SBIR-STTR Award

Demodex (folliculorum and brevis) mites are microscopic ectoparasites that commonly infest the pilosebaceous unit of the skin. Uncontrolled overgrowth of these mites has been implicated in causing rosacea in the face, blepharitis in the eyelid, and other inflammation-associated conjunctival and corneal abnormalities. We have conducted a number of studies to substantiate the potential pathogenicity of demodex mites in causing eye irritation and inflammation in patients. We have improved the accuracy of diagnosing demodex infestation based on sampling lashes from the patient, and established that lashes harboring cylindrical dandruff are a reliable sign indicative of demodex infestation. Furthermore, we have developed an in vitro assay to screen agents that can potentially kill adult demodex mites. Using this assay, we have discovered that the Baby Shampoo does not, but tea tree oil (TTO), an essential oil distilled from Melaleuca alternifolia does, kill mites. We further showed that weekly office lid scrub with 50% TTO solution followed by daily home lid hygiene with tea tree shampoo can eradicate ocular Demodex in a majority of the suffering patients. However, this regimen achieves eradication of demodex infestation in the majority, but not all, of the patients, generates eye irritation in some patients, and is still not simple enough for patients to self administer it at home. In the SBIR Phase I application, we would like to identify the most active ingredient in TTO that may kill adult demodex mites in vitro, to examine the safety/toxicity of ophthalmic formulations containing this active ingredient in an in vitro cytotoxicity test and rabbit eyes, and to determine the stability of such formulations under different storage conditions and durations. Accomplishment of these three aims will allow us to collect sufficient data for obtaining an IND approval from the FDA so that we may conduct, in Phase II, clinical studies, eventually leading to the development of the first FDA-approved prescription ophthalmic formulation containing the most active ingredient in TTO to eradicate ocular demodex infestation in this most common eye disease.

Public Health Relevance:
This research is aimed to developing the first FDA-approved prescription drug containing the most active ingredient in tea tree oil to eradicate Demodicosis (the microscopic infestation of the hair follicle and the oil gland by Demodex mites) commonly occurring in the skin and the eyelid. Demodicosis is one of the leading causes of blepharitis, a common eye disease, for which eradication has not been achieved by any over-the-counter lid scrub regimen. Because Demodex infestation is prevalent in the older population, an effective treatment as such for eradicating Demodicosis for the eye will address an important public health concern when the aging population is increased, and help to develop a similar treatment for the skin in the future.

Public Health Relevance Statement:
PROJECT NARRATIVE This research is aimed to developing the first FDA-approved prescription drug containing the most active ingredient in tea tree oil to eradicate Demodicosis (the microscopic infestation of the hair follicle and the oil gland by Demodex mites) commonly occurring in the skin and the eyelid. Demodicosis is one of the leading causes of blepharitis, a common eye disease, for which eradication has not been achieved by any over-the-counter lid scrub regimen. Because Demodex infestation is prevalent in the older population, an effective treatment as such for eradicating Demodicosis for the eye will address an important public health concern when the aging population is increased, and help to develop a similar treatment for the skin in the future.

NIH Spending Category:
Aging; Eye Disease and Disorders of Vision; Infectious Diseases; Vector-Borne Diseases

Project Terms:
21+ years old; Accuracy of Diagnosis; Acne Rosacea; Address; Adult; Assay; Bioassay; Biologic Assays; Biological Assay; Blepharitis; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Conjunctivitis; Cornea; Data; Development; Diagnostic Method; Diagnostic Procedure; Diagnostic Technique; Drug Formulations; Drug Prescribing; Drug Prescriptions; Dryness of eye; Eye; Eye diseases; Eyeball; Eyelash; Eyelid structure; Eyelids; FDA approved; Face; Formulation; Formulations, Drug; Future; Gland; Goals; Hair Follicle; Hair follicle structure; Home; Home environment; Human, Adult; Hygiene; INFLM; In Vitro; Inflammation; Killings; Lesion; Lipids; Mammals, Rabbits; Melaleuca; Melaleuca alternifolia; Melaleuca alternifolia Oil; Methods; Microscopic; Mites; Modification; Mono-S; MonoS; Ocular Rosacea; Oils; Oils, Essential; Oils, Volatile; Older Population; Oryctolagus cuniculus; Palpebra; Pathogenicity; Pathology; Patients; Phase; Plant Leaves; Posterior blepharitis; Prescriptions, Drug; Protocols, Treatment; Public Health; RGM; Rabbit, Domestic; Rabbits; Refractory; Regimen; Research; Rest; Rosacea; Rosaceae; SBIR; SBIRS (R43/44); Safety; Sampling; Self-Administered; Sight; Skin; Small Business Innovation Research; Small Business Innovation Research Grant; Solutions; Steam; Symptoms; Tea; Tea Tree Oil; Terpene Compound; Terpenes; Terpenoids; Therapeutic Agents; Toxic effect; Toxicities; Treatment Protocols; Treatment Regimen; Treatment Schedule; Trees; Vascularization; Vision; Volatile Oils; adult human (21+); aging population; base; clinical investigation; conventional therapy; corneal; cytotoxic; cytotoxicity test; diagnostic accuracy; dry eye; effective therapy; eye disorder; eye dryness; facial; improved; in vitro Assay; irritation; leaf; meibomian gland dysfunction; ophthalmopathy; public health medicine (field); public health relevance

