Treatment pipeline expands as understanding of dry eye disease grows
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Over the last 18 months, rapid developments have occurred in the dry eye and ocular surface disease space.
After years of limited treatments in these areas, recent approvals include Tyrvaya (varenicline solution, Oyster Point Pharma) and Eysuvis (loteprednol etabonate ophthalmic suspension 0.25%, Kala Pharmaceuticals), and patient awareness of dry eye problems is on the rise.
Source: Preeya Gupta, MD
“Patients are actually paying attention, so doctors are looking for it more and more,” Healio/OSN Board Member Kenneth A. Beckman, MD, FACS, said. “We also have more diagnostics and a better ability to determine what the underlying problem is.”
Additionally, physicians now have a better understanding of the impact of ocular surface issues and emphasize their diagnosis.
“They realize that, particularly for patients undergoing cataract or LASIK surgery, they need to have the tear film optimized to get the best results,” Beckman said.
In the Prospective Health Assessment of Cataract Patients’ Ocular Surface study, published in Clinical Ophthalmology in 2017, researchers found that the incidence of dry eye in patients scheduled to undergo cataract surgery was higher than previously thought. In the study, more than 60% of patients had a tear breakup time of 5 seconds or less, 77% of eyes had positive corneal staining, and 50% of eyes had positive central corneal staining.
In the United States, it is estimated that as many as 40 million people have dry eye or ocular surface disease.
“People thought it was a nuisance disease and didn’t realize the impact it had on vision,” Beckman said. “Doctors shied away from getting involved, gave patients artificial tears and moved them along. Since that time, it’s almost as if every aspect of dry eye has been enhanced.”
Healio/OSN Board Member Laura M. Periman, MD, said the field is seeing rapid growth in both scientific understanding and therapeutic offerings.
“The pipeline is rich, deep and diverse, and we’re poised to continue that exponential growth in the clinical offerings that we have,” she said. “That ranges from home devices to in-office treatments to pharmacologics. All of that means that there is a lot of good news coming down the pike for patients with dry eye.”
There are many aspects of dry eye and ocular surface disease, and OSN Associate Medical Editor Elizabeth Yeu, MD, said knowledge in those areas has come a long way in the last 5 to 10 years.
“In dry eye, we’ve recognized that it really is an imbalance of the tear film,” she said. “Whether that’s the aqueous layer, an evaporative component or an imbalance with the meibomian gland, that’s what dry eye really is. However, we have a much better understanding on the diagnostic and definition side than we do on the therapy side.”
Treatments
Treatment options for dry eye have come a long way over the past decade.
“If we look back 10 years, we had one product that was FDA approved to treat dry eye,” OSN Cornea/External Disease Section Editor Preeya Gupta, MD, said. “Now, we have a lot more than that. The amount of innovation that continues to happen is tremendous. What’s really exciting is that companies are developing products that are taking advantage of novel pathways and complement existing treatments. As a clinician, I’m excited to have multiple treatment options that I can tailor to different patients.”
Dry eye is a chronic and progressive disease. Beckman said many patients experience flares and need a short course of steroids to resolve their symptoms. Having an option such as Eysuvis has been an important addition to the clinician’s tool kit.
“Those patients with chronic, progressive DED could experience episodic flares where their eyes are just miserable for 5 days every couple of months,” he said. “Now, doctors are more comfortable with having a patient use steroids to cool things off. While the concept of using steroids is not new, the comfort with the idea of letting patients regulate with a safe steroid for a short period of time to put out the fire has really helped us.”
The FDA approved Eysuvis for the short-term treatment of dry eye disease signs and symptoms in October 2020. The drug was the first ocular corticosteroid approved for dry eye disease.
In the phase 3 STRIDE 3 trial, Eysuvis demonstrated a significant improvement in ocular discomfort severity at day 15 in the intent-to-treat population (P = .0002) and in a predefined subgroup of patients with more severe discomfort at baseline (P = .0007). Patients also experienced improvements in conjunctival hyperemia at day 15 (P < .0001) and total corneal staining at day 15 (P = .0042).
Nasal spray
The newest addition to the dry eye tool kit is the nasal spray Tyrvaya, which was approved in October 2021.
“This is hot off the press,” Gupta said. “It takes advantage of the trigeminal nerve pathway, which is a really important pathway for maintaining homeostasis on the ocular surface. Through this pathway, it triggers the lacrimal gland to produce the aqueous layer of tears, meibomian glands to secrete oil and goblet cells to release mucins.”
In a presentation at the 2021 American Academy of Ophthalmology annual meeting in New Orleans, Marjan Farid, MD, presented data from the phase 3 ONSET-2 trial that evaluated the cholinergic agonist in patients with dry eye disease.
Researchers randomly assigned 758 patients with a Schirmer’s score of less than 10 mm into one of three groups: 0.03 mg OC-01, 0.06 mg OC-01 or vehicle control. Patients underwent treatment twice daily for 28 days. The primary endpoint was percentage of patients with at least 10 mm in change in Schirmer’s score from baseline.
