Novel modality circumvents eye drop adherence concerns

Prescribing corticosteroids plus nonsteroidal anti-inflammatory drugs is routine for the management of inflammation and pain after cataract surgery. Prolonged inflammation puts patients at increased risk of secondary ocular complications that include IOP spikes, cystoid macular edema, posterior synechiae formation, and posterior capsule opacification. Patients with untreated postoperative pain are likely to be less happy with their surgery.^1–3

Despite common use, the dosing frequency of postoperative cataract surgery medications-topical drops-is suboptimal.

Drops are problematic for several reasons, including poor adherence by patients, ineffective formulations, and inconsistent bioavailability. Numerous studies show that patients not only have difficulty successfully administering the correct number of drops, but they often miss their eye altogether.^4–7

Consider the following as aspects of the clinical reality of patients and eye drops: the burden of regimen frequency and complexity, forgetfulness, and issues with physical dexterity (particularly in the elderly). This combination of factors has a negative impact on the efficacy of postoperative topical medications.^8,9

SUSTAINED-RELEASE ALTERNATIVE
A sustained-release dexamethasone ophthalmic insert for intracanalicular use (Dextenza, Ocular Therapeutix) (0.4 mg dexamethasone) may be an alternative. The surgeon postoperatively places the hydrogel insert containing dexamethasone in the canaliculus, where it then provides a sustained and tapered delivery of the drug to the ocular surface over the next 30 days.

Sustained release of dexamethasone reduces the risks of improper corticosteroid tapering and unwanted fluctuations in drug concentration.¹⁰ It also avoids the peaks and valleys associated with topical drop administration.

A preclinical model showed that the insert has the potential to increase bioavailability (versus topical drug use) from 5% to 70%,¹¹ and the amount of drug used is just a small portion of the total dose a patient would take during a typical monthly topical course.

The burden of patient adherence is eliminated, and the side effects associated with the topical administration of corticosteroids may be reduced with this delivery mode. The dexamethasone formulation is preservative-free, and the hydrogel insert softens over time and is cleared through the inferior nasolacrimal canaliculus. If necessary, the insert can be expressed.

The dexamethasone insert’s efficacy was evaluated in patients for pain and inflammation in patients undergoing cataract surgery was shown in two multicenter, randomized, phase III registration trials (n = 488).

A statistically significantly greater proportion of subjects receiving the insert in both studies were found to have an absence of pain at day 8 compared with those receiving placebo (study 1: 80.4% versus 43.4%, p < 0.0001, difference: 37.0%; study 2: 77.5% versus 58.8%, p = 0.0025%, difference: 18.7%). A greater proportion of subjects in the dexamethasone group had an absence of anterior chamber (AC) cells at day 14 in both studies as well. This difference was statistically significant in the first but not the second study.¹²

The dexamethasone insert’s safety profile was favorable in both studies, and the most common adverse events were AC inflammation (insert 5.9% versus placebo 7.3%), increased IOP (insert 5.6% versus placebo 4.3%), iritis (insert, 4.0%; placebo, 9.1%), and corneal edema (insert, 1.6%; placebo, 5.5%).¹²

THIRD STUDY
A third phase IIIc study (published in the Journal of Cataract and Refractive Surgery) in patients undergoing cataract surgery was designed to further evaluate the effect of the dexamethasone insert on inflammation and pain.^13,14 It was similar in design to the previous studies with some differences with respect to randomization, study visit schedule, and the use of rescue medication.

A total of 435 subjects completed the study (214 in the dexamethasone insert arm and 221 in the placebo insert arm). The demographics and baseline characteristics of the two groups were comparable, and the study met both of its primary endpoints.

At day 14, significantly more subjects in the dexamethasone insert arm compared with the placebo insert arm had an absence of anterior chamber cells (52.3% versus 31.1%; p < 0.0001). Also, at day 8, significantly more subjects in the dexamethasone insert arm compared with the placebo arm had an absence of ocular pain (79.6% versus 61.3%; p < 0.0001).

Inflammation: Closer Look
In terms of inflammation, at each time point between days 4 and 45, significantly more subjects assigned to the dexamethasone insert had an absence of AC cells compared with the placebo arm (p < 0.05).

The mean AC cell score in the dexamethasone insert arm was lower than in the placebo arm at all postoperative study visits. Mean AC cell score (scale, 0–4) peaked in both treatment and placebo arms at day 1 postoperatively (study day 2), with the scores declining rapidly in the treatment arm (mean score, 0.44 by day 14) versus a slow decline in the placebo arm (mean score, 0.92 by day 14).

At all postoperative visits, fewer eyes assigned to the insert versus placebo arm had an AC cell score of grade ≥3, the level at which investigators could consider prescribing rescue medication. At each time point between day 2 and day 30, significantly more insert-assigned subjects compared with placebo (p < 0.05) had an absence of AC flare.

