Take home: John Sheppard, MD, highlights results of a phase III randomized, double-masked, placebo-controlled trial of lifitegrast in dry eye patients previously on artificial tears. He presented these results, a subset analysis of the OPUS-1 phase III trial, at the 2013 meeting of the American Society of Cataract and Refractive Surgery.
Reviewed by John Sheppard, MD, MMSc
—A small-molecule integrin antagonist designed to treat dry eye has shown statistically significant improvement in both the signs and symptoms of dry eye. The investigational agent, lifitegrast, blocks the chronic inflammation mediated by T-cells that is central to many forms of dry eye disease.
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“This is the latest in biotechnologically driven drug development custom created for a specific site and a specific condition, and it is showing very encouraging initial phase III clinical results,” said John Sheppard, MD, MMSc, president and partner, Virginia Eye Consultants, Norfolk, VA. “Dry eye is a very heterogeneous, multifactorial disease that has been surprising clinical investigators worldwide into remarkable frustration.”
Dr. Sheppard presented the results of a subset analysis of the OPUS-1 phase III trial.
New agents intended to treat dry eye face a particularly difficult regulatory hurdle with the FDA, Dr. Sheppard said. Dry eye products must demonstrate safety and efficacy against two distinct predetermined endpoints: a sign of dry eye and a symptom of dry eye. The only currently approved agent to treat dry eye, cyclosporine (Restasis, Allergan), was approved based upon statistically significant improvement in clinical signs of dry eye, but did not show a significant improvement in dry eye symptoms.
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What is unique about agent
Lifitegrast is designed to immunomodulate a key pathway in the development and progression of dry eye. The inflammation associated with dry eye is largely mediated by T-cells which feature increased expression of intracellular adhesion molecule-1 (ICAM-1). Lifitegrast is an ICAM-1 decoy that blocks a key binding interaction between ICAM-1 and lymphocyte function-associated antigen-1 (LFA-1) expressed on the T cell surface. The blockade inhibits T-cell activation, adhesion, migration, proliferation and cytokine release in the eye, effectively down regulating inflammation and the resultant ocular surface disease.
Lifitegrast is an aqueous, sterile, non-preserved and stable agent specifically designed to be delivered as an eye drop. An initial phase III study, OPUS-1, compared 5% lifitegrast with placebo. The active agent showed significant improvement of inferior and total corneal staining scores from baseline to week 12 (p
= 0.0007 and p
= 0.0148 respectively), meeting the signs criteria. The active agent also showed significant improvement in mean ocular discomfort score and eye dryness score at week 12 (p
= 0.0273 and p
= 0.0291 respectively).
The problem, Dr. Sheppard explained, is that investigators had chosen improvement in the Ocular Surface Disease Index (OSDI) as the primary symptom endpoint. Though OSDI scores improved with lifitegrast, the improvement was not statistically significant.
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“That’s like Babe Ruth saying, ‘I’m going to hit the ball over the left field fence,' and when he hits a home run over the right field fence, the umpire says it doesn’t count!” Dr. Sheppard said. “This is life with the regulatory process. You go back to the data.”
Phase II data
Phase II data had shown a strong link between use of artificial tears and improvement with lifitegrast. OPUS-1 included a planned subanalysis of artificial tears users, a subset that comprised about 44% of the total OPUS-1 population of 588 patients. There were 129 placebo patients who used artificial tears in the 30 days before starting lifitegrast and 128 active ingredient patients. Artificial tears patients in both arms were well matched demographically and clinically, Dr. Sheppard said.
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Dry eye signs began to improve by day 14 of the 12-week study for the lifitegrast arm, he continued. At day 84, both the inferior corneal staining score and the lissamine staining score had improved significantly (p
= 0.0142 and p
= 0.0128 respectively. )
Dry eye symptom scores also showed significant improvement. Eye dryness improvement reached statistical significance by day 42 (p
= 0.0013) and ocular discomfort by day 14 (p
= 0.0179). By day 84, eye dryness and ocular discomfort scores in the lifitegrast arm showed even greater improvement over baseline compared to placebo (p
= 0.0012 and p
= 0.0001 respectively).
“The symptom issue with OPUS-1 may be that patients, as a group, weren’t sick enough in terms of their dry eye symptoms to show a statistically significant change: a floor effect,” Dr. Sheppard said. “It has never been accomplished before that any symptoms have shown significant improvement in clinical trials, so the results of OPUS-1 were outrageously successful. It’s just that we didn’t call the right endpoints for the primary analysis.”
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A confirmatory phase III trial, OPUS-2, has already been completed and the dataset locked, he continued. Enrollment criteria required more severe OSDI scores and eye dryness/ocular discomfort were selected as the primary symptom endpoints. Only artificial tear users will be included. Data analysis should be complete during the first quarter of 2014.
“The results will create a tremendous amount of noise in the dry eye community,” Dr. Sheppard said. “I would expect the data to be expeditiously presented to the FDA. We should get an indication as to whether it is approvable by the end of 2014.”
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John Sheppard, MD, MMSc
E: [email protected]
Dr. Sheppard was formerly a consultant for SARcode Bioscience. He is a clinical investigator for Shire Pharmaceuticals.