Topical medication compliance is an ongoing struggle for many optometric practices today. Patients report issues with frequency of administration, cost of medication and associated side effects of instillation (e.g., stinging, hyperemia), while practitioners struggle with lack of patient adherence. Since the process of ensuring medications are adequately taken can be frustrating for all those involved, researchers continue to search for newer and better ways to deliver therapeutic doses of medicine via simpler methods.
Dextenza (sustained-release dexamethasone 0.4mg, Ocular Therapeutix) aims to provide a new way to deliver steroid therapy. Rather than administering a drop or injection, an intracanalicular depot is inserted into the puncta to provide a one-month tapered release of preservative-free medication to the ocular surface. At the end of 30 days, the biodegradable hydrogel depot is absorbed by the body, eliminating the need for removal. Ocular Therapeutix is evaluating the use of Dextenza in various conditions, including allergic conjunctivitis, postoperative pain and inflammation, and inflammatory-related dry eye. Below, let’s examine these conditions individually.
The initial Phase III clinical trial for Dextenza in the fall of 2015 yielded mixed results. While it did meet the primary endpoint of relieving ocular itching from allergic conjunctivitis (p<0.0001), it did not achieve the secondary endpoint of relieving conjunctival redness. Still, the drug was qualified as safe and well-tolerated. Researchers have since revised the protocol for a second, Phase III multicenter, 1:1 randomized, double-masked, vehicle-controlled trial, where the sole primary endpoint will be a reduction in ocular itching by day seven following insertion.
Post-op Ocular Pain
Ocular Therapeutix received acceptance for a New Drug Application (NDA) from the FDA for the treatment of ocular pain following ophthalmic surgery, based on data from a single Phase II and two Phase III clinical trials—the latter of which achieved the primary endpoint of reduction of ocular pain but not the second primary endpoint of absence of cells in the anterior chamber.
In the Phase II trial of 247 patients, researchers found statistically significant differences between the Dextenza-treated group and placebo for both pain and absence of cells in the anterior chamber (p<0.005). All patients retained the device through day 14, and 97% of patients retained it through day 30. No long-term intraocular pressure spikes were observed. Rescue medications were required by a smaller number of Dextenza subjects (20.7% vs. 72.4%) compared with the number of placebo subjects at days 14 and 30; the Dextenza subjects also exhibited fewer adverse events (13.8% vs. 43.8%).
Unfortunately, the 240-patient Phase III trial failed to meet the primary endpoint for reduction of ocular inflammation (Dextenza 39.4% vs. placebo 31.3%). A third Phase III trial aimed at achieving the same primary endpoint recently began enrolling patients, and it is the company’s intention to file a supplement to the NDA if the study is successful.
The two prospective, multicenter, randomized parallel-arm, double-masked, vehicle-controlled Phase III trials were completed with a total of 487 patients undergoing unilateral clear corneal cataract surgery. Patients were randomized 2:1 to receive either Dextenza or a placebo vehicle punctal plug. As stated, the two primary efficacy endpoints were absence of cells in the anterior chamber at day 14 and the absence of pain, subjectively reported on a scale of 0 to 10, at day eight. Secondary efficacy endpoints were absence of flare in the anterior chamber at each visit and absence of cells and absence of pain at each visit, other than the day used for the primary efficacy measure.
The new Phase III trial expected to constitute the supplement to the NDA allows for modifications of the original protocol, including a 1:1 (rather than 2:1) randomization of patients; the exclusion of patients undergoing treatment with high doses of oral NSAIDs; and improved training and guidance for on-site clinical investigators regarding adherence to study protocols, including the appropriate use of rescue medications.
Inflammatory Dry Eye
At the end of 2015, results from a Phase II exploratory clinical trial for the treatment of signs and symptoms of moderate to severe dry eye disease were released. The prospective, randomized, parallel-arm, double masked, vehicle-controlled study included 43 patients (86 eyes) at two sites in the United States. Patients were initially treated with a placebo punctal plug for 45 days; those patients who benefited were excluded from the subsequent treatment phase. Treated patients were randomized 1:1 to receive either Dextenza or a placebo vehicle for 30 days.
Total corneal staining at day 30 showed the Dextenza group had statistically significant improvement at day 30 as compared to placebo (p=0.018). Subjectively, there was improvement as measured by the standard patient evaluation of eye dryness (SPEED) questionnaire for dryness, itchiness and scratchiness. There were no intraocular spikes noted, and there was a 96% retention rate of the drug depots throughout the 30-day trial.
While the results from these trials are mixed, it remains clear that an alternative method of drug delivery can be effective for certain ocular conditions and symptoms. Hopefully, this is the gateway to further research that will enable us to offer our patients a cost-effective, safe and easy method to overcome some common ocular issues that are undermined not by pharmaceutical shortcomings but, rather, human ones.