Focus on Dry Eye

Assessing the dry eye drug pipeline

Many new concepts show promise.

By Salim Butrus, MD

About the Author
	Salim Butrus, MD, is in solo private practice at the Eye Center on Capitol Hill in Washington, D.C. He is affiliated with Georgetown University Hospital, where he teaches, conducts research and performs complex procedures. Disclosure: Dr. Butrus has disclosed no relevant conflicts with any companies mentioned in this article.

The battle to combat the inflammation that has been identified as one of the primary characteristics of dry eye disease goes back hundreds of years.

We can trace the development of anti-inflammatories back to willow bark, which had long been known to have beneficial therapeutic properties. These were first characterized as early as 1763, and in 1897 were isolated and prepared commercially by Bayer. Today we call it salicylic acid, or aspirin. In 1948, Edward Calvin Kendall, PhD, revolutionized the treatment of inflammation with the discovery of steroids. Options to fight inflammation were further expanded by nonsteroidal anti-inflammatory agents (NSAIDs) in the last half of the 20th century.

NEW TREATMENTS NEEDED

As ophthalmologists, we have come a long way in the treatment of ocular inflammatory and immunemediated diseases such as dry eye syndrome, blepharitis, ocular allergy, uveitis, scleritis, chorioretinitis, glaucoma, macular edema and AMD. Nevertheless, we do not as yet have a complete armamentarium of treatment options with an optimal risk-benefit ratio, and we still rely too heavily on steroids to treat inflammation, dealing with their well–known adverse effects.

With regard to dry eye, scleritis and other diseases whose etiologies are not completely elucidated or are not solely inflammatory in origin, the potential treatment options lag behind those available for treatment of analogous systemic diseases. Underscoring this point is the fact that a decade after the approval of Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan, Irvine, Calif.), it is still the only prescription drug approved for the treatment of dry eye. But that may be changing soon. Here, we will explore the pipeline of investigational drugs, some of which are likely to constitute the next generation of therapies for the treatment of dry eye disease.

Dry eye numbers growing

Figures for the incidence of dry eye disease vary, but using a broad range of estimates, from 5% to 30% of people in the United States experience dry eye symptoms, with the incidence increasing with age.¹ One recent analysis by researchers at the University of Utah indicated that the average annual cost of managing a patient with dry eye was $783 from the payers’ perspective. When adjusted to the prevalence of dry eye disease nationwide, the overall burden for the US health-care system would be $3.84 billion. ²

From a societal perspective, the average cost of managing dry eye disease was estimated to be $11,302 per patient.² These costs take into account that the majority of patients experience mild to moderate symptoms, although these are easily exacerbated by frequent computer use or low humidity conditions.

Triggers for dry eye disease

This complex ocular condition has a significant, but not exclusive, inflammatory component. Elevated tear film osmolarity, a universal feature of dry eye disease, stimulates the production and release of cytokines. This is mediated by a group of key signaling molecules called mitogen-activated protein kinases (MAPKs), which have three subgroups: C-jun n-terminal kinase (JNK), extracellular signal regulated kinases (i.e., ERK) and P38 MAPK.

We can identify three major players in the etiology of dry eye disease:

• T-cell activation.

• Increased production of cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-a.

• Production of matrix metalloproteinases (MMP) such as MMP-1, MMP-9, and MMP-13.

Elevated tear levels of MMP-9 in patients with dry eye disease have been shown to cause conjunctival epithelial desquamation, increased apoptosis and cell death. We have growing evidence that inflammation on the ocular surface is responsible in large part for the ocular surface epithelial disease and irritating symptoms that develop in dry eye disease.

Restasis is only a start

Various types of anti-inflammatory agents have been used in treating dry eye disease, including topical corticosteroids, oral tetracyclines, oral omega-3 dietary supplements and Restasis, but clearly there is room for newer and different therapeutic concepts that could provide ophthalmologists with a larger arsenal of weapons to combat dry eye disease. For example, Allergan currently has a next-generation version of Restasis in phase 2 clinical trials.

Restasis is considered a breakthrough in the treatment of dry eye disease. It is an immunomodulatory agent that prevents the synthesis and secretion of proinflammatory cytokines such as TNF-a and IL-6. In clinical trials, Restasis was shown to improve Schirmer test values in a subset of dry eye subjects.

Nevertheless, Restasis addresses only some of the inflammatory components relevant to dry eye disease. The investigational therapies we list here display a wide variety of mechanisms that could prove beneficial in treating patients who do not respond sufficiently to existing dry eye therapies.

INVESTIGATIONAL DRY EYE THERAPIES

Candidates in study phase

Ongoing clinical studies are targeting different pathways in dry eye disease. They include:

• Tofacitinib (Pfizer, New York), a topical ophthalmic Janus kinase (JAK) inhibitor.

