In 2021, Ocular Therapeutix Inc. further expanded the indications for dexamethasone ophthalmic insert 0.4 mg ( Dextenza) upon its FDA approval to treat ocular itching associated with allergic conjunctivitis (AC). It is the first such physician-administered intracanalicular insert that delivers a preservative-free drug, lasting up to 30 days.

The intracanalicular insert was originally approved in 2018 for the treatment of ocular pain after ophthalmic surgery. In 2019, the drug-delivery platform received an added indication for postoperative ocular inflammation. It is currently undergoing clinical studies for the short-term treatment of the signs and symptoms of dry eye disease.

The current approval for ocular itching associated with AC was based on the results of three randomized, multicenter, vehicle-controlled studies that included 255 patients with a positive history of ocular allergies and positive skin test reaction to perennial and seasonal allergens.

 The dexamethasone insert was associated with lower mean ocular itching scores versus vehicle at all time points throughout the study duration of up to 30 days.

In terms of safety, just 3.2% of patients experienced a transient elevation of IOP which was not in any way severe and quickly resolved when the insert was either flushed out or allowed to finish its course of treatment.

INTRACANALICULAR INSERT WITHOUT DEXAMETHASONE

In the years since the introduction of punctal plugs, eye care practitioners have been concerned that their use could trap allergens in the ocular adnexa and on the ocular surface. The question was, if allergens were not allowed to dilute with the tear film and be cleared promptly, could patients experience prolonged or worsening disease symptomatology?

A study that explored this question found that not only does punctal occlusion using a polyethylene glycol hydrogel insert with no active ingredient not worsen or prolong symptoms, but on its own was associated with a decrease in hyperemia and patient-reported subjective itching.

 This post-hoc pooled analysis included data from 128 subjects who received the placebo-vehicle insert as part of the three randomized masked clinical trials of dexamethasone ophthalmic insert 0.4 mg using a modified repeat Conjunctival Allergen Challenge Model (Ora-CAC). The insert hydrates and swells to fit the canaliculus, occluding the punctum. The medication is released over 30 days with the hydrogel dissolving and flushing through the lacrimal system.

Ocular itch scores decreased over a 1-month period following punctal occlusion: on days 7, 14 and 28, ocular itching scores were statistically significantly reduced from baseline (

 <.05). Following punctal occlusion, post-CAC conjunctival redness scores decreased from baseline for 1 month. On days 7, 14 and 28, conjunctival redness scores were statistically significantly reduced from baseline (

EXPERIENCE WITH INSERT, PRACTICAL PERSPECTIVE

The dexamethasone-eluting insert gives us a very powerful treatment option that can be used either as a stand-alone method of treatment or in conjunction with a non-steroidal topical medication if the patient’s symptoms are more moderate to severe. As one of the principal investigators, I was masked to who had placebo versus the investigational product, but it was clear that some patients were having a tremendous response. The data bore this out with statistical significance; treated patients demonstrated decreased subjective symptoms of AC and decreased conjunctival hyperemia. It works, it is straightforward to insert, and it does not require the physician to make any adjustments to their practice flow and scheduling.

Using the dexamethasone-containing insert for AC treatment will be similar to our use of punctal plugs in dry eye patients, with the puncta is dilated and the moisture dried. The user must stretch the lid, pulling it temporally to straighten out the puncta and canaliculus to allow the insert to slide in easily. Similar to diagnosing a patient with dry eye and inserting a punctal plug at that time, there is no reason to have patients return for a separate appointment. We can keep an inventory of dexamethasone ophthalmic insert 0.4 mg on hand and place it when the patient is in the chair and symptomatic. I have been gratified by how quickly patients improve once the insert is in place, as evidenced by not only the slit-lamp examination but more importantly, how much better they feel.

TOXICITY RISKS, COMPLIANCE ISSUES ASSOCIATED WITH DROPS

A major benefit of the intracanicular insert is that it does not require patient compliance and avoids the overuse of medication as can happen in patients symptomatic with allergic conjunctivitis. This timed and titrated dose of dexamethasone is a real game-changer for our treatment regimens, removing concerns around misuse as well as the worry of the potential for significant or prolonged elevated IOP.

We know from our use of dexamethasone ophthalmic insert 0.4 mg to alleviate postoperative pain and inflammation that patients are very happy to have one less medication to remember. Decreasing the burden of eye drops increases adherence and decreases the potential risk of medicamentosa and epithelial surface toxicity from multiple exposures to preservatives. Patients like the convenience and doctors appreciate the safety, consistency, and efficacy of the product for surgical indications as well as allergic conjunctivitis. This really is another advance in our efforts to get away from topical eye drops.

