Shire has reported mixed results from its OPUS-2 Phase III trial of its dry eye syndrome treatment lifitegrast, missing one endpoint by failing to show inferior corneal fluorescein staining after 12 weeks compared with placebo—but meeting a second endpoint by demonstrating a significant change in patient-reported dry eye score over the same period.
The mixed results, reported yesterday, prompted Leerink Swann to lower its valuation of Shire by $4 per American depository share, to $154 from $158—and also slash its updated risk-adjusted peak sales estimate for lifitegrast to $125 million from $300 million.
The firm, however, later highlighted positive commentary from a meeting with Shire management, which according to Leerink Swann speculated that the failure to hit the staining endpoint was due to OPUS-2 being largely comprised of moderate-to-severe patients, making the endpoint more challenging. Shire also stressed the study’s relative success given 14 earlier failed clinical programs for dry eye treatments and its larger patient population than those studies.
In a note to investors, Leerink Swann analysts Jason Gerberry, J.D., and Christopher W. Kuehnle, J.D., said Shire is left with two options: file for marketing authorizations based on OPUS-2 results, which they predicted was unlikely to result in approval, or conduct a third Phase III trial, which they said would likely add one year to the development timeline.
“The latter seems like the more plausible scenario, given that lifitegrast has shown activity in DED and the fact that Phase III trials are relatively short (1 year) and inexpensive,” Gerberry and Kuehnle said in their note.
Shire’s only comment about its next move came in a statement by CEO Flemming Ornskov, M.D.: “We will be examining the totality of the data for lifitegrast in OPUS-2, as well as OPUS-1 and across the entire clinical trial program. We look forward to discussing the lifitegrast program with regulatory authorities.”
The OPUS-2 trial, which was launched in December 2012, included 718 patients who had dry eye and a history of active artificial tear use within 30 days prior to screening. The trial was a safety and efficacy study comparing lifitegrast to placebo in both signs and symptoms of dry eye disease.
Shire acquired global rights to lifitegrast along with its original developer SARcode Bioscience in March, in one of Dr. Ornskov’s first deals during his succession from Angus C. Russell. Shire agreed to pay $160 million up front, plus undisclosed additional payments tied to clinical, regulatory, and/or commercial milestones.
At the time, Shire stated that it anticipated launching lifitegrast in the United States as early as 2016 pending a positive outcome of the Phase III clinical development program and regulatory approvals.
Lifitegrast is a small-molecule integrin antagonist, designed to work by reducing inflammation through binding inhibition of two proteins associated with lymphocyte function—associated antigen 1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1), which in turn influence T cell activation and cytokine release.
The interaction between the two proteins plays a key role in the chronic inflammation associated with dry eye, a major contributing factor to which is inflammation caused by T cell infiltration and proliferation and inflammatory cytokine production that can lead to ocular surface damage and reduction in tear film quality.
Some 25 million people are affected by dry eye disease in the United States alone, a number expected to grow substantially in the next decade due to an aging population—a key reason for Shire’s interest in the treatment.
Lifitegrast, which is administered via a preservative-free topical eye solution, has been the subject of three clinical trials. The 588-patient OPUS-1 trial, concluded last year, met its co-primary endpoint of reducing signs of dry eye, but not the other co-primary endpoint of reducing symptoms. Nevertheless, OPUS-1 led to what Shire called a positive meeting with the FDA, and continuation of the Phase III clinical program.
The other Phase III trial, SONATA, was also launched in December 2012, with the goal of assessing lifitegrast’s safety compared with placebo after one year in 300 dry eye patients. “This trial is scheduled for completion in mid-2014,” Shire stated.