• Kineret (Amgen, Thousand Oaks, Calif.), an interleukin- 1 (IL-1) receptor antagonist.

• EBI-005 (Eleven Biotherapeutics, Cambridge, Mass.), an IL-1 signaling inhibitor;

• MIM-D3 (Mimetogen, Montreal, recently optioned to Bausch + Lomb), the tyrosine kinase receptor agonist.

• Lifitegrast, an integrin antagonist (Shire plc, Dublin, Ireland).

• Mucin-stimulating drugs such as rebamipide (Otsuka Pharmaceuticals, Tokyo) and diquafosol (Merck, Whitehouse Station, N.J.).

• Dual JAK/spleen tyrosine kinase Syk inhibitors (Aciex Therapeutics, Boston).

Tofacitinib

In 2012, Melissa Liew, MBBS, MRCophth, and colleagues published the results of a clinical trial in subjects with dry eye disease using topical ophthalmic tofacitinib, which has proven to be successful orally in the treatment of rheumatoid arthritis. ³

Eighty-two patients with moderate to severe dry eye disease received concentrations of 0.003% or 0.001% B.I.D. or 0.005% once daily, compared to a negative control (vehicle) and active control (cyclosporine 0.05% emulsion) B.I.D. for eight weeks. The investigators analyzed conjunctival cells for cytokines and inflammatory markers.

Results showed a decrease in human leukocyte antigen (HLA-DR) conjunctival cell surface expression in patients who received 0.005% once daily and 0.003% B.I.D.: 71% and 67%, respectively, compared to a 33% increase in HLA-DR expression in the vehicle group. Cytokines such as MMP3 in tears were reduced to 40% of baseline at eight weeks in the 0.005% group compared to 77% of baseline in the vehicle group. IL-1β also showed a decrease to about 36% of baseline compared to 85% in the vehicle group. The investigators observed an association between changes in HLA-DR and tear inflammatory markers.³

Kineret

A randomized clinical trial studied the efficacy of the topical IL-1 receptor antagonist kineret in 75 patients with refractory dry eye disease and meibomian gland dysfunction. The study assessed T.I.D. treatment for 12 weeks two concentrations, 2.5% (N=30) and 5.0% (N=15) kineret, compared to vehicle control (N=30, 1% carboxymethyl cellulose), evaluating corneal fluorescein (CF) staining, bilateral CF clearing, dry eyerelated symptoms, tear film break-up time (TBUT) and meibomian gland quality.

CF staining was reduced by 46% in the 2.5% kinerettreated group, 17% in the 5% kineret group and 19% in the vehicle group. The 2.5% kineret group also showed a 30% reduction in symptoms, the 5% kineret group, a 35% reduction, and the vehicle group, a 5% reduction. These results indicate that topical 2.5% kineret treatment for 12 weeks is safe and significantly reduced the symptoms and corneal epitheliopathy of patients with dry eye disease.⁴

EBI-005

Eleven Biotherapeutics recently announced positive clinical results from a six-week randomized, double-masked, placebo-controlled phase 1b/2a study of EBI- 005 in patients with dry eye disease. The company says EBI-005 reflects a new approach to the treatment of dry eye disease and is the first IL-1 signaling inhibitor designed for topical ocular administration.

EBI-005 demonstrated statistically significant improvements in signs and symptoms of dry eye vs. baseline, the company said. EBI-005 also met the predefined efficacy criteria of the study and showed a differential effect between subjects who received EBI-005 and those who received only the vehicle. Data showed that EBI-005 was generally safe and well tolerated.

MIM-D3

MIM-D3 is a proteolytically stable, cyclic peptidomimetic shown to be a partial TrkA receptor agonist. MIM-D3 demonstrates activities similar to nerve growth factor (NGF), but does not bind to the p75NTR receptor, and can potentiate the effects of suboptimal concentrations of NGF.

In vitro studies in cultured primary rat conjunctival cells demonstrated that MIM-D3 stimulated mucin-like secretion and activated MAPK1/2 systems involved with mucin production. In vivo acute topical treatment of rats resulted in a statistically significant 2.3-fold increase in the concentration of tear fluid mucin-like substances. In a scopolamine-induced dry eye model in rats, topical dosing of 1% MIM-D3 followed by one week of no dosing produced a statistically significant 50% reduction in corneal staining; an improvement associated with increased tear mucin-like substances and tear film break-up times.⁵

A clinical study assessed the effects of MIM-D3 in 150 patients randomized to treatment with 1% or 5% MIM-D3 or placebo vehicle B.I.D. for 28 days. Patients were placed in a controlled adverse environment (CAE) at study intervals to determine the protective effects of MIM-D3 during an acute desiccating challenge.

