The FDA approval last week of Xiidra (lifitegrast ophthalmic solution) from Shire plc represents a major milestone for the dry eye market. Restasis, which was a $1 billion product last year for Allergan plc, had been the only FDA-approved prescription drug for dry eye prior to the Xiidra approval. Importantly, Xiidra is the first prescription drop approved to treat both the signs and symptoms of dry eye.
Allergan seemingly answered the news with a milestone of its own. This week, the company filed a de novo application with the FDA for Oculeve’s Intranasal Tear Neurostimulator device.
The news reflects the tumultuous but promising state of the Dry Eye Market as conveyed at the Breakfast Breakout Session at OIS@ASCRS, moderated by Edward Holland, MD, director of cornea services at Cincinnati Eye Institute.
The path to FDA approval for Xiidra was a long one, and no discussion of dry eye therapeutics can begin without a review of the high regulatory hurdles that companies face in seeking FDA approval for new products. Kim Brazzell, PhD, chief medical officer for Kala Pharmaceuticals, which is developing nanoparticle-based treatments for dry eye and other ocular diseases, said that for dry eye drugs that have failed to gain FDA approval, “it’s one of two things: either the drug didn’t work, or the clinical trial wasn’t designed well enough to show that the drug worked. I think a lot of the failures in the past probably were due to the drug mechanism, potency, or delivery. But it’s difficult to know that. The clinical trials are tough.”
Dr. Brazzell noted several challenges in designing clinical trials for dry eye, including the fact that dry eye itself is not fully understood. Although the FDA requires efficacy to be demonstrated for both signs and symptoms of dry eye, in many populations, signs and symptoms do not correlate, so it can be difficult to show improvement in both in a single study. There’s also the placebo effect: “When your control arm improves by 20% to 30%, it’s difficult to show that your drug works.” There’s a subjective component to measuring dry eye signs and variability in how these tests are conducted, and “in clinical trials, variability is what kills you.” Increasing use of photographic techniques and reading centers should help address the issue of subjectivity.
John Sheppard, MD, president of Virginia Eye Consultants, added, “We have opportunities to look at other important biomarkers in our clinical trials now which may have some credibility with the FDA, such as tear osmolarity and inflammatory indicators [such as MMP-9].” He believes that the FDA will not likely approve such biomarkers and point-of-service diagnostics as primary endpoints for clinical trials, but these tests can be useful for screening populations for clinical studies, to increase the likelihood of success. These tests are also useful in clinical practice for targeting interventions for individual patients. Over the next few years, with the move toward capitated, value-based health systems, eye care professionals will have a strong business motivation to find the best intervention for each individual patient, thereby reducing the need for frequent office visits.
Dr. Holland noted that Shire changed the regulatory approach with Xiidra by addressing signs and symptoms in separate studies instead of a single study. Given the FDA requirement for confirmatory studies, this resulted in four clinical trials instead of two. Said Dr. Sheppard, “SARcode and Shire have invested in over 2,500 patients in five trials analyzed by the FDA. That’s an incredibly expensive precedent that will make things difficult for other companies as well.” However, Sheppard continued, “It’s far less expensive to do four trials than it is to have a failed trial shooting for both signs and symptoms at the same time.” Dr. Brazzell added, “If you look at the cost of dry eye trials versus retina trials, then it’s not expensive. If it is, indeed, a billion-dollar drug, then the investment is not that big.”
Although dry eye therapeutics under development have typically targeted aqueous tear deficiency, treatment of meibomian gland dysfunction (MGD), which can lead to evaporative dry eye, was highlighted as a critical unmet need. Said Dr. Holland, “If we look at how well Restasis has done, and if we look at projections for lifitegrast, if you had an indication for MGD, it would be significantly larger than what we’re seeing with anti-inflammatories.”
Regarding the future prospects for a drug to treat MGD, Dr. Brazzell noted that we don’t yet know exactly how to treat MGD, including how to get a drug into the lid and plugged meibomian glands. “I think we’ll get there at some point, but it’s going to take a while. We’ll do trials, and learn from our failures. It’s a big indication – if it were easy, it would have been done.” Dr. Sheppard concurred, saying, “I’ve been in several MGD trials, and I still don’t know what I’m looking at. It’s very difficult to quantify the signs in MGD. So the industry has punted – we’re going away from FDA approval. MGD is a burgeoning market in clinical practice, with devices that are not funded by insurance, such as thermal pulsation, warm compresses, lid scrubs, and antiseptics. This is driving retail sales in clinicians’ practices.”
Michael Ackermann, PhD, VP of neurostimulation at Allergan plc, noted that there are fewer regulatory precedents and less FDA guidance for dry eye devices than for drugs. As founder and CEO of Oculeve Inc., which was acquired by Allergan in 2015, Ackermann led development of a novel device that activates the nasolacrimal reflex. “Anybody who has put too much wasabi on their sushi knows exactly what this is.” The Oculeve device stimulates the trigeminal nerve inside the nasal cavity, which is responsible for one-third of resting tear production. A single use of the device seems to provide about four hours of symptomatic relief. “In movement disorders and pain management, neurostimulation is a multibillion-dollar industry and it’s been around for a long time, but it’s new to ophthalmology,” said Ackermann. “What we’re finding from the practitioner and patient perspective is, at the end of the day, if it works, it works – patients feel better, they see the response.” Added Dr. Sheppard, “I’ve seen patients use this in clinical trials, and it will be the patients who convince the clinicians to recommend this technology. It truly is unprecedented.”
Dr. Sheppard summarized the importance of continuing to pursue dry eye treatment on multiple fronts: “The more drugs we have on the market, with a variety of mechanisms of action, the better we’ll serve our patients. Because of the heterogeneity of this disease, we’re looking for devices, interventions, minor surgeries, and drugs that will work together to help an individual.”