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Exciting products on the horizon for dry eye therapy

The premium surgeon should soon have access to novel therapeutic approaches to go along with advanced diagnostic technologies.

The world of ocular surface disease has drawn great attention over the last few years, due mainly to the large expansion of diagnostic technologies to help decipher the dry eye code.

Tear osmolarity (TearLab), MMP-9 detection (InflammaDry, RPS), Lipi-View and LipiView II with dynamic meibomian imaging (TearScience), in-office allergy skin testing (Doctors Allergy) and Sjö testing for early disease stage antibody detection (Bausch + Lomb) are just a few of the tools in the ever-expanding diagnostic armamentarium of dry eye disease. Nevertheless, our therapeutic approach to dry eye has been fairly limited in growth relative to this diagnostic expansion. Current mainstay treatments have been excellent thus far but limited to Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan) for long-term anti-inflammatory control with minimal to no side effects, short-term pulsed topical steroid therapy such as Lotemax (loteprednol 0.5% gel, Bausch + Lomb), punctal plugs, autologous serum drops (inconvenient for patients), advanced artificial tear formulations such as Refresh Optive Advanced (Allergan), Systane Balance (Alcon) and Soothe XP (Bausch + Lomb), and long-term omega therapy such as HydroEye (ScienceBased Health) with its unique omega gamma-linolenic acid anti-inflammatory activity or PRN’s Dry Eye Omega therapy. The good news is that many products are in the pipeline and may be available to the premium surgeon as soon as the fourth quarter this year.

Lifitegrast, mucin enhancers

The newest anti-inflammatory in its final FDA approval phase is topical lifitegrast 5% (Shire) applied twice daily for up to 12 weeks in the OPUS-2 and OPUS-3 clinical trials. Lifitegrast is a small molecule integrin antagonist that inhibits T cell activation by blocking two key cellular surface proteins, lymphocyte function-associated antigen 1 and its binding to intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is overexpressed in corneal and conjunctival tissues in dry eye disease. Lifitegrast is fast acting and aqueous soluble; the 7.0 pH is close to that of the natural tear film, and the drug potentially is complementary with Restasis therapy. It may be the first drug to be approved for both signs and symptoms of dry eye disease treatment.

Mucin enhancers are currently in clinical trials as well, based on the presence of mucin as one of the three key tear film layers. MIM-D3 (Mimetogen Pharmaceuticals) is a mimetic of nerve growth factor, a secretagogue for mucin, which stimulates mucin MUC5AC from conjunctival goblet cells. The treatment is currently in phase 3 trials, and phase 2 showed improvement in signs and symptoms of dry eye at week 8 of treatment. Rebamipide suspension (Otsuka Pharmaceuticals) increases mucin production in the conjunctiva as well and is also in phase 3 trials, with phase 2 results meeting the threshold of noninferiority and superiority to sodium hyaluronate in corneal and conjunctival staining tests; in addition, it was better than placebo in relieving foreign body sensation, eye pain and blurred vision.

Delivery systems

Different delivery systems such as nanotechnology, iontophoresis and intracanalicular punctal plugs are novel approaches to getting drug to work more effectively in dry eye. Nanotechnology involves drug encapsulation to allow rapid penetration in mucosal tissues. KP-121 (Kala Pharmaceuticals) is in phase 2 trials, looking at loteprednol etabonate mucus-penetrating particle 0.25% in meibomian gland dysfunction vs. placebo. Valeant Pharmaceuticals is looking at a 0.38% formulation of low-dose loteprednol etabonate in a nanoparticle-based vehicle for pain and inflammation after cataract surgery.

Iontophoresis is a noninvasive technique of delivering any drug that has a positive or negative charge to the eye with a secondary electrode on the forehead that drives that charge through the eye. EyeGate Pharmaceuticals is looking at iontophoresis of a dexamethasone formulation (EGP-437) in a phase 3 trial for anterior uveitis, and so far it has been statistically superior to topical prednisolone without any IOP rise. Phase 2 trials for dry eye, however, did not meet statistical significance. Nevertheless, this technique is new and bold and may prove to be a long-term approach for more severe dry eye disease in the future. Lastly, sustained release of dexamethasone administered as a one-time absorbable intracanalicular plug placed in the lower punctum (OTX-DP, Ocular Therapeutix) and designed for a 4-week tapered release recently was submitted as a new drug application to the FDA for pain control in cataract surgery patients.

There were no IOP spikes or adverse events, and with punctal plugs already popular for dry eye treatment, this approach appears promising for dry eye and/or ocular allergy in low steady doses.

Recombinant human serum albumin, or RU-101 (R-Tech Ueno), has been deemed safe thus far in an ophthalmic solution in a phase 1 trial; the maximum safety dose up to 12 weeks in a phase 2 trial is underway for efficacy in severe dry eye disease. Human albumin protein by itself is a potent anti-inflammatory, especially in wound healing, and could translate in repair of the ocular surface in severe dry eye disease. Autologous human serum tears have already been proven to work, but they are cumbersome, expensive, difficult to access and have a slight risk for infection once compounded.

In the end, there are many potential novel dry eye therapeutic approaches on the horizon, ready to meet the diagnostic technological advances that already exist for dry eye disease.

