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Exclusives

Demodex: Prevalent, underrecognized, and undertreated

Posted on January 14, 2021

By Elizabeth Yeu, MD

We cannot see what we are not looking for.

Before I began purposefully looking for signs of Demodex during my slit-lamp exams, I thought the prevalence in my patients was about 10% to 15%. This is because I was more focused on lower lid activity—evaluating tear film quality across the lower lid, meibomian gland health, and performing expression to determine meibum quality and assessing the lid margin architecture. I realized I was only making a Demodex blepharitis diagnosis when infestation was so severe there was evidence on the lower lashes. My “a-ha” moment came when a patient seated at the slit lamp looked down to fix her mask: I had not been paying enough attention to the skin side of patients’ upper lids and lashes. Now, I find collarettes—evidence of Demodex infestation—in approximately 3 out of 4 patients.

A prospective study of 1121 consecutive patients from geographically diverse practices has found that 58% have collarettes.1 Further, of the 20% of these patients who were on cyclosporine or lifitegrast, 60% had collarettes.1 This not only shows how common collarettes are but also the extent to which Demodex blepharitis overlaps with dry eye disease.

Much of the symptomatology associated with other cornea external disease is similar to that of Demodex blepharitis, such as loss of lashes, redness, foreign body sensation or irritation, burning, and itching. Often, patients with moderate to severe infestation will actually point across their lash margin indicating the specific area (base of lashes) where the eyelid burns and itches. Debris from the infestation can also fall onto the corneal surface causing further redness and burning.

Managing Demodex

The presence of just one collarette means that there is significant Demodex activity. Even a mild infestation should be treated as it will otherwise progress, leading to more disease, lash loss, inflammation, and an overgrowth of bacteria. Left untreated, eventually, Demodex infestation can lead to corneal involvement. Cataract patients with unmanaged mites are more likely to have a refractive surprise or even be at higher risk for postoperative infections.

In these patients, I take steps to manage the biofilm with BlephEx or thermal pulsation, plus I add antibiotic ointment, a steroid, and a hypochlorous acid 0.01% spray or tea tree oil-based foam or wipe to target the Demodex mites.

Although these therapies help manage the symptoms, we cannot get to the root cause of Demodex blepharitis unless we kill the mite itself. The compliance rate with eyelid hygiene and homeopathic options, however, tends to be quite low. The treatments are cumbersome at best and uncomfortable at worst, hypochlorous acid and tea tree oil—although somewhat effective—can sting, especially if the eye is very inflamed. In fact, a recent study showed that terpinen-4-ol or T4O—the tea tree oil component that has shown the most efficacy in killing Demodex mites—is toxic to human meibomian gland epithelial cells in vitro.2 This was shown even at levels 10-fold to 100-fold lower than the demodicidal concentration used to kill the mites.

New Drop Poised to Change the Paradigm

TP-03 (Tarsus Pharmaceuticals, Inc), a drop under investigation, has shown strong efficacy against Demodex in 4 clinical trials. The treatment is designed to paralyze and eradicate mites through the inhibition of parasite-specific GABA Cl channels. Results from the company’s Mars and Jupiter Phase 2 studies have shown TP-03 is well tolerated and effective at reducing collarettes and Demodex density with 28 days of treatment and maintaining results through 90 days.3,4 The studies evaluated a total of 75 patients, showing statistically significant decreases in collarettes and Demodex density as early as day 14 of treatment. No treatment-related adverse events were observed, and patients reported the drop to be comfortable.

These results were further validated in the Phase 2a Io and the Phase 2b Europa studies that included a total of 72 patients.5 In the single-arm open-label trial Io, TP-03 was effective at achieving the primary and secondary endpoints, respectively, of collarette cure in 72% of participants and Demodex mite eradication in 78% of patients at Day 42. The randomized vehicle-controlled Europa study achieved statistically significant results for the primary endpoint of collarette cure in 80% of participants on TP-03 compared to 16% on vehicle (P < 0.001) at Day 42, and the secondary endpoint of mite eradication in 73% of participants on TP-03 compared to 21% on vehicle (P = 0.003) at Day 42. TP-03 was well tolerated and there were no reports of serious adverse events or treatment discontinuations due to adverse events in either study. Participants in Europa rated the eye drops as “neither comfortable nor uncomfortable,” “comfortable,” or “very comfortable” 87% of the time.

Tarsus announced it has begun patient enrollment and treatment in its Saturn-1 Phase 2b/3 pivotal trial. Saturn-1 is a larger, multicenter trial with the same endpoints as Europa. Enrollment in a second pivotal trial, Saturn-2, is expected to begin in 2021.

Conclusion

It is quite simple to observe Demodex infestation as we can see it clinically at the slit lamp via collarettes—we do not need to pluck lashes and look under a microscope to see the mites themselves. We can be definitive in our Demodex diagnosis, and with TP-03, if approved, we may be definitive in our treatment as well. Once the Demodex mites are eradicated, we can better identify additional steps that may be needed to treat any overlapping disease processes. This possibility is truly exciting for the more effective and complete management of ocular surface disease because there will be a true blepharitis therapeutic available.

Elizabeth Yeu, MD is a cataract, corneal, and refractive surgeon, Virginia Eye Consultants, Norfolk, Virginia; [email protected]

Financial disclosure: Consultant to Alcon, Allergan, Bausch + Lomb, BlephEx, CorneaGen, Dompe, Johnson & Johnson Vision, Kala, Ocular Science, Ocular Therapeutix, Ocusoft, Novartis, RegenerEyes, Science Based Health, Sight Sciences, Surface, Tarsus, Thea, TearLab, Tissue Tech

Reference 
1. Tarsus collarette prevalence study; data on file.

2.Chen D, Wang J, Sullivan DA, et al. Effects of terpinen-4-ol on meibomian gland epithelial cells in vitro. Cornea. 2020. Online ahead of print. DOI: 10.1097/ICO.0000000000002506

3. Gonzalez-Salinas R, Ramos-Betancourt N, Corredor-Ortega C, et al. Pilot study to evaluate the safety and efficacy of TP-03 for the treatment of blepharitis due to Demodex infestation (Mars Study). Paper 2984-80042 presented at: Association for Research in Vision and Ophthalmology 2020.

4. Hom MH, Ceballos JC, Massaro-Corredor M, et al. Randomized controlled trial to evaluate the safety and efficacy of TP-03 for the treatment of blepharitis due to Demodex infestation (Jupiter Study). Poster presented at: Optometry’s meeting 2020.

5. Tarsus Releases Data from Io and Europa Trials for TP-03 to Treat Demodex Blepharitis and Begins Enrollment and Treatment in Phase 2b/3 Saturn-1 Trial. https://www.prnewswire.com/news-releases/tarsus-releases-data-from-io-and-europa-trials-for-tp-03-to-treat-demodex-blepharitis-and-begins-enrollment-and-treatment-in-phase-2b3-s

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