Method of treatment

Abstract

A new method of treating a skin disease or condition in a human subject caused by a parasite, particularly Demodex mite infestations that result in demodicosis, with moxidectin. The demodicosis is typically Demodex blepharitis.

Description

Method of treatmentRelated Application

[0001] This application claims priority to United States provisional application no 63 / 669787 (filed 11 July 2024) and Australian provisional application no 2024902536 (filed 14 August 2024), the entire contents of which are incorporated herein by reference.Field of the invention

[0002] The invention relates to a new method of treating a skin disease or condition in a human subject caused by a parasite, particularly Demodex mite infestations, with moxidectin.Background of the invention

[0003] Parasites can infest the skin, leading to itching, inflammation, and various skin manifestations. Common parasites causing skin infections and conditions include mites, lice, and worms.

[0004] The Demodex mite is commonly found in healthy human adults. It is also found in dogs and can cause mange. Demodex mites however are host-specific and the diseases caused between humans and dogs differ significantly. The causative mites in dogs are Demodex canis or Demodex injal. Hence the treatment must be tailored for the mite.

[0005] Demodex folliculorum and Demodex brevis, are the mites found in human skin, especially the cheeks, nose, and eyelids. Mite density is low in healthy skin however skin symptoms may occur, usually because of one or more of imbalance in the immune mechanisms, declining health and increasing age. Demodicosis, also known as demodicidosis, is the term for Demodex mite infestation and typically presents with a variety of clinical manifestations. Pityriasis folliculorum manifests as erythematous patches with dry, rough skin due to increased scale within hair follicles on the face; rosacea-like demodicosis consists of dry, itchy, burning erythematous skin with papulopustular lesions; and folliculitis-like demodicosis typically manifests as localised follicular pustules mimicking acne or folliculitis Demodicosis may also present with clinical symptoms that looked like acne vulgaris. (Paichitrojjana, 2022).

[0006] While Demodex and scabies are both mite infestations, they are different mites, with different pathologies that cause distinct conditions. Scabies is caused by the human itch mite (Sarcoptes scabiei) which burrows into the epidermis to lay eggs, causing intense itching and a rash. Demodex mites in contrast colonise hair follicles, so treatments against Demodex mites face different challenges to treatments for the scabies mites.

[0007] As a result of this colonisation of hair follicles, which includes eye lashes, Demodex mite infestations in humans have also been implicated in ocular demodicosis, often presenting as blepharitis, a chronic inflammation of the eyelid margin characterised by erythema, ocular irritation and discomfort, discharge and debris on the eyelids and lashes, and eyelash anomalies. In more advanced stages, there may be corneal involvement, such as punctate epithelial erosions, infiltrates, epithelial defects, or keratitis. The chronic and recurring nature of some eyelid infections including Demodex blepharitis is a reflection of the challenge in treating them. And repeated infections can lead to scarring of the inner eyelid which makes future treatments even more challenging.

[0008] T reatments for dermatological presentations of Demodex infestation are numerous (Paichitrojjana, 2022) and include topical metronidazole, permethrin, benzoyl benzoate, crotamiton, lindane, and sulfur. Tea tree oil has also been utilised but is unproven in mite eradication and it not acaricidal below a concentration of 50%. Permethrin cream 5% was effective in reducing the number of demodex mites and blepharitis symptoms (Hecht et al., 2019). But most of these treatments have highly variable outcomes depending on what condition is being treated, and moreover, some are limited to being symptomatic therapies that often failed to eradicate the mites.

[0009] Off label use of topical ivermectin 1% has also been investigated (Trave et al., 2019) as has oral ivermectin (Holzchuh, F. G. et al. 2011 ; and Aleksandra L L, et al. 2022). Topical ivermectin however can lead to an increase in inflammation and discomfort, and the oral ivermectin can cause gastrointestinal discomfort, nausea, and diarrhea.

[0010] A recently approved treatment for Demodex blepharitis is an eyedrop formulation of lotilaner which must be instilled into the eyes of effected patients twice daily for 6 weeks (Yeu et al., 2023).

[0011] There are no approved oral treatments for demodex infestation, and as outlined above, the other existing treatments are either poorly effective, effective for only short periods of time, have undesirable side effects (especially for Demodex infestations in the sensitive eyelid skin), fail to eradicate the mites or are inconvenient to use. There is therefore a need for more effective, more convenient methods to treat Demodex infestations in subjects with clinical symptoms of infestation.

[0012] Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and / or combined with other pieces of prior art by a skilled person in the art.Summary of the invention

[0013] Given the long half-life of moxidectin, it is expected to remain at efficacious concentrations in tissues that are infested with Demodex mites for an extended period of time leading to death of both adult demodex mites and their progeny and thereby conferring the advantages to the invention over existing treatments.

[0014] In a first aspect of the invention there is provided a method of treating or preventing a parasite infection in a human subject comprising administration of moxidectin, or a pharmaceutically acceptable salt thereof.

[0015] In a related aspect of the invention there is provided a method of treating or preventing a skin disease or condition in a human subject with a parasite infection, comprising administration of moxidectin, or a pharmaceutically acceptable salt thereof.

[0016] In an alternative aspect of the invention there is provided use of moxidectin, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a parasite infection in a human subject or for treating a skin disease or condition in a human subject with a parasite infection.

[0017] In a further aspect of the invention there is provided moxidectin, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a parasite infection in a human subject or for use in treating a skin disease or condition in a human subject with a parasite infection.

[0018] In each of these aspects of the invention, the parasite infection is an ectoparasite, preferably a Demodex mite. Human Demodex mites are Demodex folliculorum or Demodex brevis.

[0019] When the parasite infection is a Demodex mite infestation, the skin disease or condition is demodicosis, including ocular demodicosis. When the skin disease or condition is ocular demodicosis, it is preferably Demodex blepharitis.

[0020] In one embodiment of the methods and uses of the invention the moxidectin, or pharmaceutically acceptable salt thereof, is to be administered orally or topically, preferably orally. In this embodiment, the oral treatment regimen is preferably 1 -3 doses of an oral formulation of moxidectin, wherein the moxidectin is a medium dose of 10- 20mg; preferably 16mg; or a high dose of 20-40mg; preferably 32mg. In the alternative embodiment the topical treatment regimen is preferably 1 -3 doses of a topical formulation of 1% moxidectin.

