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.

CONCLUSION

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.