Shire's Xiidra Gets Advantageous Label Covering Signs, Symptoms Of Dry Eye Disease

By examining the "totality of the data" including a Phase II study, FDA approved drug for both measures of dry eye, despite mixed results in pivotal trials.

The delay caused by receiving a complete response letter in the end enabled Shire PLC'sXiidra (lifitegrast) to get the best possible indication – to treat both the signs and symptoms of dry eye disease.

The drug cleared FDA July 11 as the first drug for that indication, despite an initial submission with mixed data and a complete response letter in October 2015. At that time, the lymphocyte function-associated antigen 1 (LFA-1) agonist had shown statistical significance for improving the symptoms of dry eye disease in one pivotal study and statistical significance for improving the signs of the disease in another. But the drug did not meet statistical significance for both measures in either the OPUS-1 or OPUS-2 trial.

A third Phase III trial, OPUS-3, was already underway at the time Shire received the complete response letter, which enabled a re-filing of the NDA roughly three months later (Also see "Quick Resubmission Has Shire Seeking Third Quarter Lifitegrast OK" - Pink Sheet, 25 Jan, 2016.)

Shire R&D Head Philip Vickers

Source: Shire PLC

In an interview, Shire Head of R&D Philip Vickers said the company is "delighted" with the label, adding that the Dublin-headquartered firm specifically designed its clinical trial program to demonstrate lifitegrast's effect on both measures. Shire urged FDA to review its NDA within the context of the "totality of the data," the exec added.

"[Demonstrating both measures] was built into the clinical development plan," he said. "A lot of patients have now received Xiidra, 2,500, and there's five controlled clinical trials, the largest ever for an investigational product in dry eye. … So we're delighted that FDA has recognized that we've demonstrated that and that that is captured in the label."

The indication for both signs and symptoms of dry eye disease should give Xiidra a significant advantage over the only drug currently approved for dry eye, Allergan PLC's Restasis (cyclosporine ophthalmic emulsion), which has yielded blockbuster sales despite marginal efficacy and a label that only cites its ability to increase tear production in patients with chronic dry eye.

Shire intends to launch Xiidra before the end of the third quarter.

Shire's dry eye disease drug Xiidra

Source: Shire PLC

The clinical trials section of the label cites Phase II data among that backing the improvement of signs of disease claim, as well as data from the third Phase III trial, OPUS-3, which anchored the Shire reply to the complete response letter (Also see "Shire Could Get More Out Of OPUS-3 Than Refiling Lifitegrast" - Scrip, 28 Oct, 2015.). "We had always understood [OPUS-3] to be a trial only tracking symptoms," Evercore ISI analyst Umer Raffat pointed out in a July 12 note.

FDA Asked To Consider Totality Of Data

The re-filed NDA was backed by the Phase II trial, all three Phase III OPUS studies and a long-term Phase III safety trial, Vickers said.

"[In] OPUS-2, we looked at the symptoms of the disease and then we repeated that study, we looked at the symptoms of the disease in OPUS-3," he explained. "If you look at the results of OPUS-3, they are extremely similar to the results of OPUS-2, thereby demonstrating improvement on the symptoms of the disease. Signs of the disease are very important but it's obviously the symptoms of the disease that patients recognize and feel, so it was extremely important to us that we were able to replicate [improvement in] the symptoms as well as the signs of the disease."

It also gave the company confirmation in a second pivotal trial, the gold standard for FDA approvals.

But Vickers stressed that the "totality of the data" across all five studies submitted – the Phase II data supporting the signs of dry eye disease claim included – helped demonstrate "reproducible effects on both the signs and symptoms of this disease."

"Nobody has previously come forward with data demonstrating signs and symptoms of dry eye disease – you obviously want to hit both of those and we felt the Phase II data added information that would be important to the FDA, when they've never had this type of data to look at before," he said. "So we provided it in that context, and we presume they recognized it was important data which contributed to their thinking and to the positive outcome we got."

In investor presentations, Shire CEO Flemming Ornskov consistently has pointed to lifitegrast as offering the potential to be a game-changer in dry eye disease and to be the fulcrum of the firm's nascent ophthalmology franchise. Talking in May about the benefits of Shire's merger with Baxalta Inc., Ornskov enthused about the drug's "phenomenal clinical trials [and] innovative mode of action." (Also see "Shire's Ornskov Maps Out Future Prospects Post- Baxalta Merger" - Scrip, 6 Jun, 2016.)

Xiidra is expected to serve as the beachhead for a portfolio of ophthalmology drugs at Shire. It was acquired in the company's 2013 acquisition of SARcode Bioscience Inc. and is joined in the pipeline by several other eye disease candidates, including the Phase II candidates SHP640 for viral/bacterial conjunctivitis and SHP607 for retinopathy of prematurity, as well as preclinical candidates for autosomal dominant retinitis pigmentosa (SHP630) and glaucoma (SHP639). (Also see "Shire Seeking 'Tuck-in' Rather Than Large-Scale M&A As It Integrates Dyax And Baxalta" - Scrip, 12 Feb, 2016.)

Shire estimates that about 16m people in the US are diagnosed with dry eye disease, but only about 900,000 currently are on drug therapy, according to Deutsche Bank analyst Richard Parkes. Many of these patients are either former Restasis patients or those who failed on Restasis therapy. In a July 12 note on the approval, Parkes predicted that Xiidra could generate sales of $1.1bn by 2020 and peak at $1.6bn in 2024 thanks to "its fast onset, good tolerability and strong efficacy."

"Although we expect Allergan to vigorously defend its position, we expect Xiidra to ultimately emerge as market leader," he wrote. "Our previous physician survey suggests potential for rapid uptake given likely use in: (1) patients dissatisfied with Restasis; (2) a large population of patients previously failing Restasis; and (3) in combination with Restasis. In addition, our survey suggests Xiidra should emerge as a preferred first prescription agent for moderate-to-severe patients and suggests potential for a significant expansion in the market for prescription dry eye disease therapies, with patients with moderate-to-severe disease treated with a prescription agent more than doubling over five years."

Shire has not yet announced pricing for Xiidra – Restasis costs $426 a month (wholesale acquisition cost). Analysts were divided on whether Shire should try to price its product at a premium – Parkes says he expects Shire to take that approach based on Xiidra's advantages over Restasis, while Leerink Partners' Jason Gerberry, in a July 11 note, said he expects the new drug to be priced at par with Restasis, which he said effectively costs about $300 a month.

Vickers was circumspect on when Shire will announce the pricing of Xiidra. "We are now rapidly moving towards the launch phase; we anticipate launching in the third quarter, so obviously it's under a lot of discussion at the moment," he said. "I don't know the timing that that information will be released but it obviously will be aligned with our plan to launch this quarter."