New agents are promising, but approvals are likely several years away.
Michelle Stephenson, Contributing Editor
Dry eye affects an estimated 25 million Americans, with estimates worldwide as high as 60 million people. Patients with dry eye can experience poor vision and chronic pain. Fortunately, there are new drugs in the pipeline that look promising for the treatment of dry eye.
“Between 10 and 15 percent of ophthalmic pharmaceuticals are dry-eye medications, and that percentage is growing. It is projected to double in the next 10 years, so it is a growing niche,” says Leonard Bielory, MD, from Rutgers University and Robert Wood Johnson University Hospital, New Brunswick, NJ.
Lifitegrast (Shire) is a small-molecule integrin antagonist that inhibits T-cell inflammation by blocking the binding of two key cellular surface proteins (LFA-1 and ICAM-1). It is currently in Phase III clinical trials.
OPUS-2 was a multicenter, randomized, double-masked, placebo-controlled, parallel-arm study comparing lifitegrast (5.0% ophthalmic solution) to placebo administered twice daily for 84 days (12 weeks) in dry-eye patients with a history of active artificial tear use within 30 days prior to screening. The study included 718 patients at 31 U.S. sites and consisted of five visits over 98 days.1
Lifitegrast met one of the co-primary endpoints for the patient-reported symptom of improvement of dry eye compared with placebo, but it did not meet a second co-primary endpoint, inferior corneal staining. The secondary endpoints were descriptive only and were consistent with improvement in symptoms and lack of improvement in signs.
None of the patients in this study experienced serious treatment-emergent adverse events. The most commonly reported treatment-emergent adverse events associated with lifitegrast were dysgeusia (16.2 percent vs. 0.3 percent for placebo), instillation site reaction (7.0 percent vs. 1.1 percent for placebo), and reduced visual acuity (5 percent vs. 6.4 percent for placebo).
Additionally, top-line results from SONATA, a prospective, randomized, double-masked, placebo-controlled study, indicated no ocular or drug-related serious adverse events.1 At day 360 of the study, the ocular adverse events that occurred in 5 percent or more of study participants included instillation site irritation (15 percent vs. 4.5 percent with placebo); instillation site reaction (13.2 percent vs. 1.8 percent for placebo), reduced visual acuity (11.4 percent vs. 6.3 percent for placebo), and dry eye (1.8 percent vs. 5.4 percent for placebo). The most commonly reported non-ocular adverse event associated with lifitegrast was dysgeusia (16.4 percent vs. 1.8 percent for placebo).
According to John Sheppard, MD, professor of ophthalmology, microbiology and molecular biology at Eastern Virginia Medical School and president of Virginia Eye Consultants in Norfolk, this agent is the leader of the pack. “It treats via a very different inflammatory pathway and offers the potential for less mechanistic and medication-based toxicity,” he says. “We all know that Restasis can be slow to act and stings some of our patients. As a result, the engineers at Sarcode actually designed this drug from the bottom up to create the ideal ocular surface medication. The molecule was designed first to have a very high and irreversible affinity for a key binding site. The drug then acts as a molecular decoy to prevent the actual signaling that occurs with ICAM-mediated inflammation.”
According to Dr. Sheppard, additional advantages of lifitegrast are that it has a pH of 7.0, which is consistent with or most prevalent in the tear film. It is also fully aqueous-soluble, so it can be delivered in saline. “Finally, it is stable at room temperature for long periods of time, giving it an excellent pharmaceutical shelf life,” he adds.
Shire intends to submit a New Drug Application for lifitegrast as a treatment for the signs and symptoms of dry eye disease in adults in the first-quarter 2015. “I think that this will be a blockbuster drug for the ocular surface to complement Restasis in the marketplace,” says Dr. Sheppard.
MIM-D3 from Mimetogen Pharmaceuticals is currently undergoing Phase III trials. The company has released top-line data from its second clinical study with MIM-D3,2 and the trial demonstrated significant improvements in signs and symptoms with 1% MIM-D3 versus placebo, along with excellent safety, comfort and tolerability profiles.
The study, which included 403 patients, used Ora’s Controlled Adverse Environment chamber to measure dry-eye patients’ ability to withstand a stressful drying environment on the eye and patient diaries to measure the severity of dry-eye symptoms during the study. In this study, MIM-D3 was superior to placebo with regard to both central and total corneal fluorescein staining at week eight as measured by the Ora Calibra Scale. It also significantly improved common vision-related function symptoms of dry-eye disease as measured by the OSDK questionnaire. Additionally, the mean dry-eye scores for blurred vision, reading, and watching TV were lower in the MIM-D3 group than in the placebo groups at week eight.
