Sun Pharmaceutical Industries Limited reported updated positive data from a phase 4 clinical trial supporting the use of CEQUA (cyclosporine ophthalmic solution) 0.09% for improving the signs and symptoms of dry eye disease (DED).
These findings are the latest in the company’s series of efficacy assessments on the product, with data last reported in October 2023.
First thing’s first: Let’s get a rundown on CEQUA.
What it is: The cyclosporine molecule (also referred to as cyclosporine A [CsA]) is a calcineurin inhibitor immunosuppressant that interferes with T-cell function in the eye by blocking their activation and proliferation to reduce inflammation within the ocular surface.
Its regulatory status: While the FDA originally approved cyclosporine for topical ophthalmic use in 1983, CEQUA (cyclosporine ophthalmic solution) 0.09%, developed under Sun Pharma, was approved in August 2018.
And its indication?
Per its prescribing information (PI), the preservative-free eye drop’s recommended dosage is one dose instilled twice daily (approximately 12 hours apart) into each affected eye.
- Notably: It can be used concomitantly with artificial tears, but 15-minute intervals are advised between products
And after use in both eyes: The single-use vial should be discarded immediately.
Talk more about its formulation.
A major differentiator from other eye drops on the market is that CEQUA is formulated with the company’s proprietary nanomicellar NCELL Technology delivery system.
About this technology: The system is designed to encapsulate cyclosporine (the active ingredient) in CEQUA to treat chronic dry eye.
How it works: By using a polymer blend to create “nanomicelles” with a hydrophobic core and hydrophilic outer layer that then surround cyclosporine to:
- Protect cyclosporine during delivery
- Penetrate the tear film’s aqueous layer
- Directly deliver cyclosporine to the ocular tissues
- Enter into corneal and conjunctival cells
- Breakup to release cyclosporine for penetration into ocular tissues
Once the cyclosporine is released, it works to reduce inflammation, improve the ocular surface, and increase tear production, according to Sun Pharma.
Nice! And exactly how quickly can patients see results?
As early as 2 weeks, according to clinical research.
The supporting data: In a randomized, dose-ranging study comparing CEQUA to a vehicle among DED, CEQUA was found to improve total corneal staining after 14 days (p = 0.0557).
And how long do these improvements typically last?
As long as 3 months, according to the product’s supporting clinical data.
By 1 month (Day 28) of twice-daily dosing of CEQUA, a statistically significant reduction in total corneal staining was noted—along with a meaningful reduction in symptom severity.
By 2 months (Day 56), statistically significant improvements in visual acuity (VA) were correlated with reduced central corneal staining.
And by 3 months, a total of 65% of central corneas were found to be completely clear (based on analysis versus vehicle, which reported 56% clear central corneas (p = 0.02).
- Also at this point: CEQUA was reportedly found to produce “significantly more hydrating tears to comfort dry eyes.”
Alrighty, now let’s move on to this phase 4 trial.
We’ll start with the basics.
- The design: A multicenter, open-label, single-arm study
- The participants: 134 patients (mean age: 65 years; 88% female)
- To note: 19 patients discontinued, resulting in 125 analyzed.
- The criteria:
- Diagnosed with “inadequately controlled DED” at least 3 months prior
- Currently taking Restasis (cyclosporine ophthalmic emulsion) 0.05% therapy for at least 3 months
- The setup: All patients received CEQUA’s recommended prescription dosage
- The duration: 12 weeks
And what was measured?
Two primary endpoints:
- Corneal fluorescein staining (CFS)
- Based on 0-4 grading scale with 0.5-point increments
- This was assessed in all five zones of the cornea
- Based on 0-4 grading scale with 0.5-point increments
- Modified Symptom Assessment in Dry Eye (mSANDE)
- Based on 0-100 scale for dryness and irritation
- Scoring totaled with sum of all five corneal area zones
- Based on 0-100 scale for dryness and irritation
Important to note: Each test core was measured at baseline and Weeks 4, 8, and 12 (and/or if a patient discontinued the study early).
Next up: these new findings.
Building on last year’s data, the company reported that CEQUA demonstrated “significant improvements from baseline in both (CFS) and best-corrected visual acuity (BCVA) at Week 12.”
Taking a closer look:
- Total CFS scores were significantly reduced from Week 5 to Week 12
- Significant improvements in BCVA were observed at Week 8 and Week 12
Give me some expert insight into this.
When speaking with Glance President Jaclyn Garlich, OD, FAAO, on this data, Josh Johnston, OD, FAAO, clinical director and residency director at George Eye Partners, noted significant findings regarding the study’s primary endpoint at 12 weeks.
“The primary endpoint achieved statistical significance at 4 weeks, 8 weeks, and 12 weeks—and the other interesting cut of that data showed improvement in visual acuity (VA),” he said.
Any adverse events reported?
While 84 participants (62.7%) reported at least one treatment-emergent adverse event (AE), the majority were notably mild in severity and “most commonly related to installation site pain,” according to Sun Pharma.
As for serious AEs—those were observed in <2% of participants.
So how do these results compare to previous data from the study?
In the company’s earlier reported findings from this trial, CEQUA was found to be “generally well tolerated, exhibiting a safety profile consistent with previous clinical data.”
- See the performance of CFS and mSANDE at baseline and Weeks 4, 8, and 12.
And the crux of those findings?
Improvements in CFS were seen as early as Week 4 (and continued to Week 12)—with most patients reporting that their eyes “felt less dryness and irritation after 4 weeks” of using CEQUA versus when they used Restasis.
- As for AEs: Less than 50% were reported to be treatment-emergent AEs and just under 75% were mild.
Now let’s talk patient preference.
With artificial tear use among participants decreasing from three times a day (when using Restasis) to just once daily (on CEQUA), a total of 69% of patients reported preferring CEQUA over Restasis by the study’s conclusion.
Moreover: The majority of patients found CEQUA to be comfortable from the get-go (the start of the study), with >95% experiencing either no or mild instillation site pain upon administration.
And why should both ECPs and patients care about this latest data?
It’s no secret: CFS is critical for diagnosing and managing dry eye patients—and for clinicians, it’s a major diagnostic that’s used. Dr. Johnston offers his input below.
Lastly, any plans for additional research on CEQUA?
Indeed there are, according to Dr. Johnston.
Why? “This data was remarkable,” he said. “It wasn’t Restasis failures—in fact, on average, these patients had been on Restasis for 38 months before coming into the clinic and switching to CEQUA for the phase 4 study.”
He added: Based on prior research, “We know that the longer they use Restasis, the better, and those improvements were still seen after the switch to CEQUA.”
- “In this phase 4 study, (the patients) were not adequately controlled on Restasis and CEQUA then allowed a significant improvement in several signs and symptoms at several time points.”
As such, investigators are continuing to research the effects of CEQUA in this real-world switch study, Dr. Johnston said, including looking at potential correlations between gender and age.