How Optometrists Are Using CEQUA^® (cyclosporine ophthalmic solution) 0.09% to Treat Chronic Dry Eye Disease

Josh Johnston, OD, FAAO

This post is sponsored by Sun Ophthalmics

Learn how Josh Johnston, OD, FAAO, approaches treatment for his dry eye patients.

How Optometrists Are Using CEQUA® (cyclosporine ophthalmic solution) 0.09% to Treat Chronic Dry Eye Disease

Josh Johnston, OD, FAAO is a paid consultant of Sun Ophthalmics.

After optometry school, I first worked in a hospital setting and was seeing patients with traumatic injuries and diseases like glaucoma and diabetic retinopathy. Dry eye disease (DED) wasn’t even on my radar yet.

Then, I began treating patients in a geriatric clinic. Seeing how greatly dry eye disease affected my patients’ quality of life inspired me to dig deeper into the pathology of dry eye disease to see how I could make a difference. I made the transition at a perfect time. Since I started seeing dry eye patients, the research, clinical studies, and treatment protocols have advanced tremendously, thanks in part to the TFOS DEWS II report and research that has been done. A decade ago, we only had a couple of markers to assess dry eye disease. Now I can assess ocular surface inflammation with an MMP-9 test, look at osmolarity, conduct staining, incorporate meibography into my diagnostic exams, and check for demodex and blepharitis.

Today, more than half of my clinical time is associated with dry eye patients because I now know how much dry eye disease hinders my patients’ ability to see their worlds clearly and comfortably—and I’m passionate about finding new treatment options for them, including CEQUA^®.

CEQUA^® delivers results as fast as 2 weeks for dry eye sufferers

When administered as directed, CEQUA^® (cyclosporine ophthalmic solution) 0.09% offers the highest FDA-approved concentration of cyclosporine—a proven anti-inflammatory treatment for dry eye disease.

I tell my patients that when they take CEQUA^® as directed, they may experience improvement in the key signs of dry eye in as little as two weeks¹ and may begin producing more tears in just three months.²

^{Study design: Phase 2b/3, randomized, multicenter, double-masked, vehicle-controlled, dose-ranging study. The co-primary efficacy endpoints were mean reduction in total conjunctival staining score and mean reduction in global symptom score at Day 84. Conjunctival and corneal staining were assessed at baseline and Days 14, 28, 42, 56, and 84/early discontinuation. Conjunctival staining was assessed in 6 conjunctival zones 1–4 minutes after instilling 1 drop of 1% lissamine green. Corneal staining was evaluated in 5 corneal regions 2–2.5 minutes after instilling 1 drop of 0.5% fluorescein.^¹}

Why I target inflammation first for my dry eye patients

While dry eye disease can be initiated by multiple factors, many of my patients’ symptoms can be traced back to ocular surface inflammation.³ Anti-inflammatory treatments are central to formulating a strategy to treat dry eye disease, because when the immune system is excessively stimulated and/or immunoregulatory mechanisms have been disrupted, the homeostatic balance between innate and adaptive phases become dysregulated—which can eventually lead to chronic ocular surface inflammation⁴ and the vicious cycle of dry eye disease.

What makes CEQUA^® unique?

The cyclosporine molecule has been used as an effective treatment for dry eye for many years, and while its exact mechanism of action is not known, it’s been proven to help restore tear production and can reduce ocular inflammation. However, delivering the cyclosporine molecule to the eye has been a hurdle in the past, due to its solubility challenges.⁵

What makes CEQUA^® stand out for me as an eyecare practitioner is that it is the first and only FDA-approved cyclosporine treatment delivered with proprietary nanomicellar NCELL^® Technology,⁶ which enhances the bioavailability of cyclosporine, resulting in potentially improved ocular tissue penetration.^7,8

Specifically, a hydrophobic core encapsulates the cyclosporine molecules and prevents the cyclosporine from being released through the aqueous layer of the tear film.^3,4,5,9 A hydrophilic shell covers the hydrophobic core and allows for transport through the tear film onto the ocular surface.^3,4,5 After the nanomicelle penetrates the aqueous layer of the tear film, the encapsulated cyclosporine molecules are then released onto the ocular surface.