Study participants reported that MIM-D3 was comfortable and well-tolerated, and there were no unexpected or serious ocular adverse events. The most commonly reported ocular adverse events were reduced visual acuity (3 percent vs. 3 percent for placebo), instillation site pain (1 percent vs. 1.5 percent for placebo), and eye irritation (0 percent vs. 1.5 percent for placebo). All adverse ocular events were mild and transient.
“MIM-D3 is a secretogogue for mucin. Mimetogen has affiliated closely with Bausch + Lomb and is carrying out Phase III trials,” Dr. Sheppard says. “We strongly believe that this new mechanism of action, which is unique in the pipeline space, will be highly complementary to other dry eye drugs in the pipeline because of the difference in their targets.”
RU-101 by R-Tech Ueno is an ophthalmic solution containing recombinant human serum albumin. Stage 1 of the Phase I/II clinical trial has been completed, and enrollment for stage 2 has begun.
In stage 1, the safety of RU-101 was evaluated using placebo as the control to understand what dose can be used in patients with severe dry eye. Stage 2 will also use placebo as the control and will evaluate the efficacy and safety of RU-101 by administering it at the maximum dose for which safety has been established in stage 1 for 12 weeks.3
“This product uses human serum albumin, which is an entirely new mechanism of action,” says Dr. Sheppard. “They have taken recombinant serum albumin and turned it into a medication. We all know that human serum tears, which are almost always autologous, produce a profound effect on severe dry-eye patients, although cytokines and growth factors may also play a part. Nevertheless, human serum tears are cumbersome, expensive, difficult to access in all but the most experienced facilities, and potentially dangerous due to the risk of infection. The biorecombinant product is in Phase II, and I believe the results could be very promising. Certainly, the side effect profile should be minimal.
Human albumin protein by itself has a lot of anti-inflammatory effect and beneficial activities in terms of wound healing that we hope will translate into the repair of ocular surface disease caused by dry eye.”
KP-121 by Kala is a loteprednol etabonate mucus-penetrating particle (MPP) drug product that is currently in Phase II trials. In the trial, investigators will study the safety and efficacy of 0.25% LE-MPP compared to vehicle dosed four times daily in patients with meibomian gland disease.4 Kala plans to enroll approximately 150 patients in up to 10 centers in the United States.
“This is a unique vehicle formulated to deliver very high doses in stable form to the ocular surface and the deeper layers of the tear film,” says Dr. Sheppard. “This particular technology is also capable of delivering many other drugs. It is also being looked at with loteprednol for other indications like allergy and blepharitis. Bausch + Lomb scientists, apparently prior to the Valeant acquisition, have also successfully reformulated a lower concentration of loteprednol in a nanoparticle-based vehicle, which should also prove to be an exciting prospect for clinical investigation in dry eye. We are really excited about new technologies for delivery with familiar, old, efficacious, safe anti-inflammatory molecules like loteprednol, as well as a host of entirely new mechanisms.”
EGP-437 from EyeGate Pharmaceuticals is a corticosteroid formulation that is currently in a Phase III trial for anterior uveitis.5 According to Dr. Sheppard, EGP-437 is dexamethasone delivered with iontophoresis, which is a way of delivering charged particles to the eye.
“Eyegate Pharmaceuticals has a major portfolio of iontophoresis intellectual property used to deliver any drug or entity that has a charge to it. You can deliver positively or negatively charged drugs to the eye with iontophoresis. It’s currently available for research as a simple cylindrical device that looks like a thimble and acts like a contact lens with a drug-laden sponge on it. A secondary electrode on the forehead drives that charge through the eye. It’s a pain-free and brief procedure,” he explains.
Dr. Sheppard notes that the Phase II trials of iontophoresis for treating dry eye were unsuccessful. “However, this bold new venture into human iontophoresis technology shows promise with further refinements in the delivery, schedule, patient selection, molecules, dosage, and indications,” he says. “The iontophoresis delivery of dexamethasone has been proven with a Phase III trial to statistically significantly improve acute anterior uveitis when compared to prednisolone. We know this drug works, and, remarkably, dexamethasone by iontophoresis doesn’t raise the intraocular pressure.”