Demodex mites are microscopic ectoparasites that commonly infest the pilosebaceous unit of the skin. Uncontrolled overgrowth of mites has been implicated in causing papulopustular lesions in the skin, rosacea in the face, and blepharitis in the eye. Blepharitis (lid margin inflammation) associated with mite-harboring cylindrical dandruff in eyelashes is one of the most common eye diseases. The conventional treatment, using lid scrub with Baby Shampoo, is ineffective in eradicating ocular Demodex infestation (demodicosis). However, we have discovered that tea tree oil (TTO), a natural essential oil steam-distilled from the leaf of Melaleuca alternifolia, is effective in treating ocular demodicosi. Our preliminary clinical studies showed that the lid scrub regimen, based on a weekly office scrub with 50% TTO followed by daily home scrubs with tea tree shampoo, is effective in resolving irritating symptoms and ocular surface inflammation, as well as in improving vision in a number of patients. However, this treatment was not convenient for patient self-administration and resulted in ocular irritation in some patients. We have completed the following three Aims described in Phase I application to identify the most active ingredient in TTO responsible for killing Demodex mites and to eliminate the remaining ingredients in order to develop single-use Cliradex(R) Pads to facilitate the patient's ease of self- administration (Aim 1), to complete preclinical safety studies to verify that this new Cliradex(R) Pad was non- irritative based on an in vitro cytotoxic assay and 9 Repeated Insult Patch Test in human subjects (Aim 2), and to demonstrate that the new formulation exerts potent anti-microbial effects, thus eliminating the need to add preservatives, and is stable both in the glass jar and in the packette (Aim 3). In this Phase II application, we propose to conduct randomized, double-blind, controlled clinical trials to demonstrate the safety and efficacy of the single-use Cliradex(R) Pad compared to the Placebo Pad for treating ocular demodicosis. In Aim 1, at a single site, we will determine the optimal regimen for applying Cliradex(R) Pads to achieve maximal reduction in ocular Demodex counts and clinical improvement in patients'symptoms and signs without eliciting adverse events by comparing three different lid scrub regimens for a period of 1 month. In Aim 2, at multiple sites, we will use the lid scrub regimen optimized in Aim 1 to determine the optimal duration to achieve maximal reduction of ocular Demodex counts and maximal efficacy in resolving patient's inflammatory symptoms and signs. Accomplishment of these two Aims will allow us to gather data for Phase III FDA pivotal studies so that an NDA can be submitted to for the ultimate goal of developing the first FDA-approved prescription ophthalmic therapy containing the most active ingredient of TTO to eradicate ocular demodicosis.

Public Health Relevance:
Our proposed randomized, double-blind, controlled clinical trials described in this Phase II application aim to demonstrate the clinical safety and efficacy o single-use Cliradex(R) Pads that contain the most active ingredient identified during the Phase I grant from tea tree oil to eradicate ocular demodicosis. During Phase I, we have gathered strong data supporting that the new formulation also exerts unique broad-spectrum anti- microbial effects, thus eliminating the need for adding preservatives. Furthermore, we have verified that this new formulation is not irritative based on an in vitro cytotoxic assay and 9 Repeated Insult Patch Test in human subjects, and the new formulation is stable both in the glass jar and in the packette. Hence, our accomplishments during Phase I justifies our further pursuit of the two Aims described herein so that we may eventually develop a new safe, effective, and convenient treatment for eradicating ocular demodicosis, which is one of the most common causes of blepharitis that has plagued patients with ocular irritation, especially in our aging population.