Change is coming in dry eye
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As the present now
Will later be past
The order is rapidly fadin’
And the first one now
Will later be last
For the times they are a-changin’
– Bob Dylan, “The Times They Are A-Changin’”
Sometimes when I think about a topic I am going to write about, I hear music. No, really, I hear something that can only be described as the soundtrack that might accompany my piece as you are reading it. It not only happens when I am writing here, for Healio/Ocular Surgery News, but also when I sit down to clear space between my ears by writing for my own blog, “Random Thoughts from a Restless Mind.” There is no reason for me to tap into Spotify and crank up the Sonos; the soundtrack is playing in my head.
When I think about dry eye disease (DED), how we diagnose it and what we use to treat it, Dylan is singing away in the background.
There have been some major changes already, especially with regard to the true, real-world availability of medications and other treatments for DED. If you have been reading my blog on Healio.com/OSN, you know that we now have three nonbranded cyclosporine options, two of which are actually, wait for it, Restasis. At SkyVision, we started getting requests to change patients to “generic” Restasis as soon as Mylan announced approval of “Fauxstasis.” We even got requests to change them to Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan) in multidose bottles that have not been available for years.
This generification of the immunomodulator market has turned prescribing patterns upside down. No matter what you (or your patient) want, you will simply have to accept that for patients younger than 65 years, there will be a “step therapy” demand that your Restasis patient be switched to a generic. No one knows if this will include all immunomodulators. If pharmacy benefit managers (PBMs) make policy based on diagnosis code (ie, DED) instead of active ingredient (ie, cyclosporine A, or CsA), then you will need to “step through” a generic CsA when you prescribe Xiidra (lifitegrast ophthalmic solution 5%, Novartis) as well. Give up all hope of choosing the generic your patient receives. No cherry-picking the one made by Allergan. Sadly, this is nothing but a cost issue for the insurance companies; your patient will get whichever nonbranded CsA is the cheapest at the moment.
What is fascinating and altogether unexpected is what is happening in the Medicare Part D market in response to the appearance of nonbranded CsA. Part D has become a “brand over generic” market. I freely admit that I did not see this coming at all. At least at the time this column is being written, only Humana is asking for prior authorization for Restasis or Xiidra. I imagine that in time Cequa (cyclosporine ophthalmic solution 0.09%, Sun Pharmaceutical) will receive similar consideration. This brand advantage looks like it may even extend to Eysuvis (loteprednol etabonate ophthalmic suspension 0.25%, Kala Pharmaceuticals), the only steroid drop with an on-label DED indication. This new market inversion means that, almost overnight, it has become easier to prescribe your preferred DED medication for patients older than 65 years than it is for your commercially insured younger patients.
Gobsmacked. I am gobsmacked.
Why does this matter? Why is this any more than just the latest example of PBMs practicing medicine? Adjust our internal protocols, and move on with our practice lives. To be honest, if this had occurred 3 or more years ago, that is pretty much what I would suggest. Put this in a short blog post and move on. But I think the DED world is about to undergo a period of significant disruption, an upheaval that is going to be all the more meaningful because of these changes in how medicines are being “covered.” The generification of Restasis will open the way for a wholesale change in how we take care of DED. Entirely new therapies that in some cases attack heretofore untreated areas will ascend, roadblocks removed in part because the downward pressure on immunomodulator prices (and profits) will create space on PBM formularies that would not have been open 3 years ago.
There are three new medications that I am thinking about. All three are on the cusp of completing the work necessary to file for a new drug application with the FDA sometime this year. If they are successful, that means that we could be looking at an entirely new way to approach DED in the clinic. Topical steroids of all kinds are used to quell acute inflammation that can lead to dryness on the ocular surface. Immunomodulators such as CsA and lifitegrast work to reduce this inflammation on a chronic basis. Both are essentially binary; in the simplest sense, T-cell activity is turned off as if a switch were flipped.
What if you could dial down all or most of the inflammatory pathways as if you were turning a rheostat rather than a switch? Reproxalap (Aldeyra Therapeutics) is a reactive aldehyde species inhibitor with activity that is upstream from multiple inflammatory pathways. Aldeyra press releases have announced positive results for both signs and symptoms of DED, including redness.
Meibomian gland dysfunction (MGD)-associated evaporative DED is the scourge of our practice lives. With the exception of AzaSite (azithromycin ophthalmic solution, Théa), my white whale if you will, we do not have any effective pharmaceutical treatments to offer patients who have symptomatic evaporative DED associated with MGD. As I sit at the keyboard, equal parts Ishmael and Ahab, Théa has not yet returned AzaSite to the market. Help is on the way, though, from two sources. Bausch + Lomb just announced that its new drug, NOV03 (perfluorohexyloctane), met all of its primary and secondary endpoints for treating evaporative DED in the last pivotal phase 3 trial before filing for FDA approval.
Tarsus Pharmaceuticals has taken a different route, addressing a common precursor to MGD itself with TP-03 (lotilaner ophthalmic solution 0.25%) to treat Demodex infestation of eyelash follicles. It has also released positive results from its latest trials and will likely pursue FDA approval in the near future. All three of these products appear to have impressive safety data as well.
What does this mean for us going forward? I think we are on the cusp of a significant paradigm shift. We may very well be able to identify a common precursor to symptomatic MGD and treat it directly. Symptomatic evaporative DED may have a solution in which the mechanism of action of the drug directly addresses the cause of the symptoms. Patients who have symptomatic inflammation may have the option to use a medication that can dial down the inflammation and presumably the symptoms that result, both episodically and chronically.
Will reproxalap, NOV03 and TP-03 replace CsA, lifitegrast and the loteprednol/fluorometholone cousins? If you had asked me 3 years ago, I would have been doubtful, if for no other reason than the negotiating power of the established pharmaceutical players who all had brands to protect. Now? I think we are on the cusp of real change in how we address the signs and symptoms of DED. Change that is the result of real innovation in drug development coming at a time when the doors of the marketplace have been blown open by the generification of CsA.
The times they are a-changin’. Let me tell you how and when I think you should still be using AzaSite ...
- For more information:
- Darrell E. White, MD, can be reached at SkyVision Centers, 2237 Crocker Road, Suite 100, Westlake, OH 44145; email: dwhite@healio.com.
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