New Drugs for Dry Eye and Demodex Blepharitis

We are fortunate to be practicing optometry in these times. We have so many innovations and new treatment options for our patients with dry eye. I would almost even call 2023 the “Year of Dry Eye,” with at least three new medications gaining and/or potentially gaining FDA approval for the treatment of dry eye disease (DED) and Demodex blepharitis. This article reviews new approvals, treatments that may gain FDA approval this year, and what’s in the pipeline.

FDA-APPROVED

In October 2021, Oyster Point Pharma received FDA approval for varenicline solution nasal spray 0.03 mg (Tyrvaya) for the treatment of the signs and symptoms of DED.¹ Varenicline is the first nasal spray approved for this indication, and it is the only dry eye medication that works by chemical neural stimulation through the nose. Varenicline nasal spray is believed to bind to cholinergic receptors to activate the trigeminal parasympathetic pathway via the nose to produce more of our basal tears, not reflex tears.¹ This pathway innervates the lacrimal functional unit, which includes the goblet cells, lacrimal glands, and meibomian glands.^2,3 Thus, it is important to note that varenicline nasal spray helps increase the secretion of our natural tears, consisting of all three layers (the mucin, aqueous, and lipid layers).

Initial clinical trials showed that after 4 weeks of use, close to 50% of patients had a greater than 10 mm increase in Schirmer test scores and a statistically significant improvement in symptoms of dry eye.⁴ In a smaller study, patients had an increase in basal cell tear production even after 12 weeks.⁵

Varenicline nasal spray is nonpreserved, so it is great for patients who are sensitive to preservatives. The most common side effect is sneezing, with 82% of patients experiencing sneezing during clinical trials.⁵ This usually resolves after about a week of continued use. The nasal spray is used every 12 hours, which is ideal for patients who are already using at least one eye drop, contact lens wearers, patients who wear eye makeup, and those who may have difficulty using eye drops due to dexterity issues.

An interesting update on the efficacy of varenicline nasal spray was published several months ago. An analysis of integrated data from two randomized clinical trials, ONSET-1 and ONSET-2, was completed, which included patients with both mild to moderate and severe forms of DED. The analysis noted that, “Compared with vehicle control, varenicline solution nasal spray improved tear production and patient-reported symptoms in patients with dry eye disease, demonstrating the consistency of effect regardless of initial presenting severity.”⁶ Therefore, regardless of severity level, varenicline improved DED.

On a personal note, in my clinic, I have noticed that combining varenicline nasal spray and cyclosporine 0.09% (Cequa, Sun Pharma) has been incredibly helpful in treating my patients with moderate to severe DED. Based on conversations with colleagues, many have noticed this also. This combination of treatments is something that would be an interesting study in the future.

Oyster Point Pharma was acquired by Viatris in January as part of its new eye care division. Stay tuned for the possibility of more new and exciting medications in the pipeline as a result of this acquisition.

NEW FDA APPROVAL IN 2023

MIEBO

The newest dry eye medication gaining FDA approval in 2023 is 100% perfluorohexyloctane (MIEBO; formerly known as NOV03, Novaliq/Bausch + Lomb). This first-in-class ophthalmic drug was developed to treat DED associated with meibomian gland dysfunction and directly targets evaporation.^7,8 It also contains EyeSol technology from Novaliq.⁷ EyeSol technology is unique in that it allows the drop to stay on the eye for up to 240 minutes, as opposed to traditional water-based drops on the market, which only last about 3 to 5 minutes.⁹ MIEBO prevents excessive tear evaporation and helps to restore tear film balance.⁷ It is water-free and preservative-free. According to the website, this drug can stabilize the lipid layer for hours and penetrate the meibomian glands.⁷ It essentially acts like a shield to protect the ocular surface.

