AZR-MD-001: A Familiar Compound in a Novel Formulation
By Laura M. Periman, MD
View Source Publication
The meibomian glands are modified sebaceous glands in the eyelid margin that are responsible for secreting meibum, the principal constituent of the outer tear film lipid layer. (This lipid layer is responsible for lubricating the ocular surface during blinking and protecting against tear evaporation.1-4) Meibomian gland dysfunction (MGD), a chronic, diffuse abnormality of the meibomian glands characterized by gland obstruction, microbiological changes, inflammation, altered meibum quality, compromised meibomian gland flow (stasis) and increased melting temperatures, and changes in the amount or quality of secreted meibum.5,6 MGD has been identified as a common component of ocular surface disease (OSD),7-11 a condition that is characterized by instability of the tear film, drying of the ocular surface, and ocular discomfort.12
Hyperkeratinization of the meibomian gland orifice and ductal epithelium, a typical finding in the obstruction component of MGD,13-15 is made up of tightly crosslinked keratin strands.16,17 MGD raises meibum melting temperature; increases meibum viscosity; and results in stasis, gland plugging, and gland obstruction. This all may ultimately lead to gland dilation, atrophy, and dropout.3,4,16-19 The understanding of MGD has expanded beyond simple obstruction, and the six interrelated mechanisms of MGD have been well described.6
Meibomian glands share strong similarities with sebaceous glands with respect to both embryologic development and structure, including the ability to undergo keratinization. Considering these similarities, the meibomian glands may be regarded as hair follicles without a hair shaft.20 In addition to being involved in diseases affecting the lid margin, the process of secretory gland hyperkeratinization plays a role in various skin disorders including acne, seborrheic dermatitis, psoriasis, and dandruff.2,21,22
Keratolytic agents that reduce hyperkeratinization of the skin and sebaceous glands have been successfully used to treat these conditions.23-25 Could a similar approach work to treat the keratinization seen in MGD?
NEW TREATMENT FOR MGD
The primary aim of treatment for MGD is to restore the normal quality, quantity, and flow of meibomian gland secretions, thereby increasing the likelihood of a healthy lipid layer and stable tear film. This can be facilitated in part by addressing the obstructing material.3 Conventional methods for removal of abnormal gland material include various mechanical (eg, Maskin Probing) and heat-based (eg, in-office thermal pulsation, warm compresses) techniques. Thermal approaches to the obstruction component of MGD treatment are effective in melting the oils but are unable to address the disulfide-bonded keratin strands in the meibum due to the high temperatures (145°C) necessary to break the bonds and solubilize the keratin strands and plugs.26 There is potential for excellent clinical synergy in addressing the keratin plugs along with the current excellent MGD therapeutic modalities.
The use of combined dermatologic-ophthalmologic approaches to treatment of MGD is on the horizon. This novel approach to MGD addresses obstruction from hyperkeratinization (in a nonthermal fashion) and the hyposecretion of meibum.27,28 Keratolytic agents that chemically, rather than thermally, break disulfide bonds hold potential for restoring meibomian gland function by targeting multiple mechanisms involved in the early stages of MGD pathogenesis. One such keratinolytic agent, selenium sulfide, can effectively treat skin disorders such as dandruff and seborrheic dermatitis.23,24
AZR-MD-001 (Azura Ophthalmics) is a novel ophthalmic formulation of selenium sulfide under development for MGD. It has a triple mechanism of action, according to data on file with Azura, to promote the breakdown of disulfide bonds in keratin, slow the production of abnormal keratin, and stimulate meibum production in vitro.
In an 18-patient company-conducted pilot study, patients received selenium sulfide in a nonoptimized formulation in one eye; the contralateral eye served as control. The study demonstrated significant improvements in tear breakup time, meibum quality, and meibomian gland secretion scores for the drug-treated eye versus the contralateral control eye, as observed by day 22 after treatment (data on file, MGSS1 Azura). Further studies are underway in the drug development process.
The clinical science behind combined dermatologic-ophthalmologic approaches to treatment of MGD is in its infancy, but a treatment such as AZR-MD-001 represents an exciting new therapeutic category in the development of strategies to address the obstruction and hyposecretion problems of MGD.
NRO-1 Could Potentially Protect, Regenerate Corneal Nerves
The first patient has been enrolled in a phase 2 clinical trial of a novel therapeutic agent that protects and regenerates corneal nerves, according to developer Neuroptika.1 This therapeutic, according to the company, has potential to protect and regenerate damaged corneal sensory nerves and to become a disease-modifying treatment. NRO-1 works to normalize the ocular surface and improve symptoms of DED.
The aim of the multicenter, randomized, double-masked, vehicle-controlled phase 2 clinical trial is to evaluate the safety and efficacy of two concentrations of NRO-1 in patients with DED. The study will enroll 120 patients with moderate to severe DED who will receive one of the two concentrations or vehicle for 28 days. Results from the phase 2 study are expected to be available in the second half of this year.
1. https://eyewire.news/articles/neuroptika-announces-enrollment-of-first-patient-in-phase-2-clinical-trial-for-dry-eye-disease/. Accessed June 24, 2020.
1. Green-Church KB, Butovich I, Willcox M, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on tear film lipids and lipid-protein interactions in health and disease. Invest Ophthalmol Vis Sci. 2011;52(4):1979-1993.