[0021] In an alternative embodiment, the moxidectin or pharmaceutically acceptable salt thereof, used in the methods and uses of the invention is a moxidectin combination regimen, wherein both oral and topical moxidectin are utilized. In this embodiment there is provided a moxidectin combination regimen for Demodex mite infection in a human subject wherein the treatment regimen is selected from: a) 1 dose of an oral formulation of moxidectin and then 1 -2 doses of a topical formulation of 1% moxidectin, wherein the oral moxidectin is a high dose of 20- 40mg; preferably 32mg, or a medium dose of 10-20mg; preferably 16mg; or a low dose oral dose of 1 -1 Omg; preferably 8mg; b) 1 dose of a topical formulation of 1% moxidectin and then 1 -2 doses of an oral formulation of moxidectin, wherein the oral moxidectin is a high dose of 20-40mg; preferably 32mg, or a medium dose of 10-20mg; preferably 16mg; or a low dose oral dose of 1 -1 Omg; preferably 8mg; c) 1 dose of an oral formulation of moxidectin wherein the oral moxidectin is a high dose of 20-40mg; preferably 32mg; and then 1 dose of a topical formulation of 1% moxidectin; andd) 1 dose of a topical formulation of 1% moxidectin and then 1 dose of an oral formulation of moxidectin wherein the oral moxidectin is a high dose of 20-40mg; preferably 32mg.

[0022] Optionally two or more additional actives may be utilized in the methods and uses of the invention.

[0023] In each of the above mentioned aspects and embodiments of the invention the moxidectin may be micronized moxidectin or unmicronized moxidectin.

[0024] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.Brief description of the drawings

[0025] Figure 1 : Molecular Structure of Moxidectin

[0026] Figure 2A: Graph of mean change in BLISS score at day 42. M / M are participants who had received two 8mg oral doses of moxidectin; M / P are participants who received a single dose of moxidectin and a placebo dose; and P / P are double placebo dose participants.

[0027] Figure 2B: Graph of day 42 collarette counts following treatment with either placebo (P / P), or a single oral 8mg dose of moxidectin (M / P) or two oral doses of 8mg moxidectin (M / M).Definitions

[0028] For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

[0029] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.

[0030] "About" as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±5%, insome instances ±1 %, and in some instances ±0.1 % from the specified value, as such variations are understood by the skilled person to be appropriate to perform the disclosed methods.

[0031] Throughout this disclosure, various aspects of the disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1 , 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0032] By “skin disease or condition” it is meant pathologic conditions that affect the body's surfaces including skin, hair, nails and associated glands. A skin disease or condition in the context of this invention is caused by a parasite. Skin encompasses all skin surfaces including the eyelid and meibomian glands.

[0033] “Parasite infestation” and “parasite infection” are used interchangeably in this specification due to the nature of the parasite. Demodex mite for example is a parasite found on normal healthy skin. However when permitted to form an infestation with clinical manifestations, this is comparable to a parasite infection.

[0034] The term "moxidectin" as used herein, refers to(1 R, 4S, 4’5, 5'S, 65, 6’S, 85, 105,135,145,165,205,215,24S)-21 ,24-dihydroxy-4’- methoxyimino-5',11 ,13,22-tetramethyl-6'-[(5)-4-methylpent-2-en-2-yl]spiro[3,7,19- trioxatetracyclo[15.6.1 .14’8.020’24]pentacosa-10,14,16,22-tetraene-6,2'-oxane]-2-one, CAS [1 13507-06-5], also known as milbemycin B, a compound of molecular formula C37H53NO8 and as shown in Figure 1 .

[0035] Any reference to moxidectin is to be understood to be a reference to moxidectin, or a pharmaceutically acceptable salt thereof.

[0036] The term “micronize” or “micronization, as used herein, refers to a process of reducing the particle size of solid substances to micron-scale dimensions. By this it isunderstood that substantially all (ie 90% or more) of the particles in a micronized sample are smaller than 10 microns. A micronized sample may also be defined in terms of its particle size distribution of a D(10) = 1 pm, D(50) = 2 pm, D(90) = 10pm.

[0037] The term “unmicronized” as used herein refers to moxidectin that has not been intentionally or deliberately subjected to any particle size reduction or micronization processes. The moxidectin may be sourced from any manufacturer / supplier of moxidectin as an ingredient.

[0038] The term “unmicronized moxidectin” may additionally, or alternatively, be characterised by the size of the particles in a sample. By this it is understood that substantially all (ie 90% or more) of the particles in an unmicronized sample are larger than 10 microns.

[0039] An unmicronized sample may additionally, or alternatively, be defined in terms of its particle size distribution. Particle size distribution (PSD) as used herein refers to the range of particle sizes present in a sample. Percentages are specified per size interval (fraction) or cumulative values are used, in which the fractions are added up in ascending or descending order of size. A PSD for micronized compared to unmicronized moxidectin may be as follows:

[0040] A D-value, or a Dv value, as used herein, is the diameter which, when all particles in a sample are arranged in order of ascending mass, divides the sample's mass into specified percentages. The percentage mass below the diameter of interest is the number expressed after the "D". The length unit, DX represents the X% of particles in the powders are smaller than this size. Typically, the unit is pm, ie microns. It can also be represented by statistical symbols such as DV10 or DV(0.1 ). V means total volume. For example, D90, DV90 or DV(0.9) means that 90% of the total particles in a sample are smaller than this size. Any reference to a D value is to be understood to be equivalent to a DV volume and vice versa.

[0041] D50 is also referred to as the median particle size.

[0042] A D value can refer to a range. For example, a D90 of 500 means that 90% of all particles in a sample are less than 500 microns. But in the context of a D90 range, it will be understood as meaning that 90% of the particles in the sample have a size range of 20-500 microns.

[0043] The term "pharmaceutically acceptable" as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation and for the end use. For example "ophthalmically acceptable " refers to compounds, compositions, and / or solutions which are, within the scope of sound medical judgment, suitable specifically for contact with the tissues of the eye, and the area surrounding the eye without excessive toxicity, or irritation.

