EW CORNEA68 September 2016

by Michelle Dalton EyeWorld Contributing Writer

an important role in our manage-ment of dry eye.”

For Dr. Hovanesian, Xiidra represents “quite a change in our treatment approach, but it’s justified by what we saw in the trials. The clinical benefit in terms of symp-toms was seen as early as 2 weeks in a high percentage of patients. That’s not something we’re used to with dry eye medications.”

While Restasis uses a medication that has an excellent, long track re-cord systemically, lifitegrast is a truly novel molecule that was designed de novo, Dr. Sheppard said, with a goal of being soluble in water, having a stable tear pH, a very long shelf life at room temperature, and a high-ly specific binding capability. He equated the molecule to a pianist’s hand, with each “finger” playing a different note in addressing the dry eye issues.

“It’s truly a brilliantly target-ed molecule that will be useless anywhere else in the body because it most likely won’t do anything in other tissues,” he said. “It’s a saline vehicle, which nearly eliminates the vehicle effect during clinical trials, in direct contrast to the Restasis lipid emulsion vehicle, a highly effective standalone lipid emulsion artificial tear.”

Those differences that set Xiidra apart from other remedies are why clinicians have been anxiously awaiting its approval—to provide an alternative treatment for those patients in whom Restasis has not been fully beneficial.

“There are plenty of patients who need additional therapy for their dry eye, and I’m looking

and clinical director, Thomas R. Lee Center for Ocular Pharmacology, Eastern Virginia Medical School, Norfolk. “It will be good for our pa-tients, good for the companies who make the diagnostic tests, all the peripheral companies as well, and, believe it or not, good for Restasis; all ships will rise with the tide of growing dry eye awareness. There’s going to be a massive amount of attention focused on dry eye now as a result of the approval, and that’s a game changer.”

Xiidra gives physicians a new treatment path for patients, espe-cially those with moderate to severe disease “who received inadequate results with the more standard conservative treatments like artifi-cial tears and warm compresses,” said John Hovanesian, MD, clinical instructor, Jules Stein Eye Institute, Los Angeles. Trial data (see sidebar) indicated the drug was “very well tolerated and had a low discontinu-ation rate and really no meaningful safety concerns,” he said.

Dr. Hovanesian thinks most cli-nicians will use Xiidra “at an earlier stage than Restasis, likely as a first line therapy for patients who are known to have moderate to severe disease at the outset. But that’s not ruling out Restasis. Restasis contin-ues to be a very effective tool that we will continue to use.”

Changing treatment approaches“Xiidra is a very promising treat-ment,” said William Trattler, MD, Center for Excellence in Eye Care, Miami. “Clinical trial data has shown improvement in patient symptoms early on, and it will play

of dry eye. The only other topical medication—Restasis (topical cyclo-sporine 0.05%, Allergan, Dublin)—is a “topical immunomodulator indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.”

For most patients who seek professional help for dry eyes, they have already tried over-the-counter remedies, and artificial tears still remain the first option for many.

The Xiidra approval “will be good for the entire space,” said John Sheppard, MD, president, Virginia Eye Consultants, Norfolk, Virginia,

The U.S. approval of Xiidra has those treating ocular surface disorders anxiously awaiting its launch

It’s been a long time coming. The U.S. Food and Drug Admin-istration approved Xiidra 5% (lifitegrast, Shire, Lexington, Massachusetts) in mid-July,

ahead of its scheduled approval date deadline. As a result, physicians treating dry eye disease finally have a second approved topical medica-tion, and this one is approved to treat both the signs and symptoms

New dry eye treatmentwelcomed with open arms

Science behind Xiidra

A ccording to Shire, Xiidra is a prescription eye drop solution used to treat the signs and symptoms of dry eye disease. It is dosed twice per day, approximately 12 hours apart, in each

eye. The safety and efficacy of Xiidra was studied in 1,181 patients (of which 1,067 patients received lifitegrast 5%) in four placebo-controlled 12-week trials. Each of the four studies assessed the effect of Xiidra on both the signs and symptoms of dry eye disease at baseline, week 2, 6, and 12. Assessment of symptoms was based on change from baseline in patient-reported eye dryness score (EDS; 0–100 visual analogue scale). Assessment of signs was based on inferior corneal staining score (ICSS; 0–4 scale).

In all four studies, a larger reduction in EDS was observed with Xiidra at 6 and 12 weeks. In two of the four studies, an improvement in EDS was seen with Xiidra at 2 weeks. At week 12, a larger reduction in ICSS favoring Xiidra was observed in three of the four studies. The most common adverse reactions reported in 5 to 25% of patients were instillation site irritation, altered taste sensation (dysgeusia), and reduced visual acuity.

