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

Authors:
  • Oculus Research, Inc.

Abstract

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.
VARENICLINE NASAL SPRAY (OC-01) FOR THE TREATMENT OF DRY EYE DISEASE:
THE ONSET-2 STUDY
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.
INTRODUCTION
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
disease”.2
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.
METHODS
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.
RESULTS
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.
REFERENCES
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
Jan;17(1):142-150.
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.
DISCUSSION
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.
CONCLUSIONS
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
abnormalities.2
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=260
n (%)
OC-01 1.2 mg/mL
N=245
n (%)
Placebo
N=251
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
DISCLOSURES
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
1.2
mg/ml
Control
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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