In the two pivotal phase 3 studies (GOBI and MOJAVE) which enrolled 1,217 patients, MIEBO demonstrated significant improvement in signs and symptoms versus the control as early as day 15 and through day 57.^7,8 Also in these studies, MIEBO met both primary endpoints in sign and symptoms which were changes in total corneal fluorescien staining and eye dryness Visual Analog Score.⁸

ANTICIPATED FDA APPROVALS IN 2023

TP-03

If approved, lotilaner 0.25% (TP-03, Tarsus Pharmaceuticals) will be a first-in-class therapy for the treatment of Demodex blepharitis. The expected PDUFA date is August 25, 2023. TP-03 works by paralyzing Demodex mites. It is lipophilic, which promotes the drug’s uptake in the oily sebum of the hair follicle, where the Demodex mites live.¹⁰

According to Tarsus’ website, “An analysis of the study (Titan) showed a high collarette prevalence among eye care patients with glaucoma (65%), those taking a dry eye prescription treatment (60%), those with cataracts (56%) and among contact lens users (51%). The data also showed a high prevalence of collarettes among patients using TTO (75%) and lid wipes (57%) to manage their disease.”¹¹ Therefore, traditional therapies that we have been using to treat Demodex may not be effective (see Don’t Forget to Look at the Lids).

Strong and consistent data for TP-03 were released in May 2022 from the Saturn-2 phase 3 trial, with endpoints achieved by day 43.¹² Complete collarette cure was achieved in 56% of patients (zero to two collarettes), and clinically meaningful collarette cure was achieved in 89% of patients (more than 90% reduction). Mite eradication was achieved in 52% of patients by week 2 (zero mites on eyelash epilation), lid erythema was cured in 31% of patients by week 3, and lid erythema was improved in 54% of patients.¹² TP-03 was found to be generally safe and well-tolerated in the Saturn-2 trials, similar to Saturn-1 trials.¹² Therefore, combined data show that consistent cures and responses were demonstrated in two pivotal trials involving a total of more than 800 patients.¹²

Reproxalap

A third potential first-in-class medication is also in the works. The novel small-molecule drug candidate 0.25% topical ocular reproxalap (Aldeyra Therapeutics) is being studied for the reduction of ocular inflammation in DED by inhibiting reactive aldehyde species (RASPs), which are elevated in a variety of inflammatory diseases, such as allergic conjunctivitis and dry eye.^9,13

In the phase 2b clinical trial, reproxalap demonstrated broad activity and improvement across a wide variety of symptoms and signs in patients with DED when compared with the vehicle.¹³ Topical ocular reproxalap has been studied in more than 1,800 patients with no observed safety concerns; mild and transient instillation site discomfort was the most commonly reported adverse event in clinical trials.¹³ The PDUFA date is November 23, 2023.¹⁴

ON THE HORIZON

AZR-MD-001 0.5% (Azura Ophthalmics) is a selenium sulfide (keratolytic) ophthalmic ointment designed to impede hyperkeratinization of the meibomian glands.¹⁵ AZR-MD-001’s mechanisms of action are that it breaks down the bonds between abnormal keratin in order to soften the blockage, as well as slows down the production of keratin to prevent future blockages.¹⁵ This action will help improve the quality and quantity of the meibum. In December, the company announced positive 3-month efficacy and safety results from its phase 2b clinical trial of AZR-MD-001.¹⁵ The trial met its coprimary endpoints of improvement in Meibomian Glands Yielding Liquid Secretion (MGYLS; number of glands secreting meibum) and Ocular Surface Disease Index score (OSDI; improved symptoms).¹⁵ Azura states that it expects to advance AZR-MD-001 into a pivotal phase 3 trial this year.¹⁶

DED CAN REQUIRE MULTIPLE FORMS OF TREATMENT

We know that the cause of DED is multifactorial. Therefore, patients may require many different forms of treatment to find the plan that is best suited for their individual needs.

We have so many more options now to treat our patients with DED. This is an exciting time for sure! With these new treatment choices available, more personalized therapy and management is easier and more successful than ever.