The inflammation associated with dry eye is thought to be primarily mediated by T-cells and associated cytokines. One effect of this process may be increased expression of intracellular adhesion molecule-1 (ICAM-1); ICAM-1 may be overexpressed in corneal and conjunctival tissues in dry eye disease. Lifitegrast is a small-molecule integrin antagonist that binds to the integrin lymphocyte function-associated antigen-1 (LFA-1), a cell surface protein found on leukocytes, and blocks the interaction of LFA-1 with its cognate ligand ICAM-1. LFA-1/ICAM-1 interaction can contribute to the formation of an immunological synapse resulting in T-cell activation and migration to target tissues. In vitro studies demonstrated that lifitegrast may inhibit T-cell adhesion to ICAM-1 in a human T-cell line and may inhibit secretion of inflammatory mediators (cytokines) in human peripheral blood mononuclear cells. The exact mechanism of action of lifitegrast in dry eye disease is not known.

“ There’s going to be a massive amount of attention focused on dry eye now as a result of the approval, and that’s a game changer.”

–John Sheppard, MD

69EW CORNEASeptember 2016

North Carolina), and TopiVert (Lon-don). Dr. Trattler has financial interests with Allergan and Shire.

forward to seeing what kind of addi-tional benefit Xiidra can offer,” Dr. Trattler said. He said he may begin patients on Xiidra initially to see the response before adding in adjunctive treatments.

Quicker onset of symptom reliefDr. Hovanesian cautions his cur-rent dry eye patients that treatment won’t “cure” the disease, nor will relief be immediate. Restasis reaches its full potential about 3 months after therapy begins; in the Xiidra studies, relief was noticed as early as 14 days.

“Restasis takes awhile before it makes a meaningful impact on patients’ tear supply,” Dr. Hovanesian said. “Some patients experience sting-ing and redness. While there is some local surface irritation that caused a few Xiidra patients to discontinue the drug, it’s not common. One of the most common symptoms people experienced with Xiidra that did not seem to be an issue with Restasis was dysgeusia, or altered taste. For most patients, it wasn’t terribly unpleasant in the study. We had patients in our office who were part of the clinical trials, and it was noticeable to some of them. That is something that we should prepare patients for when we prescribe Xiidra.”

Down the roadDr. Hovanesian hopes the Xiidra approval will open the door for other companies and that barriers to approval will become easier to overcome.

“Dry eye is such an important and common disease,” he said. “Shire had a new mechanism of action with lifitegrast, and over the past decade or so, the pendulum has swung toward more rigor than is probably appropriate. Since the approval of Restasis 13 years ago, we’ve had several failed drugs that attempted to get an indication for dry eye.” Those include diquafosol, which showed significant promise but did not pass the rigorous FDA re-quirements, although it is approved elsewhere.

The “FDA is doing its job of try-ing to protect the public from unsafe or ineffective treatments, but we hope that the requirements will ease up a bit,” Dr. Hovanesian said.

There are currently more than 100 clinical studies underway eval-uating dry eye treatments. Drugs in the pipeline also address the inflam-matory cascade aspect of the disease. Shire’s study involved more than 2,500 patients, and other companies are enrolling equally high numbers of subjects.

Dr. Sheppard named several other potential dry eye treatments, including a sodium channel blocker, an aldehyde blocker, a neurotrophin mimetic, narrow spectrum kinase inhibitors, testosterone analogues, topical forms of loteprednol, new cyclosporine concoctions, direct nasal neurostimulation, drug-eluting punctal plugs, and a recombinant human serum albumin protein that are all being evaluated in topical form.

“There continues to be inter-est in this space, and I’m sure we’ll eventually find there are a few peo-ple who don’t respond adequately to Xiidra,” Dr. Sheppard said. “These other treatments may end up being those patients’ salvation.”

Dr. Trattler said there may be synergies between Xiidra and Restasis, but data is needed and real-world outcomes need to be reported before he advocates using the two as a combination with other tried and tested therapies.

“Each new offering changes the game for our dry eye patients,” Dr. Hovanesian said. “If there’s one thing we know about dry eye, it’s that no one treatment works for every patient. We have to custom-ize and to some extent experiment with individuals to find their best treatment.” EW

Editors’ note: Dr. Hovanesian has financial interests with Allergan and Shire. Dr. Sheppard has financial in-terests with Alcon (Fort Worth, Texas), Aldeyra Therapeutics (Lexington, Mas-sachusetts), Allergan, Bausch + Lomb (Bridgewater, New Jersey), LacriScience, Novaliq (Heidelberg, Germany), Ocular Therapeutix (Bedford, Massachusetts), Paragon (Baltimore), Parion (Durham, North Carolina), Rapid Pathogen Screening (Sarasota, Florida), Science-Based Health (Houston), Shire, TearLab (San Diego), TearScience (Morrisville,

Contact informationHovanesian: jhovanesian@harvardeye.comSheppard: jsheppard@vec2020.com Trattler: wtrattler@gmail.com