One of the most powerful statements about the efficacy and benefit of this product is the fact that the FDA has given it three on-label different indications for treatment in various sites of care, which should be very reassuring to both doctors and patients with regard to its safety, efficacy, and ease of use.

1. Ocular Therapeutix announces FDA approval of supplemental New Drug Application (sNDA) for DEXTENZA (dexamethasone ophthalmic insert) 0.4 mg for intracanalicular use for the treatment of ocular itching associated with allergic conjunctivitis. October 11,2021. https://tinyurl.com/yfkp48je. Accessed May 16, 2022.

2. Rubin JM, Silverstein SM, Kenyon KR, et al. Pooled analysis evaluating efficacy and safety of an intracanalicular dexamethasone insert for the treatment of allergic conjunctivitis. Paper presented at: ASCRS Annual Meeting; July 23-27, 2021; Las Vegas.

3. Silverstein SM, Sato MA, Meier EJ, et al. Effects of punctal occlusion on ocular itching and conjunctival redness in subjects with allergic conjunctivitis. Paper presented at: SCRS Annual Meeting; April 22-26, 2022; Washington, DC.

E: ssilverstein@silversteineyecenters.com

Silverstein is the president of Silverstein Eye Centers in Kansas City, Missouri and assistant clinical professor of ophthalmology at the University of Missouri School of Medicine in Kansas City. He is a researcher, lecturer, and advisor for Ocular Therapeutix.

Articles

As dexamethasone adds indications, a study confirms efficacy of punctal occlusion for allergic conjunctivitis.

Intracanalicular insert linked to reduced hyperemia and itching

By Doina Gherghel, MD, PhD, MEd; Jeffrey Gemi, MD; Gustavo De Moraes, MD, PhD, MPH

Although the existence of the meibomian glands (MGs) was first recognized in 200 AD by Galen,

 their obstructive pathology was only first mentioned in 1977 by McCulley and Sciallis

 and named meibomian gland dysfunction (MGD) by Korb and Henriquez in 1980.

Nonetheless, by the late 1990s and early 2000s, the importance of lipids produced by the MGs for the tear film homeostasis was fully appreciated, as was the role played by MGD in the pathogenesis of dry eye disease (DED).

In MGD, due to reasons not fully known, meibum exhibits a higher phase-transition temperature than normal.5 In addition, in MGD, meibum lipids become more saturated and contain less-branched chain hydrocarbons and more protein, therefore becoming more viscous. Thus, the delivery of meibum to the lid margin is impeded.

 As such, historically, therapies for MGD consisted mainly of mechanical application of heat, lid hygiene, and massage of the eyelid.

All these methods are intended to facilitate the secretion of lipid products at the ocular surface by unclogging gland orifices and “softening” the meibum.

 In addition, lipid-based artificial tears and meibomian gland expression (MGX) have been advocated as efficient. Nevertheless, as discussed by Tang et al, because many of these methods are time consuming and somehow uncomfortable,

 they are impeded by low patient adherence and have limited effectiveness, especially in more advanced stages of the disease.

When bacterial colonization is present, oral agents of the tetracycline family (tetracycline, doxycycline, and minocycline) have also been found to improve the clinical picture in MGD. However, these therapies need to be given over long periods (usually months) and, therefore, in addition to low patient adherence, they can often be contraindicated for some patients or, if indicated, can lead to adverse effects that limit their success.

In 2010, Maskin proposed a method of inserting stainless steel probes, up to 6 mm in size, directly into the meibomian gland orifices, with immediate relief in lid tenderness following treatment and improvements lasting 4 weeks.

The discovery that a therapeutic temperature level of 41 °C applied at the tarsal conjunctiva is critical for the effective liquefaction and clearance of meibum obstructions has resulted in more efforts to optimize methods to deliver targeted, controlled, noninvasive thermal treatments at this level. In 2005, intense pulse light (IPL) therapy, due to its thermal effect that facilitates meibomian gland secretion by softening meibum, was proposed as an efficient method of treating MGD in patients with DED.

In 2017, a report from the Tear Film and Ocular Surface Society’s Dry Eye Workshop II proposed IPL/MGX as a method to be used in MGD treatment.

 Nevertheless, many cases are refractory to this type of treatment and there are no clinical guidelines for using IPL/MGX in MGD, although it has been proposed that this method could be more efficient in early stages of the disease.

There are many other devices on the market designed for delivering therapeutic levels of heat and pressure to the eyelids to melt altered meibum and to clear meibomian gland obstruction. These are summarized in the 

Among these, the TearCare system, the most recent such device to enter the market, represents a blink-assisted device that applies heat to the eyelids in patients suffering from MGD, DED, and/or blepharitis.

