Oxymetazoline eye drops offer promise for the treatment of acquired ptosis: JAMA

Current evidence identifies ptosis as a common disorder of the eyelid, particularly among elderly patients. Ptosis is broadly categorized as either congenital or acquired, with the acquired form classified based on underlying etiology as involutional (aponeurotic), neurogenic, myogenic, traumatic, or mechanical.

Standard of care is surgery, often targeting the upper eyelid retractor muscles. While effective in improving visual function and quality-of-life measures, there are risks associated with surgical intervention, including asymmetry, overcorrection/undercorrection, bleeding, lagophthalmos, and infection. An effective, noninvasive, pharmacologic treatment option might enable treatment of a wider range of affected individuals.

The superior tarsal, or Müller, muscle arises from the levator muscle and inserts on the tarsus, where it helps maintain upper eyelid elevation provided by the levator, while providing 2 to 3 mm of additional elevation. Therefore, Müller muscle is a common surgical target. Because it expresses adrenergic receptors, Müller muscle is also a target for pharmacologic intervention. A limited number of studies have described the use of adrenergic drugs (phenylephrine, apraclonidine) for ptosis treatment.

Oxymetazoline hydrochloride, 0.1%, ophthalmic solution is a novel pharmacologic agent approved for the treatment of acquired ptosis. Oxymetazoline is a potent, direct-acting α-adrenergic receptor agonist that binds the α1 and α2 subtypes. It is used, at low concentrations, as a topical nasal decongestant, and ocular administration of less than 0.025% oxymetazoline has been shown to reduce hyperemia. It is hypothesized that oxymetazoline, 0.1%, stimulates α-adrenergic receptors on Müller muscle, causing muscle contraction and upper eyelid lift.

Slonim et al carried out an analysis to examine the efficacy and safety of oxymetazoline, 0.1%, for the treatment of acquired ptosis, when administered once daily as a single drop in each eye after instillation at 1 and 14 days, and then followed up with continued treatment for 6 weeks in 2 randomized clinical trials.

This pooled analysis of 2 randomized, double-masked, placebo-controlled, multicenter phase 3 clinical trials included participants 9 years and older with acquired ptosis and superior visual field deficit. The 2 studies were conducted across 16 and 27 sites in the United States. Patients were enrolled from May 2015 to April 2019. Analyses for the individual trials were initiated after database lock and completed on September 6, 2017, and May 16, 2019. Pooled analysis was completed on August 25, 2019. Participants (randomized 2:1) received oxymetazoline, 0.1%, or vehicle, self-administered as a single drop per eye, once daily, for 42 days.

The primary efficacy end point was change from baseline in the number of points seen on the Leicester Peripheral Field Test (LPFT), a test to detect superior visual field deficits due to ptosis, on days 1 (6 hours after instillation) and 14 (2 hours after instillation). The secondary end point, change from baseline in marginal reflex distance 1 (MRD 1), was assessed at the same time points.

In total, 304 participants were enrolled and randomized to receive oxymetazoline, 0.1% (203 [66.8%]), or vehicle (101 [33.2%])

At baseline, the mean (SD) number of points seen in the top 4 rows on the LPFT was the same across treatment groups, suggesting an equivalent superior visual field deficit.

On day 1 (6 hours), the mean (SD) number of points seen increased to 23.1 (6.5) in the oxymetazoline, 0.1%, group and 19.1 (6.1) in the vehicle group, with a significantly greater mean change in the oxymetazoline, 0.1% group.

Two hours after instillation of oxymetazoline, 0.1%, or vehicle on day 14, the mean (SD) numbers of points seen were 24.3 (6.0) and 19.5 (6.0), respectively, with a significantly greater mean (SD) change from baseline in the oxymetazoline, 0.1%, group (P < .001).

Mean (SD) baseline MRD-1 in the study eye was similar across treatment. Mean (SD) change from baseline on day 1 (6 hours) was 0.96 (0.89) mm with oxymetazoline, 0.1%, and 0.50 (0.81) mm with vehicle (P < .001). On day 14 (2 hours), mean (SD) change from baseline in MRD-1 was 1.16 (0.87) mm and 0.50 (0.80) mm in the oxymetazoline, 0.1%, and vehicle groups, respectively (P < .001).

These clinical study results support the efficacy and safety of oxymetazoline, 0.1%, for the treatment of acquired ptosis, a potentially important finding given the lack of other approved pharmacologic options for this condition, as well as the barriers to and potential risks associated with surgery.

Reliable visual field testing is essential to accurately assessing the effect of any potential therapy for ptosis. While the LPFT used for the primary outcome in these trials has been shown to detect functional disability (superior visual field loss) in patients with ptosis with high specificity, owing to the wide superior visual field tested and inferior shift in the target of fixation, which may help prevent compensatory behaviors, the clinical relevance of the effects identified in this study is not known, nor were the efficacy or safety beyond 6 weeks determined by this trial.

The positive change from baseline on the LPFT among participants who received oxymetazoline, 0.1%, may be a meaningful functional improvement of the aspect of the visual field directly affected by ptosis after instillation at day 1 and day 14, the primary outcome assessment times for these trials. Supporting this observed functional improvement, MRD-1 analysis provides evidence of a significant effect of oxymetazoline, 0.1%, on the characteristic appearance of ptosis by reducing the amount of upper eyelid droop.

The efficacy and safety of oxymetazoline, 0.1%, ophthalmic solution after instillation at day 1 and day 14 demonstrated in 2 randomized phase 3 trials suggest that this novel pharmacologic agent may represent a promising treatment option for acquired ptosis. However, the clinical relevance of oxymetazoline, 0.1%, effects in clinical practice are not yet known, and the results of these studies can be used to generate hypotheses for future clinical evaluation of this treatment. Given the lack of other noninvasive treatment options, oxymetazoline, 0.1%, may potentially allow for more expansive treatment of acquired ptosis, including patients who may not qualify for or desire ptosis repair surgery if benefits and safety beyond 6 weeks can be demonstrated.

Source: JAMA Ophthalmol. 2020;138(11):1168-1175.

doi:10.1001/jamaophthalmol.2020.3812