Additionally, a significantly greater proportion of eyes in the dexamethasone arm were observed to have 5 or fewer AC cells at the day 14 visit versus placebo (81.5% versus 52.3%; p < 0.0001). The mean AC flare score in the insert-assigned subjects peaked at the day 2 visit (score, 0.8), declining steadily and reaching 0.1 by the day 30 visit.

The mean AC flare score in the placebo arm was highest at the visits on days 2, 4, and 8 (score, 0.9), declining to 0.2 by day 45. Few eyes experienced a flare score of grade ≥3, the level at which investigators could consider prescribing rescue medication.

Pain: Deeper Dive
At each time point between days 2 and 30, significantly more subjects in the dexamethasone insert arm had an absence of ocular pain arm compared with placebo (p < 0.05). Eyes in the insert arm had a peak mean ocular pain score of 0.6 score units (scale, 0-10) at the day-2 visit and subsequently declined to a mean of 0.2 units at the day-45 visit.

The mean pain score in placebo group, on the other hand, was 1.2 units on day 2 and declined to 0.5 units by day 45. At the day 2 visit, 5.6% of subjects receiving the insert versus 11.3% of subjects receiving placebo reported moderate to severe ocular pain. If pain reached grade ≥4, then investigators could consider prescribing rescue medication. At day 8, 4.3% of subjects in the insert group reported moderate to severe pain versus 10.4% of subjects receiving placebo.

Fewer than 5% of subjects in both arms used rescue medication through day 8. At day 14, 5.6% of subjects in the dexamethasone insert arm, compared with 10.9% of subjects in the placebo arm used rescue medication.

SAFETY
A total of 29.2% of subjects in the dexamethasone insert arm and 38.9% in the placebo arm experienced at least one adverse event (AE).

One AE in the dexamethasone insert arm, increased lacrimation in the study eye, was judged to be related to treatment. AEs were primarily ocular in nature, with 25.5% of subjects in the dexamethasone insert arm and 33.9% in the placebo group having at least one ocular AE in the study eye. The majority experienced events that were of mild or moderate severity; only three subjects in each treatment arm experienced an AE that was considered severe. One serious AE in the dexamethasone insert arm was ocular in nature, a retinal detachment, it was not related to treatment.

The most common ocular AEs reported in the insert eye were inflammation (8.3%),increased IOP (7.4%), and AC inflammation (6/216; 2.8%). No treatment-related nonocular AEs occurred, and no subjects were withdrawn from the study participation due to AEs.

CONCLUSION
An integrated assessment of efficacy across all three phase III Dextenza trials to date achieved statistical significance in both primary efficacy endpoints, with 42.7% of patients observed to have no AC inflammation cells at day 14 (placebo: 56.9%; p < 0.0001), and 79.2% of patients observed to have no ocular pain at day 8 (placebo: 27.5%; p < 0.0001).14

The sustained-release intracanalicular dexamethasone insert’s design allows for a constant, low-dose drug load to the ocular surface with no preservatives, better bioavailability, and a self-tapering of corticosteroid delivery postoperatively.

Additionally, the insert is absorbable and can be removed, if necessary.

Most importantly, the surgeon-placed insert removes a significant part of the treatment burden of a complex postoperative regimen of topical eye drops.
By 2020, 30 million Americans may have cataracts, based on U.S. census data and population-based studies.15 Optimizing the delivery of postoperative medications used to treat inflammation and pain would improve patients’ outcomes and overall surgical experience in a clinically meaningful way. 

Disclosures:

Sydney L. Tyson, MD, MPH
p: 856/691-8188
Dr. Tyson is president of Eye Associates and SurgiCenter of Vineland, NJ. Dr. Tyson has received research support from Ocular Therapeutix.

References:

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11. Data on File OTX-DEX-007, Bioavailability of OTX-DP. Ocular Therapeutix Inc., Bedford, MA.
12. Walters T, Bafna S, Vold S, et al. Efficacy and safety of a sustained release dexamethasone insert for the treatment of ocular pain and inflammation after cataract surgery: results from two phase 3 studies. J Clin Exp Ophthalmol. 2016;7:4.
13. Talamo JH, Tyson SL, Bafna S, et al. Results of a phase 3, randomized, double masked, vehicle controlled study (Phase 3c) evaluating the safety and efficacy of Dextenza (dexamethasone insert) 0.4 mg for the treatment of ocular inflammation and pain after cataract surgery. Presented at ARVO; May 6, 2018; Baltimore, MD.
14. Tyson SL, Bafna S, Gira JP, et al. Multicenter randomized phase 3 study of a sustained-release intracanalicular dexamethasone insert for treatment of ocular inflammation and pain after cataract surgery. Tyson SL, et al. J Cataract Refract Surg. 2018. In press. https://www.ncbi.nlm.nih.gov/pubmed/30367938
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