2. Bron AJ, Tiffany JM. The contribution of meibomian disease to dry eye. Ocul Surf. 2004;2:149-165.
3. Blackie CA, Korb DR, Knop E, Bedi R, Knop N, Holland EJ. Nonobvious obstructive meibomian gland dysfunction. Cornea. 2010;29(12):1333-1345.
4. Knop E, Knop N, Millar T, Obata H, Sullivan DA. The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Invest Ophthalmol Vis Sci. 2011;52(4):1938-1978.
5. Nichols KK. The international workshop on meibomian gland dysfunction: Introduction. Invest Ophthalmol Vis Sci. 2011:52;1917-1921.
6. Geerling G, Baudouin C, Aragona P, et al. Emerging strategies for the diagnosis and treatment of meibomian gland dysfunction: Proceedings of the OCEAN group meeting. Ocul Surf. 2017;15(2):179-192.
7. Lemp MA. Report of the National Eye Institute/industry workshop on clinical trials in dry eyes. CLAO J. 1995;21(4):221‐232.
8. Goto E, Endo K, Suzuki A, et al. Tear evaporation dynamics in normal subjects and subjects with obstructive meibomian gland dysfunction. Invest Ophthalmol Vis Sci. 2003;44:533-539.
9. Mathers WD. Ocular evaporation in meibomian gland dysfunction and dry eye. Ophthalmology. 1993;100:347-351.
10. Mathers WD, Lane JA. Meibomian gland lipids, evaporation, and tear film stability. Adv Exp Med Biol. 1998;438:349-360.
11. Mishima S, Maurice DM. The oily layer of the tear film and evaporation from the corneal surface. Exp Eye Res. 1961;1:39-45.
12. Schaumberg DA, Nichols JJ, Papas EB, Tong L, Uchino M, Nichols KK. The international workshop on meibomian gland dysfunction: report of the subcommittee on the epidemiology of, and associated risk factors for, MGD. Invest Ophthalmol Vis Sci. 2011;52(4):1994-2005.
13. Foulks GN, Bran AJ. Meibomian gland dysfunction: a clinical scheme for description, diagnosis, classification, and grading. Ocul Surf. 2003;1:107-126.
14. Jester JV, Nicolaides N, Smith RE. Meibomian gland dysfunction. I. Keratin protein expression in normal human and rabbit meibomian glands. Invest Ophthalmol Vis Sci. 1989;30(5):927-935.
15. Jester JV, Nicolaides N, Kiss-Palvolgyi I, Smith RE. Meibomian gland dysfunction. II. The role of keratinization in a rabbit model of MGD. Invest Ophthalmol Vis Sci. 1989;30(5):936-945.
16. Ong BL, Hodson SA, Wigham T, et al. Evidence for keratin proteins in normal and abnormal human meibomian fluids. Curr Eye Res. 1991;10:1113-1119.
17. Tomlinson A, Bron AJ, Korb DR, et al. The international workshop on meibomian gland dysfunction: report of the diagnosis subcommittee. Invest Ophthalmol Vis Sci. 2011;52(4):2006-2049.
18. Obata H. Anatomy and histopathology of human meibomian gland. Cornea. 2002;21(7 Suppl):S70‐S74.
19. Nelson DJ, Shimazaki J, Benitez-del-Castillo JM, et al. The international workshop on meibomian gland dysfunction: report of the definition and classification subcommittee. Invest Ophthalmol Vis Sci. 2011;52(4):1930-1937.
20. Knop E, Ludescher M, Knop N. Keratinisation status and cytokeratins of the human meibomian gland epithelium. Acta Ophthalmol. 2009;87:2232.
21. Plewig G, Kligman AM. The effect of selenium sulfide on epidermal turnover of normal and dandruff scalps. J Soc Cosm Chem. 1969;20:767-775.
22. Rapaport M. A randomized, controlled clinical trial of four anti-dandruff shampoos. J Int Med Res. 1981;9(2):152-156.
23. Wong AS, Fasanaella RM, Haley LD, Marshall CL, Krehl WA. Selenium (selsun) in the treatment of marginal blepharitis. AMA Arch Ophthalmol. 1956;55(2):246-253.
24. Piérard-Franchimont C, Arrese JE, Piérard GE. Sebum flow dynamics and antidandruff shampoos. J Cosmet Sci. 1997;48:117-121.
25. Cohen PR, Anderson CA. Topical selenium sulfide for the treatment of hyperkeratosis. Dermatol Ther (Heidelb). 2018;8(4):639‐646.
26. Istrate D, Popescu C, Möller M. Non-isothermal kinetics of hard alpha-keratin thermal denaturation. Macromolecular Bioscience. 2001;9(8):805-812.
27. Akyol-Salman I, Azizi S, Mumcu U, Baykal O. Efficacy of topical N-acetylcysteine in the treatment of meibomian gland dysfunction. J Ocul Pharmacol Ther. 2010;26(4):329-333.
28. Akyol-Salman I, Azizi S, Mumcu UY, Ates O, Baykal O. Comparison of the efficacy of topical N-acetyl-cysteine and a topical steroid-antibiotic combination therapy in the treatment of meibomian gland dysfunction. J Ocul Pharmacol Ther. 2012;28(1):49-52.
Laura M. Periman, MD
Founder and Director of Clinical Research, Periman Eye Institute, Seattle
Consultant (Alcon, Allergan, Bruder, Eyedetec, Eyevance Pharmaceuticals, Horizon, Johnson & Johnson Vision, Lumenis, Novartis, Olympic Ophthalmics, Quidel, Science Based Health, Sight Sciences, Sun Pharmaceuticals, TearLab, Visant Medical)