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

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 VARENICLINE NASAL SPRAY (OC-01) FOR THE TREATMENT OF DRY EYE DISEASE:
THE ONSET-2 STUDY
Patrick M. Vollmer 1,2 ⬧ Carol A. Aune 3,4 ⬧ Alan G. Kabat 5,6

1 Vita Eye Clinic, Shelby, NC; 2 Core (Clinical Ophthalmic Research Exploration), Shelby, NC; 3 Oculus Research, Raleigh, NC; 4 eyecarecenter, Raleigh, NC; 5 Oyster Point Pharma, Inc., Princeton, NJ; 6 Pennsylvania College of Optometry at Salus University, Elkins Park, PA.

INTRODUCTION Table #1
Most Frequent Adverse Events in >5% of Subjects
Dry eye disease is a common ocular disorder affecting tens of millions of people in the % Subjects with ≥10 mm Change from Baseline in Mean Change From Baseline in Schirmer's Score
Reported Adverse Event OC-01 0.6 mg/mL OC-01 1.2 mg/mL Placebo
United States alone.1 A recent global consensus paper, published in December of 2020, Schirmer's Score (mm) @ Week 4 (mm) @ Week 4
N=260 N=245 N=251
redefined dry eye disease as follows: n (%) n (%) n (%)
Sneezing 247 (95.0) 237 (96.7) 73 (29.1)
“Dry eye is a multifactorial disease characterized by a persistently unstable and/or Cough 49 (18.8) 53 (21.6) 5 (2.0)
deficient tear film causing discomfort and/or visual impairment, accompanied by Throat irritation 35 (13.5) 44 (18.0) 5 (2.0)
variable degrees of ocular surface epitheliopathy, inflammation and neurosensory Instillation Site Irritation 19 (7.3) 35 (14.3) 3 (1.2)
abnormalities.” 2
DISCUSSION
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 Though dry eye disease is estimated to affect more than 30 million American adults, the
consistent diagnosis of this condition across the globe. Criteria for the clinical definition condition continues to be both underdiagnosed and undermanaged.6,7 Most current
of dry eye has varied considerably, including such elements as tear deficiency, treatments target downstream disease sequelae, such as ocular surface inflammation,
symptoms of discomfort, ocular surface damage, tear hyperosmolarity, inflammation of while expert consensus continues to recommend therapies that restore tear film stability
the ocular surface, tear film instability, loss of homeostasis and neurosensory and homeostasis.1,2 A relatively recent therapeutic strategy for the management of dry
abnormalities.1-4 According to the new 2020 global consensus definition of dry eye eye disease involves activation of the parasympathetic trigeminal pathway. Friedman
disease by Tsubota et al.,2 tear film stability is a sensitive measure of tear dysfunction and associates demonstrated the efficacy of an intranasal, electrical neurostimulation
that can be easily determined, making it a clinically practical and reproducible marker of device for increasing tear production and reducing symptoms of dry eye disease.8
tear dysfunction, and “it should be the key criterion in a clinical definition of dry eye Further studies with this device revealed its ability to stimulate complete, natural tear
disease”.2 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
OC-01 (varenicline) nasal spray contains a small-molecule nicotinic acetylcholine Figure #3
this same trigeminal parasympathetic pathway via pharmacologic stimulation, with
receptor agonist. OC-01 has been proposed as a treatment for dry eye disease due to its similar complete, natural tear production.12 It is postulated that, by augmenting the
ability to increase natural tear production via the trigeminal parasympathetic pathway, as Mean Change in Baseline Eye Dryness Score in
the Controlled Adverse Environment (CAE®) natural tear film rather than addressing downstream inflammatory sequelae, OC-01 may
seen in preclinical and clinical studies.5 ONSET-2 is a Phase 3 clinical trial to evaluate potentially target the core mechanism of dry eye disease more directly, alleviating tear
the efficacy and safety of OC-01 nasal spray vs. placebo (vehicle) for the treatment of film instability and restoring homeostasis to the ocular surface environment.
signs and symptoms of dry eye disease.
Control 1.2
mg/ml
CONCLUSIONS
METHODS
In this multicenter, randomized, masked, placebo-controlled clinical trial of subjects with
758 subjects (aged ≥22 years) across 22 clinical sites were randomized in a 1:1:1 fashion
dry eye disease, OC-01 nasal spray was shown to stimulate tear production as reflected
to receive either 0.6 mg/mL OC-01 nasal spray (N=260), 1.2 mg/mL OC-01 nasal spray
by a statistically significant increase in patients with 10 mm or greater change in
(N=246), or placebo (vehicle) nasal spray (N=252). Subjects in all three groups received
Schirmer's Test Score from baseline versus placebo at 28 days. Additionally, the data
the nasal spray BID for 28 days. The primary efficacy measure involved the percent of
reflect that patients receiving OC-01 had (nominally) statistically significant improvement
subjects achieving ≥10 mm improvement in Schirmer's Test Score (STS) from baseline at
in Eye Dryness Scores from baseline at 14 and 28 days, as compared to placebo. The
Day 28. Secondary efficacy measures included: mean change from baseline in STS at
most common adverse events related to OC-01 were mild, transient sneezing, cough,
Day 28; mean change from baseline in Eye Dryness Score (EDS) by visual analog scale
throat irritation and instillation site irritation following administration of the nasal spray.
(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 REFERENCES
and recorded throughout the study. 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.
Mean Change in Baseline Eye Dryness Score at Week 1, 2, & 4 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.
RESULTS Defining Dry Eye from a Clinical Perspective. Int J Mol Sci. 2020 Dec 4;21(23):9271.
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4. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop
Subjects in both the 0.6 mg/mL and the 1.2 mg/mL OC-01 groups showed statistically (2007). Ocul Surf. 2007 Apr;5(2):75-92.

significant improvement compared with placebo, as indicated by a gain in STS of ≥10 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
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mm from baseline at Day 28. This effect was seen in 47.3% and 49.2% of subjects 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.
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The mean change from baseline in STS was 11.3 mm and 11.5 mm, respectively, vs. 6.3 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.
mm for the placebo group [Figure #2]. No significant changes were seen in mean change 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.
from baseline in EDS in the CAE® chamber at Day 28 [Figure #3], however a (nominally) 10. Pondelis N, Dieckmann GM, Jamali A, Kataguiri P, Senchyna M, Hamrah P. Infrared meibography allows detection of dimensional changes in
significant reduction in EDS from baseline was demonstrated in the clinic in both the 0.6 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
mg/mL and 1.2 mg/mL groups as compared to placebo at both Day 14 and Day 28 production in subjects with dry eye disease during intranasal tear neurostimulation: Results from two pivotal clinical trials. Ocul Surf. 2019
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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,
The data from ONSET-2 also demonstrate that OC-01 nasal spray was safe and well- November 13, 2020.

tolerated at both the 0.6 mg/mL and the 1.2 mg/mL concentrations. The most commonly * Controlled Adverse Environment (CAE®) is a registered trademark of Ora, Inc.

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 DISCLOSURES
of the drug [Table #1]. The vast majority of AEs were reported as mild. No serious drug- PMV – Clinical Investigator, Oyster Point Pharma, Inc.
CAA – Clinical Investigator, Oyster Point Pharma, Inc.
related adverse events were reported. AGK – Full-time employee (Medical Director), Oyster Point Pharma, Inc.

This study was funded and supported by Oyster Point Pharma, Inc. (Princeton, NJ, USA)
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Presented at the New Technologies and Treatments in Eye Care Conference. March 19-20, 2021 & June11-12, 2021.