SmartLids, which is the TearCare system’s eyelid-worn, open eye, blink-assisted technology (

), is designed to offer conformance and adherence across the entire geography of eyelids and to deliver targeted, transtarsal thermal energy to the underlying MGs. It also allows complete removal of liquefied meibum with a tailored gland-by-gland approach under optimal visualization.

The TearCare software and sensor technology also enable tight control as well as the maintenance of a maximized external eyelid temperature of up to 45 °C for 15 minutes.

 Because the device allows patients to blink during the procedure, it is comfortable to wear. 

A recently published, 1-month follow-up study demonstrated that a single TearCare treatment resulted in statistically and clinically significant improvements of all signs of DED in patients with MGD. In addition, this result was equivalent in its safety and effectiveness profile to the LipiFlow treatment.16 Moreover, this study showed that TearCare offered significantly better symptomatic relief as measured by proportion of subjects achieving Ocular Surface Disease Index improvement by at least 1 severity category and as reflected in the reduced need for use of lubricating drops compared with LipiFlow.

MGD includes an array of MG disorders, ranging from congenital to acquired. The common denominator for these disorders is the change in tear film composition that results in ocular discomfort, visual disruption, and evaporative dry eye. Congenital factors, aging, hormonal imbalance, diet, medications, contact lens wear, trauma, inflammation, and even the ocular surface’s microbiome have been implicated in the etiology of MGD. In the attempt to control MGD, many treatments have been tried with various success rates. Methods using a combination of noninvasive thermal treatments and MGX, such as TearCare, seem to have gained some advantages. 

2 McCulley JP, Sciallis GF. Meibomian keratoconjunctivitis. 

. 1977;84(6):788-793. doi:10.1016/0002-9394(77)90497-4

3 Korb DR, Henriquez AS. Meibomian gland dysfunction and contact lens intolerance. 

4 Bron AJ, Tiffany JM. The contribution of meibomian gland disease to dry eye. 

. 2004;2(2):149-165. doi:10.1016/s1542-0124(12)70150-7

5 Foulks GN, Borchman D. Meibomian gland dysfunction: the past, present, and future. 

. 2010;36(5):249-253. doi:10.1097/ICL.0b013e3181ef0d37

6 Nagymihalyi A, Dikstein S, Tiffany JM. The influence of eyelid temperature on the delivery of meibomian oil. 

. 2004;78(3):367-370. doi:10.1016/s0014-4835(03)00197-0

7 Paranjpe DR, Foulks GN. Therapy of meibomian gland disease. 

. 2003;16(1):37-42. doi:10.1016/s0896-1549(02)00106-2

8 Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction. 

. 2011;52(4):2050-2064. doi:10.1167/iovs.10-6997g

9 Tang Y, Liu R, Tu P, et al. A retrospective study of treatment outcomes and prognostic factors of intense pulsed light therapy combined with meibomian gland expression in patients with meibomian gland dysfunction. 

. 2021;47(1):38-44. doi:10.1097/ICL.0000000000000704

10 Dougherty JM, McCulley JP, Silvany RE, Meyer DR. The role of tetracycline in chronic blepharitis. Inhibition of lipase production in staphylococci. 

11 Maskin SL. Intraductal meibomian gland probing relieves symptoms of obstructive meibomian gland dysfunction. 

. 2010;29(10):1145-1152. doi:10.1097/ICO.0b013e3181d836f3

12 Toyos R, Buffa CM, Youngerman SM. Case report: Dry-eye symptoms improve with intense pulsed light treatment. 

13 Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. 

. 2017;15(3):575-628. doi:10.1016/j.jtos.2017.05.006

14 Mukamal R. 12 devices for treating dry eyes. American Academy of Ophthalmology. November 12, 2020. https://www.aao.org/eye-health/tips-prevention/how-to-treat-dry-eye-devices

15 Tauber J, Owen J, Bloomenstein M, Hovanesian J, Bullimore MA. Comparison of the iLUX and the LipiFlow for the treatment of meibomian gland dysfunction and symptoms: a randomized clinical trial. 

. 2020;14:405-418. doi:10.2147/OPTH.S234008

16 Gupta PK, Holland EJ, Hovanesian J, et al. TearCare for the treatment of meibomian gland dysfunction in adult patients with dry eye disease: a masked randomized controlled trial. 

. 2022;41(4):417-426. doi:10.1097/ICO.0000000000002837

The treatments typically include application of heat, lid hygiene, and massage of eyelid.

