The Dry Eye Patient In Focus: An Expert Panel Review

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Sun Ophthalmics is a part of the multinational company Sun Pharma. As a highly specialized division of eye care professionals, Sun Ophthalmics is able to respond quickly to the ever-changing world of optometry and ophthalmology.

Since 2015, the company has been laser focused on advancing eye care through the development of leading technologies. Recognizing the power of science, Sun Ophthalmics is committed to adding treatment options in eyecare, particularly in the realm of novel delivery mechanisms. This dedication is reflected in the company’s current ophthalmic product offerings, as well as the more than 2,000 products that Sun Pharma has brought to the healthcare community.

Treating dry eye disease with CEQUA™

Dry eye is a burdensome, chronic disease affecting millions of patients around the world, with a significant population, greater than 16 million patients, in the United States.^1-2 Dry eye disease (DED), as defined by the National Eye Institute (NEI), a division of the U.S. National Institutes of Health [NIH]), occurs when the quantity and/or quality of tears fails to keep the surface of the eye properly lubricated. In October 2019, Sun Pharma launched CEQUA for topical ophthalmic use for the treatment of DED in the U.S.

CEQUA (cyclosporine ophthalmic solution) 0.09% is the first and only FDA-approved cyclosporine treatment delivered with NCELL™ Technology.^3,4 Cyclosporine (CsA) has been used as an effective way to treat dry eye disease for many years. But due to its poor aqueous solubility, cyclosporine faces challenges in its delivery.⁵

NCELL is engineered to address cyclosporine solubility challenges to better reach the ocular surface.^3,5 By using a protective hydrophilic shell, NCELL Technology delivers encapsulated cyclosporine in a secured hydrophobic core to the ocular surface.^3,5,6,7

NCELL encapsulates

NCELL Technology uses nanomicelles composed of a blend of polymers. These polymers self-assemble into the hydrophobic core protecting the cyclosporine so it isn’t released in the aqueous layer of the tear film.^3,6

NCELL penetrates

The small size facilitates entry into corneal and conjunctival cells. Nanomicelles are able to penetrate the aqueous layer of the tear film because of their hydrophilic outer layer.^3,5,6

NCELL delivers

The nanomicelles then break up to release cyclosporine for penetration into ocular tissues.^5,6 Once released, cyclosporine gets to work to reduce inflammation, helping improve the ocular surface and increase tear production.^8,6

NCELL provided superior delivery over emulsion—up to 3x CsA concentration across the ocular tissues—in a single-dose, preclinical study of cyclosporine delivered with NCELL Technology (0.05%) vs a commercially available cyclosporine emulsion (0.05%).^3,8

Study design: Ocular tissue distribution of cyclosporine was evaluated in a total of 26 female New Zealand White rabbits that received a single dose (administered to both eyes) of vehicle, cyclosporine 0.05% or 0.1% with NCELL Technology, or a commercially available cyclosporine 0.05% emulsion (Restasis,^® Allergan). Pharmacokinetic parameters for cyclosporine exposure were assessed in tears, whole blood, and ocular tissues.^3,8

CEQUA proven results

CEQUA was studied in two 12-week, randomized, vehicle-controlled trials of 1048 patients with dry eye disease.^9,10 Patients enrolled in these trials experienced results as early as 1 month, with significant improvements across major measures of dry eye disease.^4,9,10Specifically, patients treated with CEQUA (vs vehicle) experienced a reduction in total corneal staining at 1-, 2-, and 3-month timepoints.⁹

CEQUA also offers a demonstrated safety and tolerability profile.^8,4,a

Most adverse events were mild.⁸

>95% of patients experienced either no or mild instillation site pain^9,b
The most common adverse events reported in >5% of patients were instillation site pain^b (22%) and conjunctival hyperemia (6%)⁴
Most ocular adverse events reported by patients treated with CEQUA were mild (80%) or moderate (17%)⁸
Discontinuation rate due to ocular adverse events was 3.2% for CEQUA vs 1.1% for vehicle⁸

a. The safety of CEQUA was evaluated in clinical trials that included 769 patients who received at least 1 dose of study treatment.⁴
b. Instillation site pain included burning and stinging.^8,9

Most patients found CEQUA to be comfortable^8,10

Incidence of blurred vision was <1%⁸
No reported taste alterations⁸

CEQUA 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.

