Dry eye disease: Tailoring solutions for a common but complex problem

Dry eye disease (DED) is a common, often chronic, and potentially progressive condition of the ocular surface that can cause ocular itching, burning/stinging, dryness, redness, and blurred or fluctuating vision. The bothersome signs and symptoms of DED can lead to impairments of daily function and emotional well-being, which can help to explain why DED is a leading cause of patient visits to an eye care practitioner.¹ However, DED can also be asymptomatic, as shown by results from studies that found high proportions of patients presenting for cataract surgery had objective signs of DED without typical DED symptoms.^2,3

The goals for treating DED are to relieve patient-reported concerns, restore ocular surface integrity, prevent disease progression, and, in the case of patients undergoing surgery, optimize surgical planning and minimize postoperative dissatisfaction. Effective management of DED requires choosing an intervention that targets the underlying etiology, and this task mandates recognition that DED is a complex, multifactorial condition that can be initiated by a variety of intrinsic and extrinsic risk factors that lead to increased evaporative tear film loss and/or aqueous tear deficiency.⁴ Inflammation plays a key etiological role in DED, as it can be a primary trigger for DED development or arise secondarily, acting to drive disease progression.⁴ Inflammation causes clinical signs and symptoms of DED, promotes ocular surface breakdown, and perpetuates the vicious circle describing DED pathophysiology. Therefore, topical treatment with anti-inflammatory agents is a mainstay for DED management.

Choosing treatment to optimize success

Topical anti-inflammatory medications used for treating DED include corticosteroids, several cyclosporine products, and lifitegrast. The counseling conversation should also include information about chosen treatments, including instructions on use, expectations for time to onset of benefit, potential adverse effects, and the reason for choosing each intervention. Proper educational counseling will give patients confidence that they are being cared for with a personalized approach tailored to their specific situation.

Access may be the determining factor affecting selection among the nonsteroidal agents. A generic cyclosporine ophthalmic emulsion 0.05% product is available, and it may need to be used as an initial anti-inflammatory treatment for DED by patients whose prescription medication insurance policy requires a step-through approval process.

If our treatment selection is not limited by formulary restrictions, we must recognize that the success of any treatment hinges on patient adherence, which is largely affected by the individual’s experience. With regard to the latter issue, it is interesting to consider results from a study that found substantial proportions of patients being treated for DED with cyclosporine ophthalmic emulsion 0.05% (Restasis; AbbVie) or lifitegrast ophthalmic solution 5% (Xiidra; Bausch + Lomb) reported ineffective relief of DED symptoms and dissatisfaction with time to onset of effect and adverse effects.⁵ The study also included patients who had switched between the 2 anti-inflammatory treatments. Inability to relieve DED symptoms was a main reason for the change in therapy, and a high proportion of patients remained dissatisfied and/or reported being unable to achieve effective symptom relief after transitioning.

It is therefore not surprising that results from a study analyzing medical insurance claims for patients with DED found very low adherence rates for lifitegrast (9.7%) and cyclosporine 0.05% (5.9%) in the 12 months after treatment initiation.⁶ Median time to treatment discontinuation was just 89 days for cyclosporine 0.05% and 29 days for lifitegrast. Treatment persistence and time to DED treatment discontinuation were investigated in another study analyzing data from a provider-
based claims database.⁷ Its results showed that patients being treated with cyclosporine ophthalmic solution 0.09% (Cequa; Sun Ophthalmics) remained on treatment longer and were less likely to discontinue treatment than patients prescribed either cyclosporine 0.05% or lifitegrast. The differences between the cyclosporine 0.09% and cyclosporine 0.05% groups were statistically significant.

Addressing the patient’s understanding

Proper educational counseling holds the key for encouraging patient acceptance of recommended treatments and motivating good adherence. For patients with DED, the discussion should provide information about the disease, including its underlying cause(s), contributing factors, and the potentially chronic and progressive nature of the condition so that patients truly appreciate the importance of adhering to their treatment regimen. The counseling conversation should also include information about chosen treatments, including instructions on use, expectations for time to onset of benefit, potential adverse effects, and the reason for choosing each intervention. Proper educational counseling will give patients confidence that they are being cared for with a personalized approach tailored to their specific situation.

Patients who were dissatisfied with their
experience using a previously prescribed anti-
inflammatory medication, whether it be generic cyclosporine or a brand name, may question the rationale for starting another agent in the same category with the same active ingredient. Explaining differences between treatment options and sharing evidence about the alternative treatment’s clinical performance are imperative in this situation to surmount patient resistance and support adherence to the new medication.