“CEQUA^® with NCELL^® Technology is the latest formulation of cyclosporine that penetrates better, works faster, and can ultimately improve vision more comfortably and more tolerably, potentially leading to increased compliance—which is a big thing for ODs.”

—Josh Johnston, OD, FAAO

Clinical trial safety data

Most ocular adverse events reported by patients treated with CEQUA^® were mild or moderate. The most common adverse events reported in patients were instillation site pain (22%) and conjunctival hyperemia (6%). Fewer than 3 patients in 100 discontinued CEQUA^® due to instillation site pain. Discontinuation rate secondary to ocular adverse events was 3.2% for CEQUA^® vs. 1.1% for vehicle.²Incidence of blurred vision was <1%. CEQUA^® had no reported taste alterations and no contraindications—making the medication an appropriate option for patients who might be suffering from DED.

Patients should be advised to be careful not to allow the vial tip to touch their eyes or any surfaces in order to help avoid potential eye injury or contamination of the product. Patients should also be advised not to use CEQUA^® while wearing contact lenses. If contact lenses are worn, they should be removed prior to using CEQUA^® and may be reinserted after 15 minutes.

CEQUA^® may improve visual acuity in patients with dry eye disease

While most eyecare practitioners witness how dry eye disease can impact visual acuity, CEQUA^® is the first FDA-approved drop that has demonstrated statistically significant improvements in visual acuity and has the potential to improve clarity of vision and the eyes’ ability to recognize small details with precision.⁸

Studies have found that central corneal staining in dry eye disease is correlated with visual performance and visual acuity.¹⁰ In the past however, dry eye medications evaluated data related to inferior corneal staining data. CEQUA^®clinical trials measured total corneal staining after 14 days,¹¹ for a potentially more accurate assessment of performance over a two-week period.

^{*In clinical trials with CEQUA^{^®}, corneal conjunctival staining was assessed in six conjunctival zones one to four minutes after instilling one drop of 1% lissamine green. Corneal staining was evaluated in five corneal regions two to two and a half minutes after instilling one drop of 0.5% fluorescein.}

After three months, clinical trial results demonstrated that 65% of central corneas were completely clear with CEQUA^®, versus 56.9% for vehicle.¹

^{(vs 56.9% for vehicle; P=0.02) At baseline, 38.3% of patients taking CEQUA^{^®} had complete clearing (vs 37.5% with vehicle).}

“Inferior corneal staining is not a highly valuable diagnostic finding for most clinicians. It’s often ignored. It’s not really a highly validated diagnostic tool.”

—Josh Johnston, OD, FAAO

^{Study design:
CEQUA^{^®} was studied in two 12-week, randomized, multicenter, double-masked, vehicle-controlled studies. Patients were randomly assigned to treatment and dosed twice a day. Study 1 included 455 patients (152 received CEQUA^{^®}) and Study 2 included 744 patients (371 received CEQUA^{^®}). The co-primary endpoints for Study 1 were conjunctival staining and global symptom scores (change from baseline to Day 84). The primary endpoint for Study 2 was percentage of eyes demonstrating an improvement of ≥10 mm in Schirmer score after 84 days of treatment. Both studies assessed corneal staining as a secondary endpoint.^{^1,2,12} Staining in each region of the conjunctiva was evaluated using a score ranging from 0 (no staining) to 3 (severe staining). Staining in each region of the cornea was evaluated using a score ranging from 0 (no staining) to 4 (severe staining).^{^1,12} Patients were excluded from the studies if they experienced prior treatment failure with cyclosporine 0.05% or used the therapy within 3 months prior to screening. Use of artificial tears was not allowed during the studies. The mean age was 59 years (range, 18-90 years). Eighty-three percent of patients were female.^¹³}