[0044] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0045] As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material which is included in the composition for a purpose other than pharmaceutical efficacy (this is not intended to exclude materials which may have some biological effect).

[0046] As used herein, "preventing" or "prevention" is intended to refer to at least the reduction of likelihood of the risk of (or susceptibility to) acquiring a disease or condition (i.e., causing at least one of the clinical symptoms of the disease not to develop in an individual that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease). Biological and physiological parameters for identifying such patients are provided herein and are also well known by physicians. The skilled artisan will appreciate that "prevention" is not an absolute term. In particularly preferred embodiments, the methods of the present invention can be to prevent or reduce the severity, or inhibit or minimize progression, of a symptom of a disease or condition as described herein. Or to prevent a recurrence in patients prone to the same, or those who are immunosuppressed. As such, the methods of the present invention have utility as treatments as well as prophylaxes.

[0047] The terms "treatment" or "treating" of a subject includes delaying, slowing, stabilising, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the disease or condition, the symptom of the disease or condition, or the risk of (or susceptibility to) the disease or condition. The term "treating" refers to any indication of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of symptoms or making the injury, pathology or condition more tolerable to the individual; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating. Treatment may not necessarily result in the complete clearance of a disease or disorder but may reduce or minimise complications and side effects of infection and the progression of a disease or disorder.

[0048] The term “therapeutically-effective amount,” as used herein, pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, or a treatment regime and the components thereof, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen.

[0049] The term “prophylactically-effective amount,” as used herein, pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, or a prevention regime and the components thereof, which is effective for producing some desired prophylactic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired prevention regimen.

[0050] The term “acaricidal amount”, as used herein, pertains to the amount of an active compound, or a material, composition or dosage form comprising an active compound, or a treatment or prevention regime and the components thereof, which is effective for killing ticks or mites, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment or prevention regimen.

[0051] The term “infestation” when used in the context of mites, is intended to refer to an increase in the numbers of mites above those commonly found in healthy, asymptomatic humans such that their presence in increased numbers results in symptoms. Parasite infestation is therefore used interchangeably with, or to be equivocal to, parasite infection.Detailed description of the embodiments

[0052] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.Moxidectin

[0053] Moxidectin (Figure 1 ), a macrocyclic lactone of the milbemycin class, is a semi-synthetic product from the actinomycete S. cyanogriseus. Moxidectin is a broadspectrum endectocide with the chemical name of(1 E,4S,4'E,5'S,6E,6'S,8E,10E,13E,14E,16E,20E,21 F?,24S)-21 ,24-dihydroxy-4’- methoxyimino-5',11 ,13,22-tetramethyl-6'-[(E)-4-methylpent-2-en-2-yl]spiro[3,7,19- trioxatetracyclo[15.6.1 .14’8.020’24]pentacosa-10,14,16,22-tetraene-6,2'-oxane]-2-one. Endectocides are drugs applied directly to hosts to kill endoparasites and ectoparasites.

[0054] Moxidectin is a stable white or pale-yellow amorphous powder. The compound exhibits low solubility and high permeability (Biopharmaceutics Classification System Class 2). Moxidectin is lipophilic (log P = 5.4), resulting in a large volume of distribution, with notable uptake in adipose tissue. It is slightly soluble in water, and readily soluble in organic solvents such as methylene chloride, diethyl ether, ethanol, acetonitrile, and ethyl acetate. Importantly for its use in the invention, resistance to moxidectin appears to emerge slowly and it is considered likely that moxidectin’s combined potency and extended duration of exposure limit the potential for development of resistance (Prichard and Geary, 2019). This is borne out in extensive veterinary experience, where moxidectin has a higher threshold for resistance and remains effective in ivermectin resistant strains.

[0055] Moxidectin has a similar molecular structure to ivermectin (IVM), a member of the avermectin family; however, moxidectin differs from ivermectin in that ivermectin has a disaccharide side chain at C-13, whereas MOX has a methoxime at C-23 and an unsaturated side chain at C-25 (Hayes 1994). These structural differences have a significant impact on the physical and physiological properties of these two drugs.

[0056] Topical moxidectin formulations have been used extensively in veterinary medicine. Despite this, and the development of other mectins such as ivermectin as a topical and oral human therapeutic, moxidectin’s use in human indications is very limited, having only been approved to date to treat river blindness (onchocerciasis) caused by the roundworm parasite Onchocerca volvulus.Methods of treatment and uses

[0057] In one aspect of the invention there is provided a method of treating a parasite infection in a human subject comprising administration of moxidectin, or a pharmaceutically acceptable salt thereof.

[0058] In another aspect of the invention, there is provided a method of treating a skin disease or condition in a human subject with a parasite infection, comprising administration of moxidectin, or a pharmaceutically acceptable salt thereof.

[0059] In the abovementioned methods of the invention, the parasite infection is an infestation by an ectoparasite, and preferably the Demodex mite. Two species live on humans: Demodex folliculorum and Demodex brevis, both frequently referred to as eyelash mites, face mites or skin mites. Accordingly, in embodiments of these aspects of the invention, there is provided: a method of treating a parasite infection in a human subject; or a method of treating a skin disease or condition in a human subject with a parasite infection, comprising administration of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the parasite infection is an infestation by Demodex mite, preferably selected from Demodex folliculorum and Demodex brevis, most preferably Demodex folliculorum.

[0060] Demodex mite infestation results in demodicosis (also known as demodicidosis). Demodicosis is an inflammatory skin disease with a variety of clinical manifestations including pityriasis folliculorum which manifests as erythematous patch with dry, rough skin due to the increased scale within hair follicles on the face; rosacealike demodicosis which consists of dry, itchy, burning erythematous skin with papulopustular lesions; and folliculitis-like demodicosis which typically manifests as localised follicular pustules mimicking acne or folliculitis.

[0061] Accordingly, in one embodiment of the invention there is provided a method of treating a skin disease or condition in a human subject with a parasite infection, comprising administration of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the parasite infection is an infestation by Demodex mite, and the skin disease or condition is demodicosis.