Therapeutic options can treat meibomian gland dysfunction

The FDA-approved fluocinolone acetonide intravitreal implant, 0.18 mg (Yutiq; EyePoint Pharmaceuticals) is a low-dose steroid implant indicated for the treatment of chronic noninfectious uveitis affecting the posterior segment of the eye.

 It is known to provide excellent control of retinal inflammation in noninfectious uveitis, and previous clinical data have demonstrated a favorable safety profile.

To explore inflammation control in patients with ongoing, active noninfectious uveitis, we developed the PANTHER study (NCT04340505). PANTHER is an ongoing, prospective, investigator-initiated study analyzing the use of the fluocinolone acetonide implant in patients with active noninfectious uveitis (N = 31).

Fluorescein angiography (FA) and optical coherence tomography (OCT) are mainstays of monitoring noninfectious uveitis affecting the posterior segment. FA images can show leakage, whereas OCT does not show frank cystoid macular edema. By contrast, OCT can show significant cystoid macular edema, whereas FA images have minimal leakage. For these reasons, PANTHER focuses on both ultrawide-field FA and OCT images at baseline and following the fluocinolone acetonide implant.

The primary outcome measures in PANTHER are the incidences of inflammation control and recurrence following the fluocinolone acetonide implant. Imaging measures were assessed using semiautomated analysis, which allows us to quantify the amount of leakage seen on FA and changes in central subfield thickness via OCT. A key distinguishing factor of PANTHER is that all included patients had active uveitis at baseline. Of the 31 patients initially enrolled, 29 patients continued through the 1-year mark.

At 1 year, it was interesting to find that patients had a high chance of needing rescue therapy within the first 6 months (38% of patients), but after 6 months the need for rescue therapy decreased significantly (7% of patients).

Thirteen of 29 patients received rescue therapy in the first year. Of the 13, 6 received a repeat fluocinolone acetonide implant. Of those who were treated with a second implant, 3 improved, 1 had no response, and 2 are awaiting further follow-up. It was up to the investigating clinician to determine whether a patient needed rescue therapy, and criteria included worsening examination findings or worsening metrics on FA and OCT.

At 1 year, FA and OCT measures were worse on average in patients who needed rescue therapy compared with nonrescue patients. At baseline, patients who had more leakage on FA and edema on OCT were more likely to need rescue therapy. In addition, there was a larger difference in OCT measures between rescued and nonrescued patients compared with FA metrics.

Additionally, the safety data are reassuring. None of the patients needed incisional surgery, and no serious adverse events were reported. Looking at the 1-year data, we saw that there were no safety issues, including in patients who received a second implant.

Even though there was a high rescue rate after 1 year, the patients who did well did exceptionally well. Because a large portion of patients in the clinical trials for the fluocinolone acetonide implant had inactive noninfectious uveitis at baseline, it is to be expected that the rescue rate would be different in this study because all patients had active noninfectious uveitis.

 The fluocinolone acetonide implant is a low-dose steroid that does a great job in providing consistent basal inflammation control over 36 months, and we look forward to obtaining more long-term data in years 2 and 3.

Sharma practices at the Cole Eye Institute, Cleveland Clinic, in Cleveland, Ohio. He is a consultant/contractor with AbbVie, Alimera, Bausch & Lomb, EyePoint Pharmaceuticals, Regeneron, Genentech/Roche, Clearside Biomedical, and receives financial support from Gilead, Genentech/Roche, Santen, and IONIS.

1 Yutiq. Package insert. EyePoint Pharmaceuticals; 2022.

2 Jaffe GJ, Pavesio CE, Study Investigators. Effect of a fluocinolone acetonide insert on recurrence rates in noninfectious intermediate, posterior, or panuveitis: three-year results. 

. 2020;127(10):1395-1404. doi:10.1016/j.ophtha.2020.04.001

3 Hamdan A, Sharma S, Chen C, et al. Imaging-based risk factors for rescue in uveitis patients treated with injectable fluocinolone acetonide. Poster presented at: The Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting; May 1-4, 2022; Denver, CO.

4 Jaffe GJ, Foster CS, Pavesio CE, Paggiarino DA, Riedel GE. Effect of an injectable fluocinolone acetonide insert on recurrence rates in chronic noninfectious uveitis affecting the posterior segment: twelve-month results. 

. 2019;126(4):601-610. doi:10.1016/j.ophtha.2018.10.033

The study investigates 3-year intravitreal implant in eyes with active noninfectious posterior uveitis.  


Ophthalmology Times: June 2022

Intracanalicular insert linked to reduced hyperemia and itching

Therapeutic options can treat meibomian gland dysfunction

PANTHER Study offers 1-year results for fluocinolone acetonide intravitreal implant

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