frequency of symptoms and the intensity of those symptoms. Associations between dry eye and risk factors were analyzed using logistic regression. The prevalence of dry eye in the BOSS was 14.5%, 17.9% of women and 10.5% of men. In a multivariate model, statistically significant associations were found with female sex (Odds Ratio (OR), 1.68; 95% Confidence Interval (CI), 1.33-2.11), current contact lens use (OR, 2.01; 95%CI, 1.53-2.64), allergies (OR, 1.59; 95%CI 1.22-2.08), arthritis (OR, 1.44; 95%CI, 1.12-1.85), thyroid disease (OR, 1.43; 95%CI, 1.02-1.99), antihistamine use (OR, 1.54; 95%CI, 1.18-2.02), and steroid use (OR, 1.54; 95%CI, 1.16-2.06). Dry eye was also associated with lower scores on the Medical Outcomes Short Form-36 (β=-3.9, p<0.0001) as well as on the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) (β=-3.4, p<0.0001) when controlling for age, sex, and comorbid conditions. The prevalence of dry eye and its associated risk factors in the BOSS were similar to previous studies. In this study, DES was associated with lower quality of life on a health-related quality of life instrument and the vision-specific NEI-VFQ-25.
Twenty-four nasal mucosa specimens were obtained from the inferior or middle turbinates of 6 normal subjects and 18 patients with chronic sinusitis, inflammatory polyp formation, or sinus allergies. Reverse transcription-polymerase chain reaction analysis was used to identify the non-neuronal nicotinic cholinergic receptor (nAChR) subunits that were expressed in the nasal mucosa. Collectively, transcripts for alpha (alpha1, alpha2, alpha3, alpha4, alpha6, alpha7) and beta (beta2, beta3, beta4) nAChR subunit genes were detected in the respiratory mucosa. The alpha3, alpha7, and beta2 subunits were expressed in 92%, 88%, and 75% of the subjects, respectively. There was a high degree of interindividual variation in nAChR subunit gene expression among subjects. A significant univariate association was found between tissue type and beta4 expression and between gender and beta3 expression. These data suggest that cells in the nasal mucosa express the necessary messenger RNAs (mRNAs) for numerous nAChR combinations. Moreover, our identification of nAChR subunit mRNAs in the nasal mucosa extends the findings of other functional studies of nAChRs in nasal epithelial cells and implies that nicotine from tobacco products such as cigarette smoke and nicotine nasal spray may have direct cellular effects on nasal mucosa cells through activation of homogeneous or heterogeneous nAChRs. A significant number of patients receiving nicotine nasal spray have reported nasal irritation, and there are reports of transient irritation of the throat and trachea with the use of smoke-free nicotine cigarettes. These adverse respiratory effects may be due to activation of nAChRs in epithelial cells of the nose and trachea.
Dry eye disease is a common and often underdiagnosed condition that affects > 10% of the adult population, > 65 years of age in the US. This condition has been classified into two separate, but overlapping, categories--aqueous deficiency and evaporative loss. Diagnosis is confused by the lack of a single diagnostic test. Fluorescein break-up time is one of the best screening tests and is augmented by Lissamine green supravital staining. New concepts of pathogenesis have shown that dry eye disease appears to be caused by inflammation mediated by T-cell lymphocytes. This finding led to the study and FDA-approval of topical 0.05% cyclosporin A (Restasis) for the treatment of dry eye disease. 0.05% Cyclosporin A offers the first therapeutic treatment for patients with moderate-to-severe dry eye disease due to aqueous deficiency.
  • J P Craig
  • J D Nelson
  • D T Azar
  • C Belmonte
  • A J Bron
  • S K Chauhan
  • C S De Paiva
  • Jap Gomes
  • K M Hammitt
  • L Jones
  • J J Nichols
  • K K Nichols
  • G D Novack
  • F J Stapleton
  • Mdp Willcox
  • J S Wolffsohn
  • D A Sullivan
Craig JP, Nelson JD, Azar DT, Belmonte C, Bron AJ, Chauhan SK, de Paiva CS, Gomes JAP, Hammitt KM, Jones L, Nichols JJ, Nichols KK, Novack GD, Stapleton FJ, Willcox MDP, Wolffsohn JS, Sullivan DA. TFOS DEWS II Report Executive Summary. Ocul Surf. 2017 Oct;15(4):802-812.