As the clinical battle against the growing prevalence of dry eye continues, the industry has responded with new products and novel approaches to address this debilitating condition afflicting millions of patients. The most common approach begins with an artificial tear regimen, and, if ineffective, a prescription eye drop. Continued dosing compliance remains challenging, as over two-thirds of patients using topical agents terminate their use within one year.¹ This high discontinuation rate is owed in part to medication side effects or perceived lack of effectiveness.

Artificial tears and eye drops are formulated to readily wet, spread and adhere to the ocular surface in mild-to-moderate dry eye disease (DED) patients. However, although new products continue to advance, evidence shows they do not provide the necessary relief to the severe dry eye patients who are most in need.²

Simply put, the ingredients used in over-the-counter lubricant and emulsion eye drops lack the biochemistry to provide the necessary coating properties to both protect and heal the ocular surface. The creation of novel excipients that meet the FDA safety criteria under the artificial tear monograph provides an expedient path to market the product over-the-counter. But there is a unique and possibly game-changing eye drop that’s likely to become available in the next six months—SilkTears (Silk Technologies). Studies show promising results for the use of silk-derived protein (SDP) as a novel wetting agent in dry eye drops, which also demonstrates natural anti-inflammatory and wound healing properties in both in vitro and in vivo animal studies.

Importance of Mucin in Tear Film

The natural tear film is complex, multilayered and multifunctional, and crucial in protecting the corneal surface from both physical and biological harm. It uses mucin protein to maintain a healthy ocular surface, which provides the innermost tear film complex, adherent to and in contact with the superficial epithelial layer of the hydrophobic corneal surface. Mucin creates a biological surface that simultaneously adheres to the cornea and aqueous tear layer to aid wetting and tear film spreading over the ocular surface.³ Its bimodal function minimizes light scatter through the cornea and provides comfort as a protective coating over the ocular surface. This coating creates a smooth refractive surface, covers the sensitive nerve endings that integrate with the epithelial layer and shields the ocular surface from the potentially abrasive inner eyelid motion. In many severe dry eye patients, mucin production and tear secretion are highly dysregulated and unable to coat the ocular surface effectively. The development of biological ingredients, such as proteins, is paramount to recreate the natural tear film.

Until now, the use of proteins has been largely relegated to autologous serum eye drops. There has been increasing promise in eye drops containing exosomes derived from explanted human placental mesenchymal stromal cells.⁵ However, the regulatory pathway to FDA approval for highly heterogenous blood-derived products is arduous and expensive. The introduction of better characterized, non-blood or animal tissue-derived proteins with mucin-like properties represents a significant advancement in eye drop formulation.

SDP-4 (1% w/w) was formulated within a preservative-free artificial tear formulation (SilkTears). SDP-4 improves formulation (A) surface wetting and (B) coating adherence properties as demonstrated when added to saline, and then placed on a wax surface. Click image to enlarge.

SDP

One such material that meets these criteria is called silk fibroin protein, which is non-toxic and non-immunogenic. Fibroin utility in biomedical applications has been under development for the past three decades, including applications in corneal tissue engineering, ocular surface repair and regenerating the corneal endothelium.^6-8 Fibroin has been successfully shown in a mouse model to increase tear production, improve corneal smoothness and provide a complete recovery of both corneal epithelial and conjunctival goblet cells.⁹ In addition, the expression of inflammatory factors was inhibited across the ocular surface and in the lacrimal glands. However, fibroin is highly unstable in solution and irreversibly aggregates after only a few weeks, making it impractical for use in shelf-stable commercial eye drops in the past.

To overcome solution instability, SDP, a novel, hydrolysate derived from fibroin, is highly soluble and stable in aqueous formulation and acts as a wetting agent with known anti-inflammatory activity. SDP has been shown to enhance wound healing and reduce inflammatory markers both in vitro and in vivo.¹⁰ When evaluating the use of SDP in vitro on a human corneal limbal-epithelial scratch assays, cell migration increased over 50%, with an approximate 60% increase in proliferation and nearly 30% decrease in scratch wound closure time.¹⁰ These results were corroborated in vivo using a rabbit model, in which there was a three-fold increase in the acute wound healing and an improved tissue healing profile through the formation of healthy epithelium and increased tight junctions.¹¹ Additional biological effects included increased epithelial proliferation with a concomitant reduction in the presence of MMP-9, a known pro-inflammatory mediator of DED.

Results of two FDA clinical trials showing improvement in signs (TBUT) and symptoms (SANDE). Click image to enlarge.

SDP-4 in SilkTears

Further work was performed in which a clinical-grade version of SDP, termed SDP-4, was formulated as an excipient into a topical formulation containing polysorbate as the active agent, and then used to treat moderate-to-severe dry eye in FDA-sponsored clinical trials. Patients diagnosed with dry eye for up to over six months were enrolled for 12 weeks in a dual cohort, multi-center, double-masked and vehicle-controlled study. The first cohort of subjects had moderate to severe baseline symptoms while the second had moderate baseline symptoms.

Eye drops containing 1% SDP-4 significantly increased tear break-up time (TBUT) from baseline, even for severe patients. On average, patients treated with the 1% SDP-4 concentration witnessed a 78% improvement. In addition, patient symptomatology from baseline continued to improve throughout the 84-day study, reaching an average total SANDE score reduction of 30 points, which was equivalent to a 46% average reduction in symptoms across the treated patient population. Patients with more severe baseline dry eye symptoms experienced significantly improved relief as early as day 14 and continued to day 56. Lastly, all SDP-4 treatment groups were well-tolerated with a low (2.6%) discontinuation rate across both cohorts. Collectively, the results strongly suggest that SDP-4-containing eye drop formulations offer a safe approach to aid in the relief of severe dry eye symptoms.

SDP-4 allows for the reduction of formulated excipients for a simpler—and ultimately healthier—approach to recreate the natural tear film chemistry, which is critical in formulations destined for chronic conditions such as DED and will provide a much-needed treatment in the battle against ocular surface disease

Dr. Karpecki is the director of Cornea and External Disease for Kentucky Eye Institute, associate professor at KYCO and medical director for Dry Eye Institutes of Kentucky and Indiana. He is the Chief Clinical Editor for Review of Optometry and chairman of the affiliated New Technologies & Treatments conferences. A fixture in optometric clinical education, he provides consulting services to a wide array of ophthalmic clients. Dr. Karpecki’s full disclosure list can be found here.