A novel cyclosporine

Cyclosporine 0.09% was developed by Sun Ophthalmics to address the need for a comfortable, fast-acting, and effective topical anti-inflammatory treatment for DED. Indicated to increase tear production, cyclosporine 0.09% is a clear, aqueous ophthalmic formulation indicated to increase tear production. Cyclosporine 0.09% uses proprietary nanomicellar technology (NCELL) to improve cyclosporine physicochemical stability and bioavailability at target sites while minimizing ocular adverse effects.⁸ NCELL is a novel delivery platform based on self-assembling amphiphilic polymers that form a nanomicellar structure with a hydrophobic core and outer hydrophilic layer (Figure 1).
The hydrophobic core encapsulates cyclosporine, whereas the hydrophilic outer layer enables the micellar structures to penetrate through the tear film aqueous layer. They can then reach the ocular surface by entering target cells and releasing cyclosporine.

Results from preclinical pharmacokinetics studies measuring cyclosporine concentrations achieved in corneal and conjunctival tissues provide proof that NCELL technology improves cyclosporine delivery to ocular surface tissues compared with the brand-name cyclosporine ophthalmic emulsion 0.05%.⁸ Consistent with its high bioavailability, cyclosporine 0.09% demonstrated its potential for early efficacy in findings from clinical trials. In findings from phase 2b/3 and phase 3 studies, mean improvement from baseline to day 28 in total corneal fluorescein staining (tCFS) and central corneal fluorescein staining was greater among patients using cyclosporine 0.09% twice daily compared with the vehicle-treated control group.^9,10 Significant improvements in corneal staining and other objective and subjective measures of DED severity were also found after 28 days of twice-daily treatment with cyclosporine 0.09% in results from an open-label study of patients presenting with DED prior to cataract surgery.¹¹

Results of a phase 4 study provide additional evidence of early efficacy and support the use of cyclosporine 0.09% to treat DED in patients who had an inadequate response to cyclosporine ophthalmic emulsion 0.05%.¹² This multicenter, open-label study included 124 patients who had a modified Symptom Assessment in Dry Eye (mSANDE) global symptom score greater than or equal to 40 and/or a tCFS score greater than or equal to 6 or CFS score greater than or equal to 2 in any zone in at least 1 eye after using cyclosporine 0.05% for a minimum of 3 months. Patients were prescribed cyclosporine 0.09% twice daily and allowed to use artificial tears as needed. At first follow-up, just 4 weeks after starting cyclosporine 0.09%, both mSANDE and tCFS scores showed improvement (Figure 2). At the end of the 12-week study, the treatment benefits were maintained and average use of artificial tears had decreased from 3 times daily at baseline to just once daily.

It is also reassuring to know that cyclosporine 0.09% is safe and well tolerated. The majority of ocular adverse events reported by patients treated with cyclosporine 0.09% for 12 weeks in vehicle-controlled studies and for up to 1 year in an open-label extension trial have been mild; in the phase 2b/3 study, mild or no irritation at 3 minutes post instillation was reported by 85% of patients using cyclosporine 0.09% vs 92% of patients using vehicle treatment.^9,10,13

Conclusion

DED is a complex disorder that has a multitude of etiologies, different subtypes, and a range of severity. Effective treatment will improve patient quality of life and prevent disease progression. A management strategy integrating education with interventions that are comfortable, fast acting, and tailored to each patient’s unique situation will favor treatment success and patient satisfaction.

References

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2. Gupta PK, Drinkwater OJ, VanDusen KW, Brissette AR, Starr CE. Prevalence of ocular surface dysfunction in patients presenting for cataract surgery evaluation. J Cataract Refract Surg. 2018;44(9):1090-1096. doi:10.1016/j.jcrs.2018.06.026

3. Trattler WB, Majmudar PA, Donnenfeld ED, McDonald MB, Stonecipher KG, Goldberg DF. The Prospective Health Assessment of Cataract Patients’ Ocular Surface (PHACO) study: the effect of dry eye. Clin Ophthalmol. 2017;11:1423-1430. doi:10.2147/OPTH.S120159

4. Bron AJ, de Paiva CS, Chauhan SK, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017;15(3):438-510. doi:10.1016/j.jtos.2017.05.011

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6. White DE, Zhao Y, Ogundele A, 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. doi:10.2147/OPTH.S226168

7. Karpecki P, Barghout V, Schenkel B, et al. Real-world treatment patterns of OTX-101 ophthalmic solution, cyclosporine ophthalmic emulsion, and lifitegrast ophthalmic solution in patients with dry eye disease: a retrospective analysis. BMC Ophthalmol. 2023;23(1):443. doi:10.1186/s12886-023-03174-y

8. 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. doi:10.1167/tvst.4.3.1

10. 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. doi:10.1016/j.ophtha.2019.03.050

11. Hovanesian JA, Berdy GJ, Epitropoulos A, Holladay JT. Effect of cyclosporine 0.09% treatment on accuracy of preoperative biometry and higher order aberrations in dry eye patients undergoing cataract surgery. Clin Ophthalmol. 2021;15:3679-3686. doi:10.2147/OPTH.S325659

12. Johnston J, Adler R, Hessen M. 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%. Poster presented at: American Academy of Optometry Academy 2023 New Orleans; October 12, 2023; New Orleans, LA.