[0062] Demodicosis may also more specifically be ocular demodicosis. Patients with ocular demodicosis may have eye irritation, itching and scaling of eyelids (blepharitis or eyelid dermatitis). More particularly, Demodex blepharitis is a chronic inflammatory disease, affecting the skin of the eye lid margin and in turn, potentially the ocular surface. Accordingly, in another embodiment of the invention, there is provided amethod of treating a skin disease or condition in a human subject with a parasite infection, comprising administration of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the parasite infection is an infestation by Demodex mite, and the skin disease or condition is ocular demodicosis, preferably Demodex blepharitis.

[0063] In humans, following oral administration, moxidectin is rapidly absorbed, extensively distributed into tissues and exhibits tissue distribution limited elimination, contributing to a long plasma t1 / 2 in humans. But Demodex mites live in hair follicles and oil glands, and these tissues are not perfused with plasma.

[0064] Without being bound by any theory, it is believed that the orally administered moxidectin of the invention penetrates the tissues where Demodex mites feed and remains at acaricidal concentrations for an extended period of time in those tissues that are infested with Demodex mites, leading to death of both adult demodex mites and more importantly, their progeny. The short-term effect of existing treatments is thought to be due to the treatments not persisting for long enough to kill the progeny, and subjects suffering from relapsing infections.

[0065] Given the Demodex mite is found on normal skin, some human subjects may find that they suffer from recurring infestations despite previous successful treatment. Normal levels of Demodex mite may increase to infestation levels that results in symptoms in human subjects who are, for example, immunocompromised, tired, ill with other infections / conditions, or in the elderly. In those human subjects they may benefit from taking moxidectin, or a pharmaceutically acceptable salt thereof, in a prophylactic manner to avoid or reduce those incidences of flare ups and recurrences. Accordingly, in embodiments of this aspect of the invention, there is provided: a method of preventing or reducing the risk of a parasite infection in a human subject; or a method of preventing or reducing the risk of treating a skin disease or condition in a human subject with a parasite infection, comprising administration of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the parasite infection is an infestation by Demodex mite, preferably selected from Demodex folliculorum and Demodex brevis, most preferably Demodex folliculorum and the skin disease or condition is demodicosis including ocular demodicosis.

[0066] In an alternative aspect of the invention there is provided use of moxidectin, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for one or more of:• treating or preventing a parasite infection in a human subject;• treating a skin disease or condition in a human subject with a parasite infection;• preventing or reducing the risk of a parasite infection in a human subject; and• preventing or reducing the risk of treating a skin disease or condition in a human subject with a parasite infection, wherein the parasite infection is an infestation by Demodex mite, preferably selected from Demodex folliculorum and Demodex brevis, most preferably Demodex folliculorum and the skin disease or condition is demodicosis including ocular demodicosis.

[0067] In an alternative aspect of the invention there is provided moxidectin, or a pharmaceutically acceptable salt thereof, for use in one or more of:• treating or preventing a parasite infection in a human subject;• treating a skin disease or condition in a human subject with a parasite infection;• preventing or reducing the risk of a parasite infection in a human subject; and• preventing or reducing the risk of treating a skin disease or condition in a human subject with a parasite infection, wherein the parasite infection is an infestation by Demodex mite, preferably selected from Demodex folliculorum and Demodex brevis, most preferably Demodex folliculorum and the skin disease or condition is demodicosis including ocular demodicosis.Pharmaceutical formulations

[0068] While it is possible for the moxidectin, or a pharmaceutically acceptable salt thereof, to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation) comprising moxidectin, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.

[0069] The moxidectin, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising moxidectin may be administered to a subject by any convenient route of administration including enteral administration, parenteral administration, topical administration and inhalation. Preferably the moxidectin, or a pharmaceutically acceptable salt thereof, is to be formulated for enteral administration, more preferably oral administration; or topical administration.

[0070] Thus, the present invention further provides pharmaceutical compositions for use in the methods of the invention, as defined above, and methods of making a pharmaceutical composition comprising admixing moxidectin, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilisers, or other materials, as described herein.

[0071] In one embodiment of the invention, the moxidectin in the pharmaceutical composition is micronized. In an alternative embodiment of the invention, the moxidectin in the pharmaceutical composition is unmicronized. The term “unmicronized” as used herein refers to moxidectin that has not been intentionally or deliberately subjected to any particle size reduction or micronization processes.

[0072] The unmicronized moxidectin of the invention may be characterized in one or more ways. i) By processThis refers to moxidectin that has not been intentionally or deliberately subjected to any particle size reduction or micronization processes. As micronization for pharmaceutical purposes typically seeks to reduce the particle size of the active to less than 10 microns, it is anticipated that substantially all (ie >90) of the particles of unmicronized moxidectin will be larger than 10 microns. ii) By particle sizeThe moxidectin particles can be characterised by their size in microns (pM). Substantially all (ie >90%) of the particles have a diameter of greater than about 10 microns, greater than about 20 microns, greater than about 30 microns, greater than about 40 microns, greater than about 50 microns greater, than about 60 microns, greater than about 70 microns, greater than about 80 microns, greater than about 90microns and greater than about 100 microns. Preferably substantially all of the particles have a diameter that is in the range of 20 to 500 microns. iii) By particle size distribution (PSD)Particle size distribution (PSD) refers to the range of particle sizes present in a sample. D50 is the most common way of defining the median particle size in a sample. Two points ie the D90 and D10 can be used to describe the coarsest and finest parts of the distribution. A three point specification featuring the D10, D50, and D90 can also be used. For example:

[0073] Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.

[0074] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

[0075] General information on types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts such as “Handbook of Pharmaceutical salts” P. H. Stahl, C. G. Wermuth, 1st edition, 2002, Wiley-VCH and S. M. Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0076] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods includethe step of bringing into association the moxidectin with the carrier which constitutes one or more accessory ingredients.

[0077] Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.

[0078] Formulations suitable for oral administration (e.g. by ingestion) may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of moxidectin; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.

[0079] A tablet may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine moxidectin in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); glidants (e.g. colloidal silicon dioxide, talc, magnesium carbonate, fumed silica); disintegrants (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxy methyl cellulose); surface -active or dispersing or wetting agents (e.g. sodium lauryl sulfate); and preservatives (e.g. methyl p- hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of moxidectin therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

[0080] Preferably when the pharmaceutical formulation of moxidectin is a tablet, the tablet is not a chewable tablet.

