Annual anti-inflammatory review
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It is September once again, time for us to review the state of the anti-inflammatory landscape in the world of dry eye disease.
Boy, it sure seems like I have done a lot of these things. You might think that there is not a whole lot more to say, and in some ways, I would agree. But as sure as the wind quickens here on the North Coast and the temperatures become more bracing, it looks like this part of the dry eye disease (DED) world has seen enough meaningful change to deserve at least half a column. With the space left over, this gives me a perfect opportunity to continue our “Back to Basics” series and discuss the basics of anti-inflammatory therapy in DED.
Let me start with steroids and the steroid marketplace. There is literally nothing new to see here. Nada. Bupkis. Nobody is doing anything interesting with anything. New molecules? Nope. Crackin’ cool new vehicle? Nah. Innovative, creative response to the scourge of pharmacy benefit managers and increasing patient out-of-pocket costs? Pshaw, please. Nothing here, and as far as I can tell, nothing on the way.
How about the new potential shining star reproxalap (Aldeyra Therapeutics)? In mid-August, it had a nice little breakthrough with a positive result in yet another phase 3 trial, this one on patient symptoms. Aldeyra announced that it will reapply for FDA approval, this time with the assistance of its new best friends at Allergan/AbbVie. If this one gets across the goal line, you are guaranteed at least one more September anti-inflammatory review next year.
Our real starting line is the newcomer to the immunomodulator market, Vevye from Harrow. Vevye is cyclosporine 0.1% dissolved in perfluorobutylpentane (F4H5), a semifluorinated alkane from the same class of water-free liquids as perfluorohexyloctane (F6H8), which we all know as Miebo (Bausch + Lomb). More on this in a moment. Vevye was assessed in the phase 3 FDA trial ESSENCE-2 compared with vehicle alone in patients with moderate to severe DED. Vevye was superior to vehicle in total corneal staining at week 4, and the effect was seen as early as week 2. The difference was statistically significant but small, roughly 0.4 grades between the two. A more impressive difference was seen in clinically meaningful reduction of total corneal staining, with Vevye registering 71.6% vs. vehicle at 59.7%. Both produced roughly equal reductions in eye dryness scores.
A follow-up study of ESSENCE-1 and ESSENCE-2 pooled data looking at patients with cataracts. The analysis emphasized the speed of total corneal staining improvement as early as week 2. Again, the responder rate was impressive for both Vevye and vehicle, 59.2% and 43.3%, respectively, in subjects noted to have cataracts and who had not yet had surgery. This lets Harrow talk about speed of onset, heretofore something that was the exclusive purview of Xiidra (lifitegrast ophthalmic solution 5%, Bausch + Lomb) at 2 weeks and Cequa (cyclosporine ophthalmic solution 0.09%, Sun Pharmaceutical) no later than 4 weeks. Harrow has essentially abandoned all hope of third-party coverage. It offers a coupon/CoverMyMeds type of program for $79 a month. Note that Sun continues to offer an end run around insurance of $89 for a 1-month supply that actually lasts for 3 months, or $29.67 a month.
So, what about that vehicle then? I am going to give the Harrow team the benefit of the doubt and attribute the early enthusiastic commentary by members of its sales team regarding the vehicle to excitement generated by the ESSENCE results above. We should be crystal clear, though, that F4H5 in Vevye does not confer an anti-evaporative benefit similar to that of F6H8 or Miebo. It is not capable of doing so because it does not reside on the ocular surface long enough. In the definitive study by Agarwal and colleagues in 2018, they showed that greater than 90% of F4H5 is gone from the ocular surface within 1 hour, whereas greater than 90% of F6H8 was still present at the 6-hour mark. Vevye cannot prevent evaporation like Miebo. Why pick F4H5 rather than use Miebo itself, F6H8 as the vehicle? Cyclosporine A 0.05% dissolves quite nicely in either liquid, but only F4H5 will dissolve 0.1%. During development, Novaliq opted for the higher concentration for the immunomodulator.
