Lifitegrast, an experimental new ophthalmic solution, relieved dry eye symptoms but did not improve signs of the condition in a newly reported phase 3 trial. The results are nearly the opposite of an earlier, just-published phase 3 trial of the drug.
Shire, the patent holder for lifitegrast, announced in a press release on December 5 that the drug had successfully treated dry eye symptoms reported by patients but not signs measured by corneal and conjunctival staining in a large, randomized clinical trial under natural conditions.
The announcement came just a week after researchers reported the complete data on an earlier, large, randomized controlled trial that showed improvements in signs of the disease, but not in a key measure of symptoms. John D. Sheppard, MD, from Virginia Eye Consultants and Eastern Virginia Medical School, Norfolk, and colleagues presented those trial results at the American Academy of Ophthalmology 2012 Annual Meeting and in an article published online November 27 in Ophthalmology.
Overall, the results were very encouraging, Dr. Sheppard told Medscape Medical News. "I saw safety and efficacy and tolerability in my patients," he said.
Although the company has not yet applied for approval for lifitegrast from the US Food and Drug Administration, Dr. Sheppard left no doubt about his hopes for the drug. "This is a paradigm-changing treatment," he said.
Working on the theory that dry eye can be caused at least partly by inflammation, researchers at SARcode Bioscience, a Brisbane, California, subsidiary of Shire, developed lifitegrast to prevent lymphocyte function-associated antigen from binding to native intercellular adhesion molecule 1, expressed on the surface of inflamed epithelial cells.
The approach worked well in preliminary studies, so the researchers decided to test it in larger clinical trials.
Drug Reduced Inferior Corneal Fluorescein Staining in OPUS-1
For the first large trial, OPUS-1, they recruited 588 adults with dry eye disease. To be included, the patients had to show worsened signs and symptoms in an environment where temperature, humidity, air flow, ambient lighting, and visual tasking were adjusted deliberately to bring on these signs and symptoms.
The researchers randomly assigned the patients to instill 1 drop in each eye twice a day of either a 5% solution of lifitegrast or the vehicle with no active ingredient. Both the patients and the administering physicians were blinded to the treatment group.
At baseline, the participants had similar scores both on objective scales where stains are used to show dry areas on the surface of the eye and on the Schirmer Tear Test, where a strip of paper measures the patient's tears. They also had similar scores on scales in which the patients rate their own symptoms.
After 84 days, 293 patients using lifitegrast and 295 using the placebo remained in the study.
At that point, 22.2% of the patients using lifitegrast had a reduction of inferior corneal fluorescein staining of at least 1 point on the 4-point Ora scale, where 0 points is no reduction and 4 points is confluent.
Only 13.9% of those using the placebo had reductions that great, a difference that was statistically significant (P = .01).
However, the mean changes in all 3 corneal regions were less than 0.4 points.
The proportion of participants with at least 1 point of reduction in nasal conjunctival lissamine staining was 24.6% for lifitegrast vs 15.6% for placebo, which was also statistically significant (P = .0074) at 84 days. However, mean changes in both the nasal and total conjunctival lissamine staining were less than half a point.
On the Schirmer Tear Test, both groups improved slightly, but there was no significant difference between them.
On a Visual Analogue Scale, where patients rate their symptoms at the moment of the test, those using lifitegrast reported significant reduction in the mean eye dryness score at day 42, with the benefit continuing through day 84 compared with placebo (P = .0291). All other symptom parameters demonstrated general improvement, but the differences compared with the placebo group were not statistically significant.
On the Ocular Discomfort Score, the lifitegrast group experienced a statistically greater (P = .0273) improvement than the placebo group after 84 days. The changes were less than 1 point in both groups.
Finally, in the Ocular Surface Disease Index Score, where patients report their symptoms during the previous week, the researchers found no statistically significant improvements at follow-up in either group. The patients had very low scores on this index at baseline, making it difficult to measure improvements, Dr. Sheppard said.
Fifty-nine percent of the lifitegrast group experienced adverse events compared with 25% of the placebo group. The ocular event the lifitegrast patients reported most commonly were intermittent and transient discomfort, primarily on the initial instilled dose at day 0. A 1-year study on the safety of the drug is now underway.
Drug Improved Eye Dryness in OPUS-2
In the second large trial, OPUS-2, researchers divided 718 patients into similar groups, one receiving lifitegrast and the other the placebo. They used similar tests to measure the patients' signs and symptoms, this time under natural conditions.
In OPUS-2, patients receiving lifitegrast reported statistically significant improvements in eye dryness from baseline to week 12 (P < .0001) compared with the patients receiving placebo. However, the drug did not improve inferior corneal staining scores in the lifitegrast group at week 12 using fluorescein staining (P value = .6186) compared with the placebo group. Shire has not released complete data from OPUS-2.
Dr. Sheppard said the overall results of the 2 trials were better than those shown for cyclosporine, a widely prescribed drug for dry eye that he has used successfully in his own private practice in Norfolk, Virginia.
Placebo Comparison Inadequate
Asked to comment, Anne Sumers, MD, a spokesperson for the American Academy of Ophthalmology, told Medscape Medical News that a head-to-head trial would be necessary to compare treatments accurately.
"This study doesn't compare lifitegrast to other treatments, it compares it to a placebo, and it isn't clear that it is much better that the placebo," said Dr. Sumers in an email.
Cyclosporine, the only drug approved for use in dry eye, also has a mixed record, being irritating at instillation, expensive, and not always effective, said Dr. Sumers, who has a private practice in Ridgewood, New Jersey.
In contrast, many people get relief from artificial tears, flax seed oil pills, or punctual plugs that keep the eyes from draining, she said.
The study was sponsored by SARcode Bioscience, Inc, a wholly owned subsidiary of Shire Plc. Dr. Sheppard reports serving as a consultant to Alcon, Abbott Laboratories, Allergan, Bausch & Lomb, EyeGate, Lux Biosciences, Merck, NiCox, Lacrisciences, Ocucure, Omeros, EyeRx Research, Provision Network, Tear Science, Science Based Health, and Tear Lab. One coauthor is also a consultant to SARcode Bioscience. The other authors and Dr. Sumers have disclosed no relevant financial relationships.
Ophthalmology. Published online November 27, 2013. Abstract
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Cite this: New Dry Eye Drug Gets Mixed Results in 2 Trials - Medscape - Dec 10, 2013.