[0081] Accordingly, there is provided:a method of treating or preventing a parasite infection in a human subject; or a method of treating or preventing a skin disease or condition in a human subject with a parasite infection, comprising oral administration of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the parasite infection is an infestation by Demodex mite, preferably selected from Demodex folliculorum and Demodex brevis and the skin disease or condition is demodicosis including ocular demodicosis.

[0082] In alternative embodiments, the moxidectin, or a pharmaceutically acceptable salt thereof is formulated for topical administration to the skin. For example, as a cream, ointment, wipe, salve, or gel.

[0083] In alternative embodiments, the moxidectin, or a pharmaceutically acceptable salt thereof is formulated for topical administration to one or more of the eyes, eyelids, or eyelashes of one or more eyes of a human subject with, or at risk of, ocular demodicosis. For example, as an eye drop, cream, ointment, eye wash, eyelid scrub, wipe, salve, or gel. For treatment of ocular demodicosis the topical formulation of moxidectin, or pharmaceutically acceptable salt thereof is formulated with ophthalmically acceptable excipients, diluents, or carriers. As would be known to the skilled person, this means using compounds, compositions, and / or solutions, suitable specifically for contact with the tissues of the eye, and the area surrounding the eye without excessive toxicity, or irritation. They include, without limitation, surfactants, pH adjusting agents, preservatives, antioxidants, chelating agents, stabilizers, viscosity increasing agents, adhesive polymers, in situ gelling polymers, penetration enhancers, diluents and tonicity adjusting agents.

[0084] An eyedrop formulation in particular may be designed to specifically and simultaneously treat blepharitis and Demodex in both the eyelash follicles and / or the meibomian glands. As Demodex mites reside in both the eye lash hair follicles and in the meibomian glands, it can be advantageous for the eye drop formulation to be directly applied to one or both of these locations.

[0085] An eyelid scrub containing moxidectin may also be formulated to specifically and simultaneously treat blepharitis and Demodex. Eyelid scrubs of the invention arenonabrasive solutions that clean the eyelids and sooth the irritation associated with blepharitis, and can kill the Demodex mites.

[0086] In an alternative embodiment there is provided: a method of treating or preventing a parasite infection in a human subject; or a method of treating or preventing a skin disease or condition in a human subject with a parasite infection, comprising topical administration of moxidectin, or a pharmaceutically acceptable salt thereof, wherein the parasite infection is an infestation by Demodex mite, preferably selected from Demodex folliculorum and Demodex brevis and the skin disease or condition is demodicosis including ocular demodicosis.

[0087] For human subjects wherein the skin disease or condition is ocular demodicosis, the topical administration of moxidectin, or a pharmaceutically acceptable salt thereof is applied directly to one or more of the eyes, eyelids, or eyelashes of one or more eyes of a human subject in need of treatment thereof, the moxidectin or a pharmaceutically acceptable salt thereof, formulated into an ophthalmic composition comprising a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eye. For ocular uses, the topical formulation is typically applied to the upper and lower eyelid and the surrounding skin using a suitable applicator. The formulation is left in place for 5-20 minutes and then removed by wiping with a suitable eye pad or cloth.Oral Dosages

[0088] In each of the embodiments of the methods and uses of the inventions wherein oral moxidectin is utilised either alone or in combination with topical moxidectin, the moxidectin, or pharmaceutically acceptable salt thereof, is an oral dosage of between 2mg and 40 mg. That is, a dosage of (in mg amounts) 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39 or 40. Preferably the dosage is between 5mg and 20mg, and most preferably a dosage between 6mg and 12mg.

[0089] The oral dose may alternatively be classified as a low dose or a medium dose or high dose oral tablet:- a low dose solid oral dose of the invention comprises 1 -1 Omg of moxidectin, preferably 8mg;- a medium dose solid oral dose of the invention comprises 10-20mg of moxidectin, preferably 16mg; and- a high dose solid oral dose of the invention comprises 20-40mg of moxidectin, preferably 32mg.

[0090] The moxidectin may be micronized moxidectin or unmicronized moxidectin.Topical Dosages

[0091] In each of the embodiments of the methods and uses of the inventions wherein topical moxidectin is utilised either alone or in combination with oral moxidectin, the moxidectin, or a pharmaceutically acceptable salt thereof, may be a topical dosage of a cream, ointment or gel that contains between 0.01 and 5% moxidectin, preferably 0.05-4%, more preferably 1 -2.5% and most preferably 1%.

[0092] The moxidectin may be micronized moxidectin or unmicronized moxidectin.Treatment regimens

[0093] Preferably, the moxidectin, or a pharmaceutically acceptable salt thereof, is an oral formulation and the methods and uses of the invention in treating a Demodex mite infestation in a human subject, or treating a skin disease or condition in a human subject with a parasite infection that is a Demodex mite infestation only requires 1 -5 dosages of the moxidectin, or a pharmaceutically acceptable salt thereof. Preferably only 1 -2 dosages are required, and most preferably, only a single dosage is required. By using moxidectin, or a pharmaceutically acceptable salt thereof, preferably as an oral formulation, and more preferably as a single dose, the invention seeks to provide methods that will be effective in treating Demodex infestations and skin diseases or conditions in a human subject with a Demodex infestations with (i) superior efficacy to currently available treatments and (ii) improved convenience for the human subject. This is particularly the case when compared to the current bilateral eyedrop needed twice daily for 6 weeks for Demodex blepharitis.

[0094] The embodiments of the invention involving a single oral dose are preferably a high dose oral dose comprising 20-40mg of moxidectin, preferably 32mg.

[0095] A treatment regimen may also involve a combination of oral moxidectin and / or topical moxidectin. Exemplary combination treatment regimens include:• 1 -3 oral doses• 1 -3 oral doses and a follow on of one topical doses to ensure complete eradication of the Demodex infestation• a single oral dose and a follow on of one or more topical doses to ensure complete eradication of the Demodex infestation• an initial topical dose for immediate relief of symptoms followed by 1 -3 oral doses• one or more topical doses followed by a single oral dose• a single oral dose and a single topical dose• one or more topical doses only.