Demonstrated results after switching from Restasis^® to CEQUA^®7

Researchers conducted a 12-week, Phase 4 multicenter study to gather data on CEQUA^® efficacy for patients whose dry eye disease and symptoms were inadequately controlled on Restasis^®.⁷

When these patients were treated with cyclosporine ophthalmic solution twice daily, data showed improved corneal fluorescein staining and modified Symptom Assessment in Dry Eye (mSANDE) scores starting at Week 4 of treatment. These improvements were maintained through Week 12.⁷

Significant improvements in total central corneal staining were seen as early as week 4 and continued to week 12.⁷
Artificial tears use reduced from 3 times to 1 time per day after switching from Restasis^® to CEQUA^® for 12 weeks.⁷
69% of patients preferred CEQUA^® over Restasis^® (22%) by the end of the study.
Adverse events were consistent with the established safety profile, and no new safety signals were observed.⁷

^{Study design:}

^{Single arm, Phase 4, 12-week, multicenter study of 124 adults with DED inadequately controlled (ie, still symptomatic and/or exhibiting disease signs) on current Restasis^{^®} therapy.^{^7,13} The co-primary endpoints were corneal fluorescein staining (CFS) and modified Symptom Assessment in Dry Eye (mSANDE) at Week 12.^¹⁴ Patients received 1 drop, 2x daily of CEQUA^{^®} in each eye.^¹³Enrolled patients were selected by their doctors based on: Clinical diagnosis of DED and treatment on Restasis^{^®} for ≥3 months; BCVA of ≥20/200; mSANDE score of ≥40; total CFS ≥6 or CFS in an individual zone ≥2 at baseline.^¹⁵}

^{Exclusions: Previous history of failure on Restasis;^{^®}discontinued/switched to a different immunomodulatory; allergic conjunctivitis; stable dose for ≥3 months of immunomodulators, antihistamines, cholinergics, antimuscarinics, phenothiazines, retinoids, or any systemic or topical corticosteroids.^¹⁵}

Most patients found CEQUA^® comfortable from the start^12,13

Instillation site pain can often lead patients with dry eye disease to discontinue certain treatments mainly due to discomfort.¹⁶ This might have been due to burning and stinging¹⁷ upon instillation or a lag time between treatment initiation and experiencing symptomatic relief. However, patients found CEQUA^® to be comfortable from the start, with no reported taste alterations or contraindications.

Compliance is key to successful outcomes

As you know, compliance can be a challenge with other dry eye treatments, as patients may stop using them if they don’t experience a change in symptoms. Because CEQUA^® targets inflammation and can enhance tear production, patients using CEQUA^®as prescribed may be motivated to continue with their treatment regimen,^1,8,11,12,15 as increased tear production can lead to enhanced ocular comfort.

According to a retrospective claims study of over 6,000 patients on Restasis^® (cyclosporine ophthalmic emulsion) 0.05% and 3,000 patients on Xiidra^® (lifitegrast ophthalmic solution) 5%, 70.8% of Restasis^® and 64.4% of Xiidra^® patients discontinued their treatment within 12 months of initiation.¹⁶ The real-world study found that after nearly a year (360 days), more patients were still using CEQUA^® than Xiidra^® or Restasis^®.

Patients may discontinue Restasis^® because it’s not working quickly enough or they may stop taking Xiidra^® because of tolerability issues. If I could encourage doctors to do anything, I would suggest looking at clinical data that demonstrates how quickly CEQUA^® works and how it can improve visual acuity. We’ve never had a medication before with data that demonstrates improved visual acuity as well as efficacy for a longer term maintenance therapy.