CEQUA case study

Dr. Rose has a private practice and a dry med spa in Cincinnati, Ohio and Dr. White has a private practice in Westlake, Ohio, just outside of Cleveland.*

Describing DED as an immune-mediated inflammatory disease that is multifactorial and includes a “vicious cycle” of various triggers and responses, Rose said these start with interrupted secretomotor nerve impulses that send a signal to the lacrimal gland, which increases inflammation, starts T-cell activation, and releases cytokine into the tears. These “inflammatory tears” irritate the surface of the eye and then disrupt the neural arc—which “is the beginning of the end of this vicious cycle.”

“A lot of things play into dry eye disease as a whole,” she said. “It’s an umbrella category.”

Among the symptoms of increased tearing, ocular discomfort, and visual disturbance that patients report, she said the last is especially important to recognize in this context.

“I think it’s important to point out that a really common symptom of dry eye is intermittent blurry vision,” Rose said. “A lot of patients have trouble connecting acuity to this anterior surface disease. So I think it's important for us to continually hammer that message home—that this does have optics side effects. Of course, we know if this goes on long enough, we can have potential erosion in the cornea.”

White agreed with the essential connection between visual disturbance and dry eye.

“I tell everybody in my office, if somebody comes in and they complain of blurred vision, they have dry eye until proven otherwise,” he said. “Dryness is such a common cause of blurred vision that I think it’s probably the second most common cause of blurriness in all of our practices. The only greater thing that causes it is that the patient forgot to put their glasses on.”

Introducing the case study, White described the individual as “a pretty typical person” they see in the office.

Case study

Carl is a middle-aged truck driver who likes to read and play cards. He has a variety of risk factors for dryness: he’s a smoker; takes medications that contribute to dryness (diuretics for hypertension and antihistamines for allergies); is diabetic and has some arthritis.

Dry eye symptoms include tearing, burning, light sensitivity, and fluctuating vision. He has been using a topical immunomodulatory therapy, as well as artificial tears.

Objective findings include: Lid margins indicative of meibomian gland disease; reduced visual acuity; fluorescein staining that also indicates incomplete blinking and nighttime exposure; lissamine green staining on the conjunctiva; and tear film debris from the meibomian gland disease. Meibography and transilluminated photos reveal some truncation and obstruction of the meibomian glands. Upon expression, the meibum is found to be extremely thick.

Rose summarized Carl’s findings.

“So what do we know about Carl? We know that he has this systemic involvement,” she explained. “He has auto-immune conditions. We know he has systemic inflammation. He is an insulin-resistant diabetic, so we know he has metabolic disease. We know that he does not have a great blink. We have nighttime exposure as indicated by inferior corneal staining, and his oil glands are sub-par. He has ocular rosacea and a harsh environment with partial blinks, exacerbated by the heat and air in the truck.”

“He's just a perfect setup for everything we see when patients come in,” White said. “So what do we want to do? He's on some treatment already, but clearly we've got some room to maneuver to make him feel better.”

Rose listed a variety of options that may be considered, including:

Lifestyle changes to address

Diet, hydration, sleep, exercise, anxiety
Limit screen time/blink exercises/take breaks
Change/discontinue current cosmetics, lotions, etc. with preservatives
Alter contact lens wearing habits, cleaning method, and/or material
Medication change in order to limit dry eye side effects

Procedures

Punctal occlusion
Intense Pulse Light therapy (IPL)
Thermal Pulsatile Meibomian Gland Evacuation
Amniotic Membrane
Scleral Lens

OTC/At-home treatments

Tear supplements, warm compress, lid scrubs
Nutraceuticals/Omega supplements

Pharmaceuticals

Topical corticosteroids
Cyclosporine 0.09% (eg CEQUA)
Lifitegrast
Topical Testosterone
Autologous Blood Serum
Antibiotics

“There are some pretty straightforward things we can pick out of that exhaustive list,” White said. “When I'm creating a treatment plan for somebody, I think of it like building a house, and we can shore up Carl's foundation at the same time that we're adding on some nice features to the house.”