Robert Latkany, MD, says that there is no question that many ophthalmologists are turning to steroid use for alleviating some of the symptoms of ocular surface disease. “I think it’s almost the norm across the board. Steroids do relieve a lot of these symptoms. The concern with any steroid is pressure elevation and cataract formation. These patients are never cured by the short-term application of steroids. It is going to require long-term usage, and the concern of the long-term use of steroids in the eye is still there and always will be there,” explains Dr. Latkany, who is founder of New York Eye and Ear Infirmary’s Dry Eye Clinic.
EBI 005 by Eleven Biotherapeutics is a bioengineered drug, with IL-1 as the target. “The team at Eleven has strategically culled data and advice from the most successful aspects of innumerable previous clinical trials,” says Dr. Sheppard. “It is well into Phase III now, with a successful Phase II.6 Based upon previously submitted data, the drug likely will be efficacious as well.”
Rebamipide ophthalmic suspension (OPC-12759, Otsuka Pharmaceuticals) met the threshold of noninferiority and superiority to sodium hyaluronate in corneal and conjunctival staining tests and was judged by patients to be significantly better at relieving foreign-body sensation and eye pain in a multicenter randomized clinical trial that included 188 patients with dry eye.
According to Rutgers’ Dr. Bielory, rebamipide was designed to stimulate increased mucus in the conjunctiva and cornea. It is approved in Japan for protection of gastric mucosa and for treatment of dry eye. It has been shown in human and animal studies to enhance secretion of mucin to support tear film adhesion and slow tear-film breakup time.
In Phase II studies, 2% rebamipide suspension was shown to be superior to placebo at improving objective measures of dry eye, including fluorescein corneal staining score and lissamine green conjunctival staining.7 Additionally, patients reported significantly more relief from photophobia, dryness, foreign-body sensations, pain, and blurred vision than patients instilling placebo.
Rebamipide is currently in Phase III trials in this country.
OTX-DP by Ocular Therapeutix is sustained-release dexamethasone that is administered as a one-time absorbable intracanalicular plug, designed with a four-week tapered release. The Phase II study included 60 patients. In this randomized, placebo-controlled, clinical trial, patients undergoing cataract surgery were administered OTX-DP or a proprietary placebo intracanalicular plug at the end of the cataract procedure. Primary endpoints included reduction of inflammation as determined by absence of anterior chamber cells and absence of pain.8,9
According to the study results, 34.5 percent of patients administered OTX-DP had an anterior chamber cell count of 0 on day 14, compared with 3.4 percent of patients in the control group. Additionally, the OTX-DP group was statistically superior to the control group for absence of pain at all time-points evaluated through day 30. All of the OTX-DP plugs were retained through day 14, and most (96.6 percent) of the plugs were retained through day 28. Results are comparable to commercially available ophthalmic corticosteroids. No increases in intraocular pressure related to OTX-DP were experienced.
Ocular Therapeutix has initiated a Phase III trial. “The wonderful aspect of using a punctal plug to deliver a medication is that it also provides a reservoir effect for tears by inhibiting outflow into the nasolacrimal system,” says Dr. Sheppard. “This uses low steady doses, which seems very promising for a wide variety of clinical indications from dry eye to allergy, glaucoma, and cataract surgery.”
None of these drugs is likely to be approved very soon. “It is frustrating because it is a very slow process to get anything approved,” Dr. Latkany says. “I’m very excited about anything that could be available that I can try on my patients, but unfortunately, I don’t see any of that happening in the next year or so. Lifitegrast and MIM-D3 are the two closest to any sort of approval.”
Dr. Sheppard agrees. “In three years, there will probably be two to five new drugs in the marketplace with many others in early Phase II, and many small companies risking everything they’ve got with venture capital to come up with another way to produce beneficial results in human clinical trials for dry eye.” he says. REVIEW
Dr. Bielory has no financial interest in any of the products mentioned. Dr. Sheppard is a consultant for EyeGate, Kala, R-Tech and Shire. Additionally, he participated in the clinical trials of lifitegrast, albumin and EBI 005. Dr. Latkany has no financial interest in any of the products mentioned. He participated in the lifitegrast clinical trial.
Corrected from an earlier online version that indicated that Shire had submitted data to the FDA, and it was under review.
Review regrets the error.
1. http://www.shire.com/shireplc/en/investors/investorsnews/ir shirenews?id=946