My 5-step protocol for managing and treating dry eye disease

Ask your patient specific questions about their symptoms The most important thing is to talk to the patient, whether that is a questionnaire or a heart-to-heart conversation during the exam.
Take a thorough patient history
Sometimes you don’t need to ask a specific question. I take into account a patient’s age, the severity of their symptoms, what their meibomian gland function is, their lifestyle, and digital device use.
Conduct several diagnostic tests to look at all possible causes of their symptoms
Next, it's important to look at key variables, including diagnostic indicators, corneal staining results, and tear breakup time.
Prescribe an immunosuppressant
If patients are symptomatic or I see decreased aqueous tear production, elevated osmolarity, and corneal staining patterns, then I’ll prescribe an immunosuppressive agent such as CEQUA^®.
Empower your patients with home and in-office treatment options
In general, if patients have some level of meibomian gland dysfunction (MGD), we recommend warm compresses and other thermal in-office procedures.

Josh Johnston, OD, FAAO, is the clinical director and residency director of Georgia Eye Partners, which is a six-location, multi-specialty OD, MD group. Additionally, Dr. Johnston oversees the practice’s dry eye clinic.

Q. What steps do you take to properly identify dry eye disease?
The most important thing is to talk to the patient, whether that is a questionnaire or a heart-to-heart conversation during the exam. We know the signs and symptoms of dry eye don't always match a patient’s complaints. So it’s really important to hear from them. Whether a patient self-selects for a dry eye consult or you discover they are symptomatic, we look at key variables, including diagnostic tests like MMP-9 tests and checking tear film osmolarity. The slit lamp exam will also look at fluorescein staining and sometimes lissamine green staining on the conjunctival tissue. Tear breakup time is also a useful diagnostic parameter to consider as well as looking at the lid margins and lashes for signs of demodex mites, blepharitis, and ocular rosacea.

Q. When talking to a patient about dry eye, what kinds of questions do you ask?
If they are naive to therapy or previous treatments—or they have had failures—I start there. I also like to inform my patients that dry eye is typically a chronic disease with no cure. However, I can recommend treatments that will improve their comfort as well as their vision.

And sometimes you don’t need to ask a specific question. I take into account a patient’s age, the severity of their symptoms, what their meibomian gland function is, their lifestyles and digital device use. I’ll also look at what diagnostics show in terms of osmolarity and inflammation with MMP-9 detection as well as the slit lamp exam to look at fluorescein staining or occasionally lissamine green training on the conjunctival tissue.

All of those factors are important. Additionally, if patients are symptomatic or I see decreased aqueous tear production, elevated osmolarity, and corneal staining patterns, then I’ll prescribe an immunosuppressant to decrease inflammation and help the body produce more natural tears. I also give my patients a personalized treatment sheet that highlights all the treatment options I recommend.

Q. What are your first level recommendations to patients you suspect might have dry eye?

In general, if patients have some level of meibomian gland dysfunction (MGD), we recommend warm compresses and other therapies like TearCare. I’m also doing a lot of intense pulsed light therapy for MGD and ocular rosacea. We can offer steroids, punctal occlusion, amniotic membranes, autologous serum, but at the heart of it, there’s inflammation. That’s where CEQUA^® comes in. There are basically three FDA-approved topical drops to treat chronic dry eye disease per se, not including neurostimulation nasal sprays. All prescription eye drops may have side effects, including discomfort, vision blur, and a taste alteration. Of those three, I often choose CEQUA^® because of its efficacy and safety profile, including that it can potentially improve visual acuity.

Q. Can you share a case study where you recommended CEQUA^®?
One that comes to mind is a 42-year old female with a previous history of getting LASIK due to contact lens intolerance. She was initially prescribed artificial tears and punctal occlusion initially after LASIK. She also tried Restasis^® but didn’t notice much improvement after a month. She then switched to Xiidra^® but was experiencing side effects—mainly visual blur and dysgeusia (a bad taste in the mouth.) She wanted another treatment option that was more tolerable based on side effects.

We did some corneal staining which I graded at about two on a scale of one to four. Some of that staining was on the central cornea. Her best corrective vision was 20/30—so not terrible but not perfect either, especially after having LASIK at the age of 42. Because she was non-responsive to Restasis^® after a month and couldn’t tolerate Xiidra^®, we switched gears to CEQUA^® twice a day.