[0096] The number of oral and / or topical doses and the choice of the treatment regimen may be dictated by, for example, the extent and severity of the infection and symptoms, whether it is a new infection or a recurrent infection, whether it is a “flare up” of a current infection, the elapsed time between initial and subsequent doses, the age of the patient, the dexterity of the patient, patient compliance, patient preference and patient concern with touching their eyes.

[0097] The number of oral and / or topical doses and the choice of the treatment regimen may also be dictated by the concentration of moxidectin in the formulations, and whether the moxidectin is in combination with other actives ingredients. For example, with reference to the regimens outline above:Table 1 :

[0098] The frequency of dosing when there is more than a single dose can also be varied subject to the parameters already mentioned. But typically, for combination regimens of oral and then topical, the first topical dose will preferably be given on the same day as the oral. Thereafter, additional topical doses (if given) would be spaced one week apart. For combination regimens of topical and then oral, the first oral dose will preferably be given either on the same day as the topical or 1 -3 days after. Thereafter, additional oral doses (if given) would be spaced one week apart. For treatment regimens that are more than one oral dose (and no topical dose), or more than one topical dose (and no oral dose), each dose is preferably given one week apart.

[0099] There is therefore provided a method of treating a Demodex mite infection in a human subject, or a skin disease or condition in a human subject with a Demodex mite infection, by one or more of the moxidectin treatment regimens outlined above, preferably in accordance with frequency of dosing outlined above.

[0100] Alternatively, there is a use of the moxidectin treatment regimens outlined above, preferably in accordance with frequency of dosing outlined above, for treating a Demodex mile infection in a human subject, or a skin disease or condition in a human subject with a Demodex mite infection.

[0101] In preferred embodiments, the human subject is first diagnosed as having a Demodex infestation. Methods of diagnosis would be well known to the skilled person but include, without limitation, slit-lamp examination of the eyes and eyelids, dermoscopy, skin biopsy and skin scraping.

[0102] Combinations

[0103] In some embodiments of the invention, the moxidectin or pharmaceutically acceptable salt thereof is the sole active ingredient.

[0104] But in alternative embodiments, the pharmaceutical formulations of the invention may include additional active ingredients. For example, moxidectin may be used in combination with other acaricides including other macrocyclic lactones (eg ivermectin, eprinomectin), synthetic pyrethroids (eg permethrin, flumethrin), chlorinated hydrocarbons (eg, DDT and lindane), carbamates (eg carbaryl), organophosphorous compounds (eg, Diazinon, coumaphos), formamidines (eg, amitraz), and phenylpyrazoles (eg, fipronil), benzyl benzoate, tea tree oil, crotamiton, pyrantel pamoate and isoxazoline parasiticides (fluralaner, sarolaner, lotilaner, afoxolaner, and fluxametamide).

[0105] Moxidectin may also be used in combination with anti-inflammatory drugs, particularly anti-inflammatory eyedrops. Anti-inflammatory drugs may be non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antihistamines and local anesthetics.

[0106] The moxidectin may also be used in the methods of the invention in combination with other symptom relieving medications such as eyelid scrubs and saline eyedrops (artificial tears) that do not contain an active pharmaceutical ingredient.

[0107] The additional actives may be formulated as a single formulation, ie two or more actives in a single dosage form, or may be separately formulated but for simultaneous or sequential administration with the moxidectin formulation. As would be understood by the skilled person, the timing for sequential administration of the second active would ensure that the maximum benefit of the two or more actives is achieved.

[0108] In the combinations of the invention the moxidectin may be micronized moxidectin or unmicronized moxidectin.Examples

[0109] The invention will now be described by reference to the following non-limiting examples.Exemplary formulations

[0110] Oral tabletTable 2:

[0111] Topical formulationTable 3:Demodex Blepharitis

[0112] A clinical study determined the impact of one or two doses of 8mg oral moxidectin on the signs and symptoms of demodex blepharitis. Participants werescreened for eligibility during an initial Screening Visit. To be eligible, participants needed to have more than ten eye lashes with collarettes or sleeves present (Grade 2 or greater) on the upper lid of at least one eye.

[0113] Consenting subjects meeting initial eligibility criteria at the Screening Visit were randomized to one of the three study arms and given either moxidectin tablets or placebo tablets to swallow.

[0114] The randomization among the three study arms was:• Moxidectin two oral 8mg doses separated by one week (8 subjects)• Moxidectin single oral 8mg dose and a placebo oral dose (8 subjects)• Placebo two oral doses separated by one week (8 subjects)

[0115] Treatment evaluation occurred 42 days after the initial treatment using the efficacy endpoints of collarette count and (BLepharltlS Symptom) BLISS. The BLISS questionnaire is designed to collect and quantify blepharitis symptoms as reported by patients.Results

[0116] At Day 42, (Figure 2A) participants who had received two 8mg oral doses of moxidectin (M / M) had a notable reduction in their BLISS scores, compared to participants who received two doses of placebo (P / P). Participants who received a single dose of moxidectin (M / P) had no discernible improvement in their blepharitis symptoms, as measured using the BLISS questionnaire.

[0117] While two doses of moxidectin had a discernible effect on blepharitis symptoms as measured by BLISS score, the effect on collarette count was minimal. Figure 2B compares baseline (before treatment) and day 42 collarette counts following treatment with either placebo (P / P), or a single oral 8mg dose of moxidectin (M / P) or two oral doses of 8mg moxidectin (P / P). Little discernible difference between treatment groups can be detected.

[0118] The clinical study showed that while treatment with one or two doses of moxidectin may impact blepharitis symptoms and collarette counts, the effect on either outcome measure was insufficiently large to provide a significant clinical benefit to patients.

[0119] This was a surprising outcome because oral doses of 8mg moxidectin have previously been shown to be safe and effective for the treatment of multiple parasitic diseases (eg onchocerciasis (Bakajika et al., 2022), strongyloidiasis (Sprecher et al., 2024) and lymphatic filariasis (Koudou et al., 2025) ). This finding led the inventors to hypothesise that penetration of moxidectin from two 8mg doses, into the eyelash hair follicles was unexpectedly not sufficient alone to expose demodex mites to toxic levels of moxidectin.