Following exposure to the CAE, patients in the 1% MIM-D3 group showed significant improvements (P < 0.05) in fluorescein and lissamine green staining after 14 and 28 days. Patients in the 5% MIM-D3 group reported significantly lower daily diary scores for ocular dryness (P< 0.05). In a subgroup defined by higher symptom scores during the run-in period, significant treatment effects (P < 0.05) were observed for diary symptoms for both MIM-D3 doses. Ocular adverse events were mild and not considered treatment- related. Treatment with topical ophthalmic MIM-D3 demonstrated protection against the effects of an adverse environmental challenge on signs of dry eye, and in the environment, reduced patient-reported diary symptoms, with a favorable safety profile.⁶

Lifitegrast

Lifitegrast, a small-molecule integrin antagonist, is believed to work by reducing inflammation through binding inhibition of the protein lymphocyte function– associated antigen 1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1), influencing T-cell activation and cytokine (protein) release. The interaction between these two proteins plays a key role in the chronic inflammation associated with dry eye. Shire plc acquired the drug when it purchased SARCode Bioscience this year.

Lifitegrast is administered via a preservative-free topical eye solution.

Three clinical trials — OPUS-1, OPUS-2 and SONATA — make up the phase 3 clinical development program for lifitegrast. OPUS-1, a safety and efficacy study, concluded in 2012. In this study, the co-primary endpoint of reducing signs of dry eye was met. Although the trial did not achieve the co-primary endpoint of reducing symptoms, OPUS-1 provided the basis of a positive meeting with the FDA and for the continuation of the phase 3 clinical program, including OPUS-2, a safety and efficacy study of both signs and symptoms of dry eye disease, which is currently ongoing. SONATA, a randomized, placebo-controlled safety study is also ongoing and fully enrolled. The OPUS-2 study also is fully enrolled, with pivotal headline data expected in the first quarter of 2014.

JAK/Syk inhibitors

In February 2013, Aciex Therapeutics entered into a collaborative agreement with Portola Pharmaceuticals to develop Portola’s kinase inhibitors for ophthalmic indications. The companies are investigating three kinase inhibitors: PRT02070, a combination JAK/Syk inhibitor, and PRT02761 and PRT02607 — two Syk-specific inhibitors. The first is already in the IND stage for systemic use, the second in preclinical development, and the third in phase 1 clinical safety evaluations. These kinase inhibitors are first being screened for use in ocular allergy, and have shown success in preclinical models of allergic conjunctivitis. The companies are also exploring a dry eye indication.

“A decade after the approval of Restasis, it is still the only prescription drug for the treatment of dry eye.”

Other efforts in dry eye therapy

Various other molecules with different mechanisms of action are in the pipeline for treatment of dry eye disease. A new anti-JAK3 agent, known as R932348 (or R348) (Rigel Pharmaceuticals, South San Francisco, Calif.), has demonstrated success in treating dry eye disease in preclinical studies. R348 also inhibits Syk kinase so it has dual JAK/Syk inhibitory action and might have more comprehensive anti-inflammatory activity than other kinase inhibitors.

Mucogenic agents are also undergoing study; two are rebamipide and diquafosol. Otsuka Pharmaceuticals’ rebamipide 2% is a mucin secretagogue already approved for dry eye in Japan. It was shown to be more efficacious than 0.1% sodium hyaluronate in improving dry eye symptoms and decreasing corneal and conjunctival staining.

Merck’s diquafosol trisodium, also known as Prolacria, has been studied at the 3% concentration six times a day. It stimulates the production of tears and mucin through elevation of intracellular Ca++ concentration, and may specifically target dry eye subjects with tear film instability and short break up times.

Finally, another treatment modality in the pipeline for severe dry eye disease is a recombinant human serum albumin (RV-101, R-Tech Ueno, Tokyo).

Continuing advances on the horizon

Ophthalmology continues to take what it can from the wide-scale pharmaceutical development of anti-inflammatory and anti-immunologic agents being studied for systemic diseases. While the ophthalmic market is much smaller, diseases such as dry eye disease and macular degeneration have a huge impact on the worldwide population, and visual function is undoubtedly vitally important. Culling these exciting new molecules for use in the eye should provide continuing advancements in the treatment of ocular inflammatory diseases. OM

REFERENCES

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3. Liew, SH, Nichols KK, Klamerus KJ, et al. Tofacitinib (CP- 690,550) a Janus kinase inhibitor for dry eye disease: results from a phase 1-2 trial. Ophthalmology. 2012;119:1328-1335.

4. Amparo Francisco, Daskjerdi MH, Okanobo, et al. Topical Interleukin1 receptor antagonist for treatment of dry eye disease: a randomized clinical trial. JAMA Ophthalmol. 2013;131:715-723.

5. Jain P, Li R, Saragovi HU, Cumberlidge G, Meerovitch K. An NGF mimetic, MIM-D3, stimulates conjunctival cell glycoconjugate secretion and demonstrates therapeutic efficacy in a rate model in dry eye. Exp Eye Res. 2011;93:503-512.

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