That was about six months ago and she’s doing well today. She has no side effects from CEQUA^®, and her vision is now 20/20 uncorrected. She has reduced her use of artificial tears and is just cruising on CEQUA^® at this point.

For me, the take-home is that CEQUA^® is well-tolerated, works quickly, and provides improvement in visual acuity as well.

Why CEQUA^® is a good option to treat dry eye disease

Other dry eye drops available for patients today either don’t work quickly enough or cause intolerable side effects. For eye dryness symptoms, Xiidra^® failed to show a significant effect at two weeks in two of four studies (although significant effects were demonstrated in four of four studies at day 42.)²⁴

In the Xiidra^® Phase III Opus-2 study, lifitegrast ophthalmic solution met the co-primary symptom end point (eye dryness) but not the co-primary sign end point (inferior corneal staining). The most common adverse events were instillation-site irritation, altered taste, and reduced visual acuity (5-25%).²⁴

For improvement in signs of dry eye disease by measuring tear production, Restasis^® produced a significant increase in tear production at 6 months.²⁵ However, the most common side effect was burning of the eye (17%).²⁵

Until CEQUA^®, patients and doctors still felt a lack of therapeutic agents that provide rapid symptom relief,^26-28 display fast onset of action,^20-22 and are tolerable,^11,29,30 so patients can more easily stay on therapy.

“A lot of patients discontinue Restasis^® because it’s not working fast enough and they discontinue Xiidra^® because of tolerability issues,” said Dr. Johnston. “If I could encourage doctors to do anything, I would suggest looking at the new data that shows how quickly CEQUA^® works and how it can improve visual acuity. We’ve never had a medication before with data that demonstrates improved vision as well as efficacy in a longer term maintenance therapy.”

CEQUA^® has no generic equivalent

CEQUA^® is formulated with ingredients in an unpreserved, isotonic, neutral-pH vehicle that is designed to provide comfort and minimize ocular adverse reactions.

Differences in inactive ingredients can have a significant effect on both the safety and efficacy of an ophthalmic drug product. While labeled as “inactive,” these ingredients buffer stability, comfort, safety, and activity. For example, excipients can regulate osmotic pressure, pH, and viscosity, while electrolytes mimic the composition of artificial tears for ocular homeostasis.

INDICATIONS AND USAGE

CEQUA^® (cyclosporine ophthalmic solution) 0.09% is a calcineurin inhibitor immunosuppressant indicated to increase tear production in patients with keratoconjunctivitis sicca (dry eye).

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS
Potential for Eye Injury and Contamination: To avoid the potential for eye injury and contamination, advise patients not to touch the vial tip to the eye or other surfaces.

Use with Contact Lenses: CEQUA should not be administered while wearing contact lenses. If contact lenses are worn, they should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following administration of CEQUA ophthalmic solution.

ADVERSE REACTIONS
The most common adverse reactions reported in greater than 5% of patients were pain on instillation of drops (22%) and conjunctival hyperemia (6%). Other adverse reactions reported in 1% to 5% of patients were blepharitis, eye irritation, headache, and urinary tract infection.

Please see the Full Prescribing Information.

References

1. Goldberg DF, Malhotra RP, Schechter BA, Justice A, Weiss SL, Sheppard JD. A phase 3, randomized, double-masked study of OTX-101 ophthalmic solution 0.09% in the treatment of dry eye disease. Ophthalmology. 2019;126(9):1230-1237.

2. CEQUA [package insert]. Cranbury, NJ: Sun Pharmaceutical Industries, Inc.; 2022

3. Bron AJ, de Paiva CS, Chauhan SK, et al. TFOS DEWS II pathophysiology report. Ocul. Surf. 2017;15(3):438-510.

4. Periman LM, Perez VL, Saban DR, et al. The Immunological Basis of Dry Eye Disease and Current Topical Treatment Options. J Ocul Pharmacol Ther. 2020;36(3):137-146.

