Shire's attempt to secure US approval for lifitegrast, a drug treatment for dry eye syndrome (DES), is back on track after the company announced positive results from its Phase III study. The results represent a turnaround for the company after Shire's bid to get lifitegrast approved in the US suffered a setback in October when the FDA issued a complete response letter (CRL). However, with FDA rejection a possibility, Shire had already been carrying out a fourth Phase III trial, named OPUS-3. With the future development of lifitegrast on the line, Shire breathed a sigh of relief as, just 11 days later, the company announced the study had shown positive top-line results from OPUS-3. Shire is now expected to resubmit a New Drug Application (NDA) in the first quarter of 2016. Analysts from GlobalData say this would keep the company on track to launch its new drug across the US in late 2016.

As a potential first-in-class, small-molecule integrin antagonist, lifitegrast is designed to lower inflammation on the ocular surface associated with DES. The drug prevents the binding of lymphocyte function-associated antigen-1 (LFA-1) with its cognate ligand, intercellular adhesion molecule-1 (ICAM-1). As a result, the secretion of pro-inflammatory and key inflammatory cytokines in both the conjunctival and corneal cells is downregulated. Lifitegrast is formulated as a 5 percent topical ophthalmic solution and is administered twice a day through eye drops.

Key opinion leaders (KOLs) interviewed by GlobalData for its recently published PharmaPoint Dry Eye Syndromes report expressed a great deal of optimism about this pipeline drug. They highlighted the chronic need for novel DES therapies in all markets globally, and believe that the arrival of lifitegrast would be a step towards satisfying this unmet need in the US.

Lifitegrast was originally developed by SARcode Bioscience, a privately held biopharmaceutical company that was acquired by Shire in 2013. Shire was eager to add this key pipeline asset to its growing ophthalmic portfolio, and gaining the global developmental rights to lifitegrast was the main driver for this acquisition deal. SARcode initiated the Phase III program for lifitegrast, which consisted of three studies, named OPUS-1, OPUS-2, and SONATA, and Shire was responsible for their completion. However, the results from the two Phase III efficacy trials, OPUS-1 and OPUS-2, did not support each other; in fact, these studies demonstrated opposing outcomes. The OPUS-1 study of lifitegrast therapy showed significant improvements in the signs, but not in the symptoms, of DES, whereas the results from the OPUS-2 study showed the opposite. The accumulated results from these three Phase III trials, in addition to those from an earlier Phase II trial, were used in support of Shire's recently failed NDA submission to the FDA. The resultant CRL issued by the FDA requested an additional clinical study of lifitegrast for improvements in the signs and symptoms of DES, and Shire is hoping that the recently released positive top-line results from the OPUS-3 study will fulfill this request and facilitate a successful resubmission of the NDA.

OPUS-3 met its primary endpoint, demonstrating a significant improvement in the symptoms of DES, and this therapeutic benefit of lifitegrast was observed as early as two weeks. Interestingly, this study only repeated, and therefore confirmed, the results from the OPUS-2 study, and improvements in the signs of DES were not included in the design of OPUS-3. However, it is unclear whether this will be sufficient for the FDA to grant approval for lifitegrast as a novel DES drug that is indicated to improve both the signs and symptoms of this ocular condition. It is possible that the FDA will require yet another clinical study that conclusively demonstrates that lifitegrast therapy can significantly improve the signs of DES. Such a request would likely be prohibitive to the future development of lifitegrast, as this clinical development program has already become the largest for an investigational DES drug, with over 2,500 enrolled patients, and has required a significant financial investment to date.

The FDA granted a priority review designation to lifitegrast in April 2015, which gives this drug an important advantage, since the NDA review process was accelerated, with a decision target of eight months, rather than the usual 12 months. Shire has already stated its intention to resubmit the lifitegrast NDA in the first quarter of 2016, and this advantageous designation means that an approval decision could be forthcoming as early as the third quarter of 2016.

At present the US DES market is dominated by Allergan's blockbuster drug, Restasis, the only approved DES drug in this market. Restasis is a cyclosporin-based therapeutic that provides clinical benefit to DES patients through the reduction of ocular inflammation, similar to lifitegrast. KOLs in the US were excited about a competitor for Restasis finally arriving, and envision strong patient uptake of lifitegrast once it is launched. Many KOLs highlighted the limitations of Restasis therapy, stating that a significant portion of DES patients are intolerant or refractory to this anti-inflammatory drug. It is a particular clinical advantage of lifitegrast that its therapeutic benefit was demonstrated after only two weeks in the OPUS-3 study, because Restasis has a notoriously long onset of action, with some sources estimating that no benefit is observed for numerous months after the initiation of Restasis therapy. This clinical attribute is certain to boost lifitegrast's ability to directly compete with such a well-established blockbuster as Restasis once it reaches the market, and GlobalData anticipates lifitegrast also reaching this much-sought after position of becoming a blockbuster drug, over the next decade.


*This article first appeared on GlobalData on 6 November 2015