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It is not too early to prepare for the possible introduction of lifitegrast
Despite a request from the FDA for more clinical data, the manufacturer remains optimistic about a 2016 product launch.
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Well, it is not the entire answer, but we now have an answer to the “when do we get lifitegrast” question. The response to the expedited review (which we should remember was not requested by Shire) came from the FDA in October regarding the fate of Shire’s new drug application for lifitegrast, with the administration requesting an additional clinical study.
Barely a week after the FDA issued its response letter, Shire announced positive topline findings from OPUS-3. Once again lifitegrast showed an effect on patient symptoms that was clinically significant at both the 2- and 6-week exams. Shire CEO Flemming Ornskov, MD, stated in the press release that the company looks forward to resubmitting its new drug application in the first quarter of 2016 and, if lifitegrast is approved, Shire will remain on track for a potential U.S. launch in 2016.
While the exact timeline for this dry eye product’s introduction is still a bit up in the air, clinicians should consider preparing themselves for this new therapeutic option. OPUS-3 answers more questions about lifitegrast, including another lesson in how to spell “dysgeusia.”
About lifitegrast
Lifitegrast is a so-called small molecule integrin antagonist. It works at the level of the lymphocyte cell membrane to inhibit the binding of lymphocyte function-associated antigen (LFA-1) with its intercellular adhesion molecule (ICAM-1). This inhibition appears not only to prevent the recruitment and activation of lymphocytes, but also to disrupt binding that has already occurred.
The studies show an onset of action (reduced symptoms and/or signs) at approximately 2 weeks. Subjects who took lifitegrast had the usual assortment of ocular side effects (mild to moderate discomfort, drop site reaction), but, interestingly, the percentage of subjects who dropped out of the safety study due to ocular side effects was higher in the placebo group. There was one significant nonocular side effect clearly related to lifitegrast. You guessed it: dysgeusia, or altered sense of taste.
With the FDA’s request for more information, this may remind us of a similar period just before the approval of Restasis (cyclosporine ophthalmic emulsion 0.05%), the blockbuster drug made by Allergan that forever changed how we think about and treat dry eye. In light of this, I think it is appropriate for us to start thinking about how we will use lifitegrast if it is eventually approved. I have a keen memory of doing this in the months leading up to the Restasis approval; doing so got our clinic off and running right away.
Before I start, let me point out that I am a paid consultant for both Allergan and Shire. As such, I am often privy to non-public information, both clinical and business in nature, from both companies. Everything noted thus far, and everything yet to come, is derived from fully public information that is readily accessible to everyone: published reports, posters at scientific meetings and posts on public websites such as Shire’s.
Implementing into practice
The lifitegrast application solidifies the concept of ocular surface inflammation as a key component underlying the signs and symptoms of dry eye. Using the strictest diagnostic criteria, there are at least 26 million dry eye patients in the U.S. If we expand the inclusion criteria to include our newer understanding of the effect of dry eye on vision, this number likely approaches 50 million. There appear to be roughly 1 million patients using Restasis. Any way you slice it, that leaves a whole lot of symptomatic patients who might be inadequately treated – patients who would be less symptomatic if their ocular surface inflammation was treated.
How am I planning on using lifitegrast in this setting if it is approved? Let me begin by saying what I will not be doing: taking a successful Restasis patient off of her medicine and changing her to lifitegrast. That makes no sense. However, I, like you, have a fair number of patients who are on chronic topical steroids to control their dry eye symptoms. I will be collecting these names and plan on attempting to wean them off of their steroid drop and over to lifitegrast.
For years we have all heard from various sources that millions of patients have filled at least one Restasis prescription and then not refilled it. The assumption is that they did not get the kind of relief they sought or had a side effect from Restasis and discontinued treatment. Eye doctors, MDs or ODs, do not get a pass on this phenomenon; inadequate education about what to expect and inadequate help in overcoming any side effects in the early going falls squarely on the shoulders of the prescribing doctors. Nevertheless, we all have patients who fall in this category. I will be on the lookout for them, and they will be at the top of my list of candidates for lifitegrast.
Given the opportunity, we will doubtless learn a lot about how lifitegrast really works once we have it in the wild. For example, if the onset of its effect on signs and symptoms does turn out to be as quick as 2 weeks after initiation or treatment, lifitegrast may be an ideal medicine to use in the setting of multifocal IOLs and PRK in patients who have untreated dry eye. Both of these cohorts of patients get better results with fewer postop symptoms if you treat even the mildest of dry eye. If I note a low tear film, some punctate staining or an elevated tear osmolarity during a preop evaluation, this is another opportunity to use lifitegrast.
In the 1-year safety study of lifitegrast, a bit more than 15% of subjects noted mild to moderate discomfort from the drug, with only 1% or 2% discontinuing the medicine because of that. Will this turn out to be our experience in the clinic? If memory serves, these numbers on discomfort are similar to those published in pre-approval and after-market studies of AzaSite (azithromycin ophthalmic solution 1%, Akorn) back in the Inspire days. In the crucible of the exam room, however, most of the patients who complained of discomfort when instilling AzaSite declined to continue treatment. Which will it be? Frankly, I do not know what to make of dysgeusia or how my staff and I will address that with our patients. Knowing who I will treat and why will help our entire team when we encounter side effects both typical (irritation) and less so (dysgeusia).
Preparing for possible approval
I am still cheering for the approval of lifitegrast in much the same way that I would cheer for an expanded range of on-label dry eye indications for AzaSite or Lotemax Gel (loteprednol etabonate ophthalmic gel 0.5%, Bausch + Lomb). Having said that, I am far from an expert on the FDA approval process, and in no way am I trying to influence the panel that is reviewing this medicine. Under the best of circumstances, it sure sounds like that job is “a rock and a hard place” kind of thing. My hat is off to the panel no matter what the outcome is.
In the event that lifitegrast is approved, I am channeling my pre-approval experience with Restasis so many years ago, preparing by thinking about the first wave of patients to be treated and ready for any surprises that we might encounter. I do not plan to make any major changes in our otherwise successful diagnostic or treatment protocols. For example, while we are learning about lifitegrast, if our algorithm for a “standard issue” dry eye patient points to Restasis, I will be prescribing Restasis as I do now, and the same goes for the LipiFlow (TearScience).
We know that dry eye is progressive and that early treatment means fewer symptoms and reduced chronic damage. My bet is that we will use more of both Restasis and lifitegrast to treat that. Both patient and doctor will be the better for it.
- For more information:
- Darrell E. White, MD, practices at SkyVision Centers in Westlake, Ohio. He can be reached at: dwhite2@skyvisioncenters.com.
Disclosure: White reports he is a consultant for Bausch + Lomb, Allergan, Shire and Eyemaginations and on the speakers board for Bausch + Lomb and Allergan.