At week 4, 47% of patients in the 0.03 mg group and 49% of patients in the 0.06 mg group met the primary endpoint compared with 28% in the control group (both P < .0001). These groups had a mean change from baseline Schirmer’s score of 11.3 mm and 11.5 mm, respectively, compared with 6.3 mm in the control group (P < .0001). Additionally, the effect was consistent across patients with mild to moderate and severe baseline eye dryness severity scores.
Gupta said the real benefit of Tyrvaya comes from its nasal delivery, which helps improve tolerability among a large part of the dry eye population.
“It might sound silly, but a lot of our dry eye patients have very sensitive ocular surfaces, and a lot of the drop medications we prescribe can have side effects such as burning and stinging,” she said. “That can be a real barrier to patient compliance.”
Beckman said it is beneficial among older patients who might have arthritis or other conditions that cause difficulty in handling vials and self-administering eye drops. Nasal spray administration is also an advantage in patients with lower tolerance or difficulties using drops, such as individuals who wear contact lenses.
“You don’t have to worry if it will absorb through the lens,” he said. “You might have some kind of surface toxicity or maybe a neurotrophic cornea, and you don’t want to introduce any other substance to the ocular surface. It’s really exciting to have this as an option.”
Demodex treatment
In ocular surface disease, the treatment of Demodex blepharitis has become a target. Yeu said that Demodex blepharitis, the most common etiology of blepharitis, can have sequelae of the ocular surface, including blepharokeratitis, erythema and loss of lashes as well as lash abnormalities. Additionally, mite infestation of the eyelash follicles and their byproducts, collarettes and inflammatory digestive enzymes, can lead to, masquerade as and/or exacerbate dry eye disease, making it an important area of diagnosis and treatment.
“There are two types of Demodex mites that infest and affect the eye: Demodex folliculorum, implicated in blepharitis, and Demodex brevis, which can clog the meibomian glands. Blepharitis alone can share some very common symptoms with dry eye disease, including irritation, redness, itching and watering,” Yeu said. “But what’s exciting is that if we’re able to have a safe, tolerable, convenient and effective treatment for Demodex blepharitis, then we actually have a treatment that can truly mitigate an arm of ocular surface disease without needing chronic daily therapy.”
Periman said it is an exciting time for Demodex treatment because of the recent advances with TP-03 (lotilaner ophthalmic solution 0.25%, Tarsus Pharmaceuticals).
“It’s exciting to see a unique approach to an underrecognized but common contributor to blepharitis, meibomian dysfunction and ocular surface disease,” she said. “When you take the time to look for collarettes on lashes and look under the microscope for mites, it’s shocking how common it is, and in the future, it will be much more commonplace for clinicians to recommend it as a targeted therapeutic.”
Yeu said lotilaner comes to ophthalmology from veterinary medicine where it has been used as an antiparasitic agent.
“Basically, it’s a neuroparalytic that is extremely specific for invertebrates,” she said. “It attacks the GABA chloride channel, essentially paralyzing the mite and eradicating them while being safe on mammals.”
The treatment was evaluated in the randomized, controlled, multicenter, double-masked Saturn-1 trial. The safety and efficacy of TP-03 twice daily in each eye was assessed in 421 patients with Demodex blepharitis who had more than 10 collarettes on the upper eyelid, at least mild erythema of the upper eyelid margin and at least 1.5 mites per lash on the upper and lower eyelids combined.
At day 43 of treatment, the study met its primary endpoint with 44% of patients on TP-03 with no more than two collarettes (grade 0) compared with 7% in the vehicle arm (P < .0001). The study also demonstrated that 81% of patients on TP-03 achieved a clinically meaningful collarette cure (10 or fewer collarettes, grade 0 or 1) compared with 23% of patients who received vehicle (P < .0001). In the secondary endpoint, 44% of patients who received TP-03 achieved complete collarette cure compared with 7% of patients in the vehicle arm at day 43 (P < .0001).
Resolution of collarettes is critical to Demodex blepharitis treatment. The reduction seen in the trial amounted to patients initially having as many as 100 involved lashes to as little as two or fewer after treatment, Yeu said.
“The most impressive part of this is that the statistically significant spread between TP-03 and vehicle was seen as early as day 8 and definitely by day 14,” she said. “This shows that TP-03 is something we can use and see results rapidly in our patients, and that is a huge advantage.”
TP-03 also demonstrated a good safety profile with high patient tolerance. Yeu said the solution is lipophilic, so it is absorbed easily into the lash follicles where mites reside, does not require scrubbing or rubbing into the eyelids, and does not have adverse events such as blurred or decreased vision, which may occur with the ointments typically used. Ninety-two percent of patients found the drop to be neutral to very comfortable to use for the duration of the 43-day study, another favorable benefit because topical drops can lead to different levels of discomfort at different time points of usage, with some leading to greater negative symptoms with longer duration of use, according to Yeu.