From the options discussed, he recommended the following treatment plan for Carl:

Lifestyle changes

Diet, hydration, sleep, exercise, anxiety
Medication change in order to limit dry eye side effects

Procedures

Intense Pulse Light therapy (IPL)

OTC/At-home treatments

Tear supplements, warm compress, lid scrubs
Nutraceuticals/Omega supplements

Pharmaceuticals

Cyclosporine 0.09% (eg CEQUA)

“When we think about topical immunomodulator therapy, we can actually think about putting Carl on a different version of cyclosporin A,” White said. “We can think about switching him to CEQUA.”

Rose agreed.

“I think CEQUA is a very valid option for quite a few different reasons,” she said. “It does increase ocular surface penetration.”

White said he also likes the fact that CEQUA is so well tolerated.

CEQUA in practice

Rose said the innovative NCELL technology in CEQUA is what makes it so effective. Citing some of the studies mentioned previously, she said seeing improvement with CEQUA so quickly is “very impressive.”

White said this is a “big deal” for surgeons.

“I think the post-op aspect is a big deal because if you don't get the outcome you expected, if there's a surprise, then it makes for a lot of challenges going downstream,” he said.

After discussing the various clinical studies mentioned previously, Rose and White described some of their experiences prescribing CEQUA for their patients.

“I think everyone wants to know that it's going to be fast and it's going to be safe,” Rose said. “You don't want to hit them with this powerhouse if they're going to have all of these other side effects, but we know that with CEQUA, we can expect the installation irritation to be mild the majority of the time. And if we can talk them through that and help mitigate it, I think it's very well tolerated.”

White agreed and said he’s been pleased to see that the positive results patients reported in clinical trials have been consistent with real-world results.

“CEQUA seems to be exactly the same as it was in the FDA trials,” he explained. “My experience has been very, very well predicted by the safety and tolerability aspect of the pivotal phase-three trials. And we're finding that if there are any side effects, they're mild and they haven't really interrupted the treatment to any degree that makes a difference for me clinically in the office.”

Rose commented on the importance of being able to treat ocular surface disease effectively—both for patients and practices. White said that since the volume of work in their office is focused so heavily on treating dry eye, having access to effective treatment options is critical.

“If we didn't have medications like CEQUA, if we didn't have the ability to dramatically reduce the amount of inflammation on the surface of the eye and thereby the amount of visual consequences and the degree of discomfort, then we’d be dead in the water,” he explained. “Because now that I've been identified as a place people can go, they're coming to see me and I just have to have these tools.”

He also acknowledged the fact that all of the immunomodulators work “extremely well.”

“But they just don't always work equally well in all patients,” White said. “So having this additional tool in the toolkit has been extremely important.”

*Disclosures: This is a promotional program developed by Sun Pharma. Drs. Rose and White presented on behalf of Sun Pharma and received an honorarium for the presentation, which will be pursuant to open payment and state laws. All information presented is consistent with the full prescribing information for CEQUA, which is available on cequapro.com.

References

New study focuses on scope of dry eye disease in the U.S. American Optometric Association; 2017. Available at: https://www.aoa.org/news/clinical-eye-care/new-study-dry-eye-disease. Accessed September 10, 2019
Stapeleton, F, et al. TFOS DEWS II Epidemiology Report. The Ocular Surface. 2017;(3):334-365
US Patent 9,937,225 B2. 2. Data on file. Cranbury, NJ: Sun Pharmaceutical Industries, Inc.
CEQUA [package insert]. Cranbury, NJ: Sun Pharmaceutical Industries, Inc.; 2019.
Cholkar K, Gilger BC, Mitra AK. Topical, aqueous, clear cyclosporine formulation design for anterior and posterior ocular delivery. Transl Vis Sci Technol. 2015;4(3):1-16.
Mandal A, Bisht R, Rupenthal ID, Mitra A. Polymeric micelles for ocular drug delivery: from structural frameworks to recent preclinical studies. J Control Release. 2017;248:96-116.
Cholkar K, Patel A, Vadlapudi AD, Mitra AK. Novel nanomicellar formulation approaches for anterior and posterior segment ocular drug delivery. Recent Pat Nanomed. 2012;2(2):82-95.
Data on file. Cranbury, NJ: Sun Pharmaceutical Industries, Inc.
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.
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.