Sustained-release formula may obviate need for post-cataract steroid therapy

March 1, 2016

Two phase III trials evaluated sustained-release dexamethasone for the treatment of inflammation and pain after cataract surgery.

Take-home message: Two phase III trials evaluated sustained-release dexamethasone for the treatment of inflammation and pain after cataract surgery.

Reviewed by Thomas R. Walters, MD

Austin, TX-The first sustained-release dexamethasone formulation for the treatment of pain following cataract surgery is under review by the FDA.

The submission followed successful completion of two phase III clinical trials for the first sustained-release topical steroid for ophthalmic use. If approved, the new formulation would obviate the need for steroid eye drops after cataract surgery.

“Compliance with drop therapy after cataract surgery is always an issue,” said Thomas R. Walters, MD, of Texan Eye in Austin.

“When we have breakthrough inflammation postoperatively, it is more commonly from compliance than other issues,” he said. “This will allow us to place the drug device immediately post-surgery, in the operating room, to deliver a stable, safe and sustained steroid therapy for a month. That is one less drop the patient will need to use postoperatively.”

Dr. Walters presented data from two U.S. studies to examine the use of sustained-release dexamethasone for inflammation 14 days after surgery and pain 8 days postoperatively. Both trials met the pain endpoint but one trial failed the inflammation endpoint. Both trials showed solid evidence of safety.

Both studies used a punctum plug composed on a polyethylene glycol-based hydrogel impregnated with 0.4 mg of dexamethasone compared with placebo. The plugs are implanted at the end of surgery to release a constant level of drug for a set period. The plugs are eventually resorbed and flushed via the nasolacrimal system and do not need to be removed. The plugs are not visible under normal illumination but fluoresce under blue light for placement and confirmation of retention.

The plug is made by Ocular Therapeutix, which sponsored the trials.

Results

 

Patients in both studies were randomly assigned 2:1 to a punctum plug loaded with dexamethasone or a placebo plug with not active drug. Patients were evaluated at days 2, 4, 8, 14, 30 and 60.

The primary endpoints were the absence of anterior chamber cells at day 14 and the absence of pain at day 8. The two studied had a total of 488 patients-247 in one study and 241 in a second study.

Both two studies showed statistically significant reductions in pain, with p < 0.001 in the first study, 0.0025 in the second study and p <0.0001 in an ad hoc pooled analysis of both populations.

The results were less robust for inflammation. The first study showed a statistically significant improvement for sustained-release drug, p = 0.0018, but not for the second study, p = 0.2182. An ad hoc pooled analysis reached statistical significant with p = 0.0025.

“The second study that did not meet the pain endpoint had differences between groups regarding in-group randomization and rescue resulting in an inability to power statistical results,” Dr. Walters said. “The sponsor is running a third phase III study to hit that inflammation endpoint. They will likely submit a second indication for inflammation if the data support it.”

Two specific issues clouded the inflammation results, he continued.

The placebo group for the second trial included patients who were already taking systemic nonsteroidal anti-inflammatory agents, such as Motrin, and did not exhibit the expected placebo effect.

The second trial also had a large number of patients in the placebo group who were rescued before day 14 and were not included in the final results.

“The number in our placebo group went down so far that we lost our ability to attain statistical power,” he said.

Safety profiles

 

Safety profiles

Both studies showed very strong safety profiles. There were numerically fewer adverse events in the drug group compared with placebo, although the differences were not statistically significant. All of the adverse events occurred after treatment, but there were no product-related or treatment-related serious adverse events in either study.

The advantages of sustained-release dexamethasone following cataract surgery are clear, Dr. Walters continued.

With drug being released at a steady rate over 30 days, there is no concern about adherence to steroid eye drops and no pulse effects in drug exposure as is seen with drops. Surgeons will almost certainly continue to prescribe antibiotic eye drops and may continue to add a nonsteroidal anti-inflammatory as needed.

This sustained-release formulation can also improve outcomes from other agents being given as drops.

“Being a punctal plug, this drug-delivery device helps other topical drops become more effective because it increases their contact time with the eye,” Dr. Walters. “This will likely be approved for cataract surgery, but I see it being used for many other conditions.”

Ocular Therapeutix is already studying a punctal plug delivery system in seasonal allergic conjunctivitis, according to Dr. Walters. The device also shows promise as induction therapy for dry eye and following LASIK.

“A punctal plug is ideal for LASIK postoperatively to increase topical tears as well as for controlled steroid delivery,” he said. “It can be used for many different indications, although this first submission is only for the one indication of post-cataract surgery pain.”

 

Thomas R. Walters, MD

P: 512/327-7000

This article was adapted from Dr. Walters’ presentation at the 2015 meeting of the American Academy of Ophthalmology. Dr. Walters did not indicate any proprietary interest in the subject matter.