“Patients really dislike ointments, and compliance can be an issue,” Yeu said. “To have a drop that is convenient to use and doesn’t blur the vision is a wonderful attribute of the medication itself.”
Pipeline and unmet needs
When it comes to future treatments, Yeu said they should have a few key attributes: fast action, comfort and the ability to address more than just the chronic inflammatory component of dry eye.
“The most exciting prospect for me is the ability to treat higher up in the cascade because two drops a day from our anti-inflammatories is not enough to negate all of the different risk factors,” she said. “We need something that is going to be a little bit more effective in preventing the byproduct, as well as mitigating the inflammation.”
CyclASol (0.1% cyclosporine A in EyeSol, Novaliq/Bausch + Lomb) is a water-free formulation currently in phase 3 trials. In a previous phase 2/3 clinical trial, CyclASol demonstrated significant improvements in sign and symptom endpoints after 4 weeks of treatment.
Water-free treatment formulations are an important area for drug development in dry eye, according to Periman.
“Water-free systems have a very low surface tension and augment the tear film in a really unique way,” she said. “They also have the advantage of eliminating the need for preservatives.”
While there have been advancements in dry eye disease treatment, some unmet needs linger. Near the top of that list, according to Gupta, is effective at-home treatments.
“We have a lot of in-office treatments, which are highly successful, but it would be nice to have a medication that patients can use at home that helps maintain the effectiveness of in-office therapies,” she said.
With so many treatments in development and emerging in practice, Periman said it will be critical to determine where they all fit in.
“It can be a little overwhelming to have all these new tools come to the fore and difficult to keep up with what they all do and what they’re best for,” she said. “It would be nice to see some continuing education on these new tools and where they fit into the complex clinical scenarios that we call ocular surface disease.”
Periman said that patient education needs to be improved, with resources such as Myze aiming to bridge that gap.
“These education pieces are key to integrating the innovations,” she said. “The landscape of treatment options may look complicated to clinicians and to patients at first blush, but there are clear paths forward to streamline the process for our colleagues and their patients”
The final piece of the puzzle is getting these treatments to patients; however, Periman said the prior authorization process remains a significant hurdle.
“I want see some radical innovation around the prior authorization process from insurance companies,” she said. “There needs to be a course correction in the escalation of prior authorizations from insurance companies, so that we can get these disease state-controlling, quality of life-enhancing new therapeutics into patients’ hands.”
- References:
- Farid M, et al. ONSET-2 phase 3 trial of OC-01 (varenicline solution) nasal spray for the treatment of the signs and symptoms of dry eye disease. Presented at: American Academy of Ophthalmology meeting; Nov. 12-15, 2021; New Orleans.
- Kala Pharmaceuticals announces FDA approval of Eysuvis for the short-term treatment of the signs and symptoms of dry eye disease. https://investors.kalarx.com/news-releases/news-release-details/kala-pharmaceuticals-announces-fda-approval-eysuvistm-short-term. Published Oct. 27, 2020. Accessed Dec. 20, 2021.
- Kala Pharmaceuticals announces statistically significant results for primary and key secondary endpoints in STRIDE 3 clinical trial evaluating Eysuvis for signs and symptoms of dry eye disease. https://www.businesswire.com/news/home/20200309005294/en/Kala-Pharmaceuticals-Announces-Statistically-Significant-Results-for-Primary-and-Key-Secondary-Endpoints-in-STRIDE-3-Clinical-Trial-Evaluating-EYSUVIS%E2%84%A2-for-Signs-and-Symptoms-of-Dry-Eye-Disease. Published March 9, 2020. Accessed Dec. 20, 2021.
- Tarsus Pharmaceuticals, Inc. announces positive results of Saturn-1 pivotal trial evaluating TP-03 for the treatment of Demodex blepharitis. https://ir.tarsusrx.com/news-releases/news-release-details/tarsus-pharmaceuticals-inc-announces-positive-results-saturn-1. Published June 21, 2021. Accessed Dec. 20, 2021.
- Trattler WB, et al. Clin Ophthalmol. 2017;doi:10.2147/OPTH.S120159.
- For more information:
- Kenneth A. Beckman, MD, FACS, can be reached at Comprehensive EyeCare of Central Ohio, 450 Alkyre Run Drive #100, Westerville, OH 43082; email: kenbeckman22@aol.com.
- Preeya Gupta, MD, can be reached at Triangle Eye Associates, 2075 Renaissance Park Place, Cary, NC 27513; email: preeyakgupta@gmail.com.
- Laura M. Periman, MD, can be reached at Periman Eye Institute, 320 W. Galer St., Seattle, WA 98119; email: dryeyemaster@gmail.com.
- Elizabeth Yeu, MD, can be reached at Virginia Eye Consultants, 241 Corporate Blvd., Norfolk, VA 23502; email: eyeu@cvphealth.com.
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