I think it is reasonable that the low incidence of discomfort experienced with Vevye is due to the vehicle F4H5. The best data suggest that Vevye does not share a mechanism of action with Miebo. Word on the street is that the Harrow sales staff no longer discusses this, and that is a good development. Vevye is a good drug that appears to be well tolerated and is being offered at a fair cost to the patient. There is plenty to be excited about just from that.
A quick word, then, on the marketplace for immunomodulators. If you want to learn about the abuses heaped upon a market by pharmacy benefit managers, all you need to do is look here. It is harder than ever to get your patient on your preferred immunomodulator through their insurance. As noted above, Cequa and Vevye have nice work-arounds available, and Bausch + Lomb continues to be more aggressive in securing traditional coverage. Making this more challenging is the clear inferiority of the true, nonauthorized (read: not made by Allergan) cyclosporine A 0.05% generic. We are experiencing alarming failure rates approaching 90% with the non-Allergan manufactured generic. Sadly, this moots the efforts made by my BFF Mark Cuban and Cost Plus Drugs because it only supplies the less effective generic.
How about the Back to Basics then? Immunomodulators continue to form the core of DED care for patients who have true aqueous-deficient dry eye (ADDE) or signs of inflammation that require long-term anti-inflammatory treatment. While some have challenging side effects and they can take anywhere from 2 weeks to 3 months for their effect to kick in, they are as a group remarkably safe and effective. If a patient has a low tear meniscus, an anesthetized Schirmer test of less than 8 mm to 10 mm, and fluorescein or lissamine green corneal or conjunctival staining, long-term anti-inflammatory treatment with an immunomodulator is indicated.
If you have a patient with more than 1+ superficial punctate keratitis or conjunctival staining, you will achieve a much more rapid decrease in the surface inflammation if you prescribe a steroid at the same time. We almost always assume that steroid treatment will be temporary. Have your patient return in 4 to 6 weeks. Whether they are feeling well and congratulating you on being such an astute practitioner or still feeling uncomfortable and not so subtly suggesting that you are not as good at this game as you think, seeing them at this point allows you to reinforce the fact that this is a chronic disease that requires ongoing treatment that begins with an immunomodulator.
They must continue to use their drops.
Three or 4 years after launching SkyVision Centers, my associates and I caught the attention of senior sales executives at what was then Allergan. Seems that we had the highest percentage of patients on Restasis who refilled their prescriptions. How was it, these execs wondered, that we were so far off the curve? We had experimented with several different return visit strategies for our patients taking Restasis. If we saw them at 3 months rather than 4 to 6 weeks after starting treatment, more than half of them had stopped taking it. The same thing was true if we put them on an annual exam schedule, only more so: More than 75% of patients were no longer on Restasis if we did not see them every 6 months. Our schedule for DED patients on an immunomodulator is therefore 6 weeks after initiation, 3 months from that visit and every 6 months for as long as they require treatment.
And there you go. Immunomodulators are still first-line treatment for ADDE. Vevye, the new kid on the block, shows promise as a well-tolerated version of cyclosporine A, and Harrow is making an aggressive play to make it affordable. Steroids continue to play a role in the treatment of symptom flares and to facilitate initiating immunomodulator treatment when necessary. And if you want your patients to continue to treat their DED, you must see them to encourage adherence to therapy.
Oh, yeah. Also, AzaSite (azithromycin ophthalmic solution 1%, Thea) is a magnificent anti-inflammatory agent that is particularly effective when treating meibomian gland dysfunction. You know, in case you forgot.
- References:
- Agarwal P, et al. Int J Pharm. 2018;doi:10.1016/j.ijpharm.2018.01.019.
- Akpek EK, et al. J Cataract Refract Surg. 2024;doi:10.1097/j.jcrs.0000000000001423.
- Akpek EK, et al. JAMA Ophthalmol. 2023;doi:10.1001/jamaophthalmol.2023.0709.
- For more information:
- Darrell E. White, MD, of SkyVision Centers in Westlake, Ohio, can be reached at dwhite@healio.com.
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