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Efficacy of Varenicline Nasal Spray in Improving the Symptoms of Dry Eye Disease of Varying Severity
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.
This study evaluated efficacy outcomes for VNS in patients with mild-moderate and severe dry eye disease.
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). Adults ≥22 years with dry eye disease, Ocular Surface Disease Index score ≥ 23, corneal fluorescein staining score ≥ 2 in ≥1 regions/≥4 all regions, and Schirmer Test Score (STS) ≤10 mm (no restrictions on eye dryness score [EDS]). Efficacy was evaluated using analysis of covariance among prespecified subgroups of mild-moderate and severe baseline disease severity defined by STS (≤5 versus >5) and EDS (<60 versus ≥60). Consistency of effect was evaluated by interaction tests.
No treatment-subgroup interactions were observed for all end points (P > 0.05). 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%CI, 2.0–5.6) and 2.3(1.3–4.0); for EDS <60 and ≥ 60 were 3.4(1.9–6.1) and 2.5(1.5–4.0). 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 <60 and ≥ 60 were − 2.9(−8.3 to 2.5) and − 8.1(−13.6 to −2.6).
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.
Does Dry Eye Disease Severity Impact Efficacy of Varenicline Solution Nasal Spray on Sign and Symptom Treatment Outcomes?Optom Vis Sci 2022 Dec 30;[EPub Ahead of Print], JD Sheppard, LE O'Dell, PM Karpecki, et al
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In this article, the authors presented integrated data from the ONSET-1 and ONSET-2 studies, comparing the outcomes of varenicline solution (OC-01) nasal spray (VNS) 0.03 mg with those of vehicle control in patients with dry eye disease based on baseline severity status. VNS 0.03 mg (Tyrvaya; Oyster Point Pharma, Inc. Princeton, New Jersey) was recently approved by the US FDA for the treatment of the signs and symptoms of dry eye disease. This integrated analysis addresses an unmet need: educating clinicians who manage a spectrum of dry eye disease (mild, moderate, and severe). Previous pivotal study designs restricted enrollment criteria to participants with more severe dry eye disease; as a result, the findings in these studies may not apply to the broad patient population commonly seen by eye care practitioners. This analysis found that VNS resulted in improved tear production and decreased self-reported symptoms in patients with dry eye disease, regardless of whether the disease was mild to moderate or severe at clinical presentation.
Upon administration, varenicline binds to nicotinic acetylcholine receptors on the terminal branches of the trigeminal nerve in the nasal cavity, activating the parasympathetic pathway and stimulating the meibomian glands, lacrimal glands, and goblet cells of the lacrimal functional unit to produce a natural tear film. VNS is unique among approved treatments for dry eye disease because: 1) it targets the nasal mucosa; 2) the active component, varenicline, is a nicotinic acetylcholine receptor agonist; 3) it is administered via the nasal cavity; and 4) its therapeutic benefit includes the endogenously expressed bioactive components (such as anti-inflammatory and antimicrobial proteins) secreted on the ocular surface from the patient’s own natural tear film.
Prespecified severity subgroups for mild to moderate versus severe dry eye disease were defined in the ONSET-2 study by baseline ocular assessments, which included the Schirmer test score (pre-procedure anesthetized; >5 mm vs ≤5 mm) and the eye dryness score (<60 vs ≥60). The severity status of mild to moderate versus severe dry eye disease at clinical presentation was primarily defined by the eye dryness score subgroup category.
The main analysis outcome measures used in comparing VNS with vehicle control as evaluated from baseline values were the proportion of patients achieving ≥10 mm improvement in the Schirmer test score with anesthesia, the mean change in the Schirmer test score, and the mean change in the eye dryness score at week 4. No treatment subgroup interactions were observed for all outcome measures evaluated at week 4 (all outcomes, P > .05). This indicates that the treatment effect of VNS compared with that of vehicle control across measures within each subgroup was consistent symptom improvement (no statistically significant differences in the treatment benefit; therefore, no subgroup drove the overall benefit). It is encouraging that the analysis suggests that the VNS 0.03 mg treatment efficacy profile was superior to that of the vehicle control across all measures, which was consistent regardless of mild to moderate or more severe disease status at clinical presentation.
The integrated analysis showed that VNS was well-tolerated, with safety outcomes comparable with those observed in the pivotal ONSET-1 and ONSET-2 studies. In summary, the most common adverse reaction reported in 82% of the patients was sneezing. The adverse events that were reported in 5% to 16% of the patients included cough, throat irritation, and instillation-site (nose) irritation. As the mechanism of action of VNS is cholinergic agonist neuro-activation of the trigeminal nerve, a valuable clinical question has emerged as to whether the use of VNS would increase the risk of latent herpes simplex virus (HSV) infection recurrence. There is currently no scientific evidence that trigeminal stimulation will increase the risk of latent HSV infection recurrence. In the pivotal ONSET-1 and ONSET-2 studies, only one participant developed non-ocular HSV infection in the vehicle control group, whereas there was no incidence of HSV infection (ocular or non-ocular) reported among the 308 participants who received VNS 0.03 mg twice daily for 28 consecutive days.