[0120] A second clinical trial was designed to test (i) higher oral doses of moxidectin than had been used for other parasitic diseases; (ii) topical formulations of moxidectin applied directly to the eyelashes of affected individuals and (iii) combinations of high oral doses in combination with topical formulations applied to the eyelashes of affected individuals.

[0121] Topical moxidectin formulations will be prepared using pharmaceutically acceptable excipients and ranges in strength from 0.1% moxidectin to 5% moxidectin, preferably 1%.

[0122] Participants will be screened for eligibility during an initial Screening Visit. To be eligible, participants needed to have more than ten eye lashes with collarettes or sleeves present (Grade 2 or greater) on the upper lid of at least one eye.

[0123] Consenting subjects meeting initial eligibility criteria at the Screening Visit will be randomized to one of the three study arms:• Participants who receive either one or two doses of 0.5-2% topical moxidectin one week apart (8 participants)• Participants who receive a single oral 32mg dose of moxidectin and a single topical dose of 0.5-2% moxidectin (8 participants)• Participants who receive a single oral dose of 32mg moxidectin (8 participants).

[0124] Treatment evaluation will occur 14 and 42 days after the initial treatment using the efficacy endpoints of collarette count, clinical assessment of erythema and (BLepharltlS Symptom) BLISS.

[0125] Based on the first trial results, it is anticipated that this trial will confirm the higher oral doses of moxidectin will reduce collarette counts. For subjects in which oral treatment alone is either not sufficient or not practical, or they cannot tolerate oraltreatment (for example, subjects with pill dysphagia), that inclusion of topical treatments will significantly reduce collarette counts, reductions in BLISS scores and resolution of erythema.Rosacea, Demodex folliculorum and folliculitis-like demodicosis

[0126] Moxidectin will be compared to either or both of a placebo and another acaricide such as lotilaner. Patients will be randomized to one of moxidectin, placebo or (if used) an active comparator such as lotilaner topical gel or other therapies that may be in common clinical use for the respective indications. In general, patients and their treating physicians will be blinded to which treatment each patient is receiving, using sham tablets and topicals to preserve the blinding in the trial when the comparators are in a different dosage form. Study patients will be selected based on them having a history of papulopustular rosacea (PPR), demodex folliculorum or folliculitis-like demodicosis. Other selection criteria will also be applied including selection based on patients' age and gender. Patients will also be those for whom systemic moxidectin or active comparator drugs (if used) are not contraindicated.

[0127] The utility of moxidectin for treating papulopustular rosacea (PPR), demodex folliculorum or folliculitis-like demodicosis will be assessed by comparing the improvement in objective measures of disease such as Investigator Global Assessment (IGA) scores in patients who are treated with moxidectin, to that of patients who are treated with placebo or active comparator (if used). The safety and tolerability of moxidectin in each population of patients will also be assessed.Embodiments of the invention

[0128] Embodiment 1 . A method of treating a Demodex mite infection in a human subject comprising administration of moxidectin, or a pharmaceutically acceptable salt thereof.

[0129] Embodiment 2. A method of treating a skin disease or condition in a human subject with a Demodex mite infection, comprising administration of moxidectin or a pharmaceutically acceptable salt thereof.

[0130] Embodiment s. A method according to embodiment 1 or 2 wherein the Demodex mite is Demodex folliculorum or Demodex brevis.

[0131] Embodiment 4. A method according to embodiment 2 wherein the skin disease or condition is demodicosis.

[0132] Embodiment 5. A method according to embodiment 4 wherein the demodicosis is one or more of Demodex blepharitis, papulopustular rosacea (PPR), demodex folliculorum or folliculitis-like demodicosis.

[0133] Embodiment 6. A method according to any one of embodiments 1 to 5 wherein the moxidectin, or a pharmaceutically acceptable salt thereof, is an oral formulation or a topical formulation.

[0134] Embodiment 7. A method according to embodiment 6 wherein the moxidectin, or a pharmaceutically acceptable salt thereof, is an oral formulation.

[0135] Embodiment 8. A method according to any one of embodiments 1 to 7 wherein moxidectin is micronized moxidectin.

[0136] Embodiment 9. A method according to any one of embodiments 1 to 7 wherein moxidectin is unmicronized moxidectin.

[0137] Embodiment 10. A moxidectin treatment regimen for Demodex mite infection in a human subject wherein the treatment regimen is selected from: a) 1 -3 doses of an oral formulation of moxidectin, wherein the moxidectin is a medium dose of 10-20mg; preferably 16mg; or a high dose of 20-40mg; preferably 32mg; b) 1 dose of an oral formulation of moxidectin and then 1 -2 doses of a topical formulation of 1% moxidectin, wherein the oral moxidectin is a high dose of 20- 40mg; preferably 32mg, or a medium dose of 10-20mg; preferably 16mg; or a low dose oral dose of 1 -1 Omg; preferably 8mg; c) 1 dose of a topical formulation of 1% moxidectin and then 1 -2 doses of an oral formulation of moxidectin, wherein the oral moxidectin is a high dose of 20-40mg; preferably 32mg, or a medium dose of 10-20mg; preferably 16mg; or a low dose oral dose of 1 -1 Omg; preferably 8mg;d) 1 dose of an oral formulation of moxidectin wherein the oral moxidectin is a high dose of 20-40mg; preferably 32mg; and then 1 dose of a topical formulation of 1% moxidectin; e) 1 dose of a topical formulation of 1% moxidectin and then 1 dose of an oral formulation of moxidectin wherein the oral moxidectin is a high dose of 20-40mg; preferably 32mg; and f) 1 -3 doses of a topical formulation of 1% moxidectin.

[0138] Embodiment 11 . A moxidectin treatment regimen according to embodiment 10 wherein the Demodex mite is Demo ex folliculorum or Demodex brevis.

[0139] Embodiment 12: A moxidectin treatment regimen according to embodiment 11 wherein the skin disease or condition is demodicosis.

[0140] Embodiment 13. A moxidectin treatment regimen according to embodiment 12 wherein the demodicosis is one or more of Demodex blepharitis, papulopustular rosacea (PPR), demodex folliculorum or folliculitis-like demodicosis.