5. Periman LM, Mah FS, Karpecki PM. A Review of the Mechanism of Action of Cyclosporine A: The Role of Cyclosporine A in Dry Eye Disease and Recent Formulation Developments. Clin Ophthalmol. 2020 Dec 2;14:4187-4200.

6. US Patent 9,937,225 B2.

7. Johnston, J. Effect of OTX-101 0.09% on corneal staining and SANDE scores in patients with dry eye disease uncontrolled on cyclosporine ophthalmic emulsion 0.05%. Abstract presented at American Academy of Optometry 2023; October 12, 2023; New Orleans, LA.

8. Malhotra R, Devries DK, Luchs J, et al. Effect of OTX-101, a novel nanomicellar formulation of cyclosporine A, on corneal staining in patients with keratoconjunctivitis sicca: A pooled analysis of phase 2b/3 and phase 3 studies. Cornea. 2019;38:1259-1265.

9. Cholkar K, Patel A, Vadlapudi AD, et al. Novel nanomicellar formulation approaches for anterior and posterior segment ocular drug delivery. Recent Pat Nanomed. 2012;2(2):82-95.

10. Kaido M, Matsumoto Y, Shigeno Y, et al. Corneal fluorescein staining correlates with visual function in dry eye patients. Invest Ophthalmol Vis Sci. 2011;52(13):9516-9522. Published 2011 Dec 16. doi:10.1167/iovs.11-8412.

11. Schechter BA, Urbieta M, Bacharach J, et al. Effect of OTX-101 in patients with dry eye disease at day 14 of treatment: ocular surface endpoint results from the phase 2b/3 clinical trial. Clin Ophthalmol. 2022;16:4145-4151.

12. Tauber J, Schechter BA, Bacharach J, et al. A phase II/III, randomized, double-masked, vehicle-controlled, dose-ranging study of the safety and efficacy of OTX-101 in the treatment of dry eye disease. Clin Ophthalmol. 2018;12:1921-1929.

13. Data on file. Cranbury, NJ: Sun Pharmaceutical Industries, Inc.

14. Effect of CEQUA in Subjects with Dry Eye Disease, ClinicalTrials.gov identifier NCT04357795. Updated Sept 09, 2022. Accessed August 29, 2023. https://www.clinicaltrials.gov/study/NCT04357795

15. Karpecki P, Barghout V, Schenkel B, et al. A retrospective analysis of real-world treatment patterns in patients with dry eye disease receiving CEQUA, Restasis, or Xiidra. Poster presented at AMCP Nexus; October 11-14, 2022; National Harbor, MD.

16. White DE, Zhao Y, OgundeleA, et al. Real-world treatment patterns of cyclosporine ophthalmic emulsion and lifitegrast ophthalmic solution among patients with dry eye. Clin Ophthalmol. 2019;13:2285-2292.

17. Mah F, Milner M, Yiu S, et al. PERSIST: Physician’s Evaluation of Restasis® Satisfaction in Second Trial of topical cyclosporine ophthalmic emulsion 0.05% for dry eye: a retrospective review. Clin Ophthalmol. 2012;6:1971-1976.

18. Chambers WA. Ophthalmic generics--are they really the same?. Ophthalmology. 2012;119(6):1095-1096.

^{CEQUA and NCELL are registered trademarks of Sun Pharmaceutical Industries Limited.
All other trademarks are the property of their respective owners.}

About Josh Johnston, OD, FAAO

Dr. Josh Johnston is the Clinical Director at Georgia Eye Partners and an adjunct faculty member at Southern College of Optometry serving as the Residency Director at GEP. He founded Oculus Consulting Partners to help eye doctors and practices start and improve their dry eye practices offering consulting that blends technology and expertise to offer simpler, more efficient, and smarter consulting.

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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Potential for Eye Injury and Contamination: To avoid the potential for eye injury and contamination, advise patients not to touch the vial tip to the eye or other surfaces.

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How Optometrists Are Using CEQUA® (cyclosporine ophthalmic solution) 0.09% to Treat Chronic Dry Eye Disease