Ocular’s OTX-DED Succeeds In Dry Eye Where OTX-CSI Failed, But More Data Needed
Executive Summary
The Phase II trial showed significant improvement in eye redness in patients with dry eye disease, but additional data are needed on DED symptom improvement.
Ocular Therapeutix, Inc. can move ahead with clinical development of its new dexamethasone ocular insert OTX-DED after showing statistically significant improvement in bulbar conjunctival hyperemia. However, the company will need to produce more data on how well the product works at actually improving dry eye symptoms, particularly as little separation appeared between the OTX-DED and vehicle hydrogel insert arms, especially entering a market that is getting crowded.
The company announced results of the randomized, double-masked Phase II study on 6 December. Among 166 patients enrolled in the modified intent-to-treat population, 55 received OTX-DED (dexamethasone intracanalicular ophthalmic insert) at 0.2mg, 56 received 0.3mg and 55 received vehicle. The trial was not powered to show statistical significance.
In October, the company announced Phase II data for its other product candidate, OTX-CSI, which is similar to OTX-DED but uses cyclosporin, showing that trial had failed. However, the company said at the time that it was not removing OTX-CSI from its pipeline just yet. (Also see "Ocular’s Dry Eye Drug Fails In Phase II, But It Isn’t Giving Up Yet" - Scrip, 22 Oct, 2021.)
A Step Forward, But Longer Road Ahead
According to the Phase II data, change from baseline using the CCLRU grading scale was -0.51 for the 0.2mg group, -0.43 for the 0.3mg group and -0.21 for the vehicle group, with the OTX-DED groups showing respective p-values of 0.004 and 0.028. While the treatment groups also showed improvements from baseline in VAS dry eye symptoms, the company said there was “little separation” between them and the vehicle group.
Side effects in the OTX-DED group included increased lacrimation (8.1%) and elevated intraocular pressure (3.6%). The most common non-ocular adverse event in the drug group was joint pain, occurring in 1.8%. Two non-ocular serious adverse events occurred in the vehicle group, but were not related to the intervention, and there were no ocular serious adverse events.
However, in a call with analysts, chief medical officer Michael Goldstein said there was more for the company to learn with in regard to symptom effects.
“In terms of symptoms, we did see a large improvement from baseline in all three groups, but did not see much separation between the active groups and the vehicle group,” he said. “And we have done some preliminary outlier and post hoc analysis which shows potential opportunities to differentiate the OTX-DED active groups and the vehicle hydrogel groups.”
The company needs to spend more time reviewing the symptom data. “There are a number of analyses we can do, including an outlier analysis looking at different demographics [and] looking at different inclusion and exclusion criteria in an effort to find the most appropriate population to use in the Phase III trial,” Goldstein said.
He also highlighted the hydrogel vehicle used in the comparator arm, noting that the one in the Phase II study had the same characteristics as OTX-DED in terms of durability, but another form of hydrogel was available that biodegrades faster and would be “more representative of a true placebo effect.”
Analysts took the data as a positive sign for the drug, especially relative to OTX-CSI.
“In contrast to the disappointing results with OTX-CSI, the study of OTX-DED demonstrated that the formulation was stable over the course of the targeted treatment course and was [statistically significant] for both dosage strengths relative to vehicle on the primary endpoint at Day 15,” Raymond James analyst Dane Leone said in a note. “Based upon the totality of the results, the development of OTX-DED will likely move into Phase 3 studies to support eventual regulatory approval.”
Leone also compared the drug with Kala Pharmaceuticals Inc.’s Eysuvis (loteprednol etabonate ophthalmic suspension), noting that OTX-DED’s reduction in eye redness was on par with that product but also pointing out that there will likely need to be modifications to Phase III study design in order to demonstrate symptom benefit. And the drug will have to succeed in two Phase III studies.
Eysuvis received US Food and Drug Administration approval in November 2020, having shown statistically significant improvement in symptoms of dry eye in two of three Phase III studies. (Also see "Keeping Track: Provention Teplizumab, AZ Anifrolumab Headline Submissions; AZ Brilinta Gains Stroke Risk Reduction Claim" - Pink Sheet, 8 Nov, 2020.)
JMP Securities analyst Jonathan Wolleben concurred that the OTX-DED data look “at least as good” as data for Eysuvis. He added that he would like to have seen a statistically significant improvement in dry eye symptoms, but acknowledged that the study was not powered for statistical significance and the hydrogel did better than anticipated. He also added that the Phase II study “could check a regulatory box for the FDA,” being an adequately well-controlled trial showing improvement in a dry eye sign.
Moving Into A Crowded Market
Several drugs for dry eye are on the market or in development, but Ocular CEO Antony Mattessich still sees room for more.
“The reason why we’re developing [OTX-DED] is because the market needs options for dry eye disease, and … the option that [works] best at the moment, or as far as active substances go, is steroids,” he told the call.
In particular, he said the market needs a steroid without a preservative.
“They need a steroid that’s not abusable since OTX-DED is physician-administered and not patient-administered,” he said. “The doctor knows the dose the patient is going to get and how long they’re going to get that dose.”
Still, the space has become increasingly crowded.
AbbVie Inc.’s Restasis (cyclosporine) and Novartis AG’s Xiidra (lifitegrast) have been available for a long time. A more recent entrant is Oyster Point Pharma Inc.’s Tyrvaya (varenicline solution), which was the first nasal spray for dry eye disease to win FDA approval, on 18 October. But Tyrvaya faces the challenge of winning a formulary tier placement that could make it competitive with Restasis and Xiidra, in a disease market where patients already must often fail on over-the-counter options before moving on to prescription drugs. (Also see "Oyster Point Prepares Major Push For New Dry Eye Drug" - Scrip, 18 Oct, 2021.)
Meanwhile, Bausch + Lomb Inc. recently reported a successful Phase III trial of its dry eye drug, NOV03, albeit for patients with meibomian gland dysfunction. (Also see "Bausch + Lomb’s Dry Eye Pivotal Data Pave The Way For Spinout" - Scrip, 13 Apr, 2021.) Aerie Pharmaceuticals, Inc.’s Phase IIb study of AR-11512 failed, but the company is moving ahead with two Phase III studies. (Also see "Aerie Misses Quick Path To Dry Eye Approval, But Is Still Moving Forward" - Scrip, 16 Sep, 2021.)