[0141] Embodiment 14. A moxidectin treatment regimen according to any one of embodiments 10 to 13 wherein the moxidectin for the oral and topical moxidectin formulations is independently selected from micronized moxidectin and unmicronized moxidectin.

[0142] Embodiment 15. A method of treating a Demodex mite infection in a human subject, or a skin disease or condition in a human subject with a Demodex mite infection, by the moxidectin treatment regimen of any one of embodiments 11 -14.References

[0143] Paichitrojjana, A. Demodex: The worst enemies are the ones that used to be friends. Dermatol Reports 14, 9339.

[0144] Hecht et al., 2019. Permethrin Cream for the Treatment of Demodex Blepharitis. Cornea 38, 1513-1518.

[0145] Trave et aL, 2019. Real-life experience on effectiveness and tolerability of topical ivermectin in papulopustular rosacea and antiparasitic effect on Demodex mites. Dermatol Ther 32,

[0146] Holzchuh, F. G. et al. Clinical treatment of ocular Demodex folliculorum by systemic ivermectin. Am J Ophthalmol 151 , 1030-1034. e1 (2011 );

[0147] Aleksandra L L, et al. Oral Ivermectin for the Treatment of Rosacea- Associated Blepharitis: Case Report. JOJ Ophthalmol. 2022; 9(2): 555759.

[0148] Yeu et al., 2023. Lotilaner Ophthalmic Solution, 0.25%, for the Treatment of Demodex Blepharitis: Results of a Prospective, Randomized, Vehicle-Controlled, Double-Masked, Pivotal Trial (Saturn-1 ). Cornea 42, 435-443.

[0149] Bakajika et al. (2022). Effect of a single dose of 8 mg moxidectin or 150 pg / kg ivermectin on O. volvulus skin microfilariae in a randomized trial: Differences between areas in the Democratic Republic of the Congo, Liberia and Ghana and impact of intensity of infection. PLoS Neglected Tropical Diseases, 16(4),

[0150] Koudou et al., (2025). Moxidectin combination therapies for lymphatic filariasis: an open-label, observer-masked, randomised controlled trial. The Lancet. Infectious Diseases.

[0151] Sprecher et al., (2024). Efficacy and safety of moxidectin compared with ivermectin against Strongyloides stercoralis infection in adults in Laos and Cambodia: a randomised, double-blind, non-inferiority, phase 2b / 3 trial. The Lancet Infectious Diseases, 24(2), 196-205.

[0152] Hayes P (1994) Moxidectin: understanding the unique persistent anthelmintic activity of this second generation macrocyclic lactone. Proceedings of the Australian Veterinary Association; March, 1994, 6.

[0153] Pritchard & Geary. (2019). Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance. Int J Parasitol Drugs Drug Resist. Aug:10:69-83.

Claims

CLAIMS1 . A method of treating a Demodex mite infection in a human subject comprising administration of moxidectin, or a pharmaceutically acceptable salt thereof.

2. A method of treating a skin disease or condition in a human subject with a Demodex mite infection, comprising administration of moxidectin or a pharmaceutically acceptable salt thereof.

3. A method according to claim 1 or 2 wherein the Demodex mite is Demodex folliculorum or Demodex brevis.

4. A method according to claim 2 wherein the skin disease or condition is demodicosis.

5. A method according to claim 4 wherein the demodicosis is one or more of Demodex blepharitis, papulopustular rosacea (PPR), demodex folliculorum or folliculitis-like demodicosis.

6. A method according to any one of claims 1 to 5 wherein the moxidectin, or a pharmaceutically acceptable salt thereof, is an oral formulation or a topical formulation, or a combination treatment of the oral and topical formulation.

7. A method according to claim 6 wherein the moxidectin, or a pharmaceutically acceptable salt thereof, is an oral formulation.

8. A method according to any one of claims 1 to 7 wherein moxidectin is micronized moxidectin.

9. A method according to any one of claims 1 to 7 wherein moxidectin is unmicronized moxidectin.

10. A moxidectin treatment regimen for Demodex mite infection in a human subject wherein the treatment regimen is selected from: a) 1 -3 doses of an oral formulation of moxidectin, wherein the moxidectin is a medium dose of 10-20mg; preferably 16mg; or a high dose of 20-40mg; preferably 32mg;b) 1 dose of an oral formulation of moxidectin and then 1 -2 doses of a topical formulation of 1% moxidectin, wherein the oral moxidectin is a high dose of 20- 40mg; preferably 32mg, or a medium dose of 10-20mg; preferably 16mg; or a low dose oral dose of 1 -1 Omg; preferably 8mg; c) 1 dose of a topical formulation of 1% moxidectin and then 1 -2 doses of an oral formulation of moxidectin, wherein the oral moxidectin is a high dose of 20-40mg; preferably 32mg, or a medium dose of 10-20mg; preferably 16mg; or a low dose oral dose of 1 -1 Omg; preferably 8mg; d) 1 dose of an oral formulation of moxidectin wherein the oral moxidectin is a high dose of 20-40mg; preferably 32mg; and then 1 dose of a topical formulation of 1% moxidectin; e) 1 dose of a topical formulation of 1% moxidectin and then 1 dose of an oral formulation of moxidectin wherein the oral moxidectin is a high dose of 20-40mg; preferably 32mg; and f) 1 -3 doses of a topical formulation of 1% moxidectin.

11. A moxidectin treatment regimen according to claim 10 wherein the Demodex mite is Demodex folliculorum or Demodex brevis.

12. A moxidectin treatment regimen according to claim 11 wherein the skin disease or condition is demodicosis.

13. A moxidectin treatment regimen according to claim 12 wherein the demodicosis is one or more of Demodex blepharitis, papulopustular rosacea (PPR), demodex folliculorum or folliculitis-like demodicosis.

14. A moxidectin treatment regimen according to any one of claims 10 to 13 wherein the moxidectin for the oral and topical moxidectin formulations is independently selected from micronized moxidectin and unmicronized moxidectin.

15. A method of treating a Demodex mite infection in a human subject, or a skin disease or condition in a human subject with a Demodex mite infection, by the moxidectin treatment regimen of any one of claims 11 -14.

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