Disclosure: Jackson reports he is a consultant for Bausch + Lomb, Ocular Therapeutix, ScienceBased Health and Allergan.

The world of ocular surface disease has drawn great attention over the last few years, due mainly to the large expansion of diagnostic technologies to help decipher the dry eye code.

Tear osmolarity (TearLab), MMP-9 detection (InflammaDry, RPS), Lipi-View and LipiView II with dynamic meibomian imaging (TearScience), in-office allergy skin testing (Doctors Allergy) and Sjö testing for early disease stage antibody detection (Bausch + Lomb) are just a few of the tools in the ever-expanding diagnostic armamentarium of dry eye disease. Nevertheless, our therapeutic approach to dry eye has been fairly limited in growth relative to this diagnostic expansion. Current mainstay treatments have been excellent thus far but limited to Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan) for long-term anti-inflammatory control with minimal to no side effects, short-term pulsed topical steroid therapy such as Lotemax (loteprednol 0.5% gel, Bausch + Lomb), punctal plugs, autologous serum drops (inconvenient for patients), advanced artificial tear formulations such as Refresh Optive Advanced (Allergan), Systane Balance (Alcon) and Soothe XP (Bausch + Lomb), and long-term omega therapy such as HydroEye (ScienceBased Health) with its unique omega gamma-linolenic acid anti-inflammatory activity or PRN’s Dry Eye Omega therapy. The good news is that many products are in the pipeline and may be available to the premium surgeon as soon as the fourth quarter this year.

Lifitegrast, mucin enhancers

The newest anti-inflammatory in its final FDA approval phase is topical lifitegrast 5% (Shire) applied twice daily for up to 12 weeks in the OPUS-2 and OPUS-3 clinical trials. Lifitegrast is a small molecule integrin antagonist that inhibits T cell activation by blocking two key cellular surface proteins, lymphocyte function-associated antigen 1 and its binding to intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is overexpressed in corneal and conjunctival tissues in dry eye disease. Lifitegrast is fast acting and aqueous soluble; the 7.0 pH is close to that of the natural tear film, and the drug potentially is complementary with Restasis therapy. It may be the first drug to be approved for both signs and symptoms of dry eye disease treatment.

Mucin enhancers are currently in clinical trials as well, based on the presence of mucin as one of the three key tear film layers. MIM-D3 (Mimetogen Pharmaceuticals) is a mimetic of nerve growth factor, a secretagogue for mucin, which stimulates mucin MUC5AC from conjunctival goblet cells. The treatment is currently in phase 3 trials, and phase 2 showed improvement in signs and symptoms of dry eye at week 8 of treatment. Rebamipide suspension (Otsuka Pharmaceuticals) increases mucin production in the conjunctiva as well and is also in phase 3 trials, with phase 2 results meeting the threshold of noninferiority and superiority to sodium hyaluronate in corneal and conjunctival staining tests; in addition, it was better than placebo in relieving foreign body sensation, eye pain and blurred vision.

Delivery systems

Different delivery systems such as nanotechnology, iontophoresis and intracanalicular punctal plugs are novel approaches to getting drug to work more effectively in dry eye. Nanotechnology involves drug encapsulation to allow rapid penetration in mucosal tissues. KP-121 (Kala Pharmaceuticals) is in phase 2 trials, looking at loteprednol etabonate mucus-penetrating particle 0.25% in meibomian gland dysfunction vs. placebo. Valeant Pharmaceuticals is looking at a 0.38% formulation of low-dose loteprednol etabonate in a nanoparticle-based vehicle for pain and inflammation after cataract surgery.

Iontophoresis is a noninvasive technique of delivering any drug that has a positive or negative charge to the eye with a secondary electrode on the forehead that drives that charge through the eye. EyeGate Pharmaceuticals is looking at iontophoresis of a dexamethasone formulation (EGP-437) in a phase 3 trial for anterior uveitis, and so far it has been statistically superior to topical prednisolone without any IOP rise. Phase 2 trials for dry eye, however, did not meet statistical significance. Nevertheless, this technique is new and bold and may prove to be a long-term approach for more severe dry eye disease in the future. Lastly, sustained release of dexamethasone administered as a one-time absorbable intracanalicular plug placed in the lower punctum (OTX-DP, Ocular Therapeutix) and designed for a 4-week tapered release recently was submitted as a new drug application to the FDA for pain control in cataract surgery patients.

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There were no IOP spikes or adverse events, and with punctal plugs already popular for dry eye treatment, this approach appears promising for dry eye and/or ocular allergy in low steady doses.

Recombinant human serum albumin, or RU-101 (R-Tech Ueno), has been deemed safe thus far in an ophthalmic solution in a phase 1 trial; the maximum safety dose up to 12 weeks in a phase 2 trial is underway for efficacy in severe dry eye disease. Human albumin protein by itself is a potent anti-inflammatory, especially in wound healing, and could translate in repair of the ocular surface in severe dry eye disease. Autologous human serum tears have already been proven to work, but they are cumbersome, expensive, difficult to access and have a slight risk for infection once compounded.

In the end, there are many potential novel dry eye therapeutic approaches on the horizon, ready to meet the diagnostic technological advances that already exist for dry eye disease.

Disclosure: Jackson reports he is a consultant for Bausch + Lomb, Ocular Therapeutix, ScienceBased Health and Allergan.