Long-term treatment of alopecia

Abstract

To provide a topical composition for use in the treatment and / or prevention of alopecia of a subject, wherein the therapeutic effects persist for at least 24 weeks or more after the last administration of the composition, and also provide kits and methods of treating and / or preventing alopecia using the composition.SOLUTION: A composition for use in the treatment and / or prevention of alopecia of a subject comprises, as active ingredients, effective amounts of an extract of Allium species, an extract of Citrus species, an aqueous extract of Paullinia species and an extract of Theobroma species, wherein the composition is administered topically for a period of time necessary to detect one or more therapeutic effects consisting of slowing down the loss of hair, stimulating its growth and / or increasing the density of hair, and wherein the therapeutic effects persist for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or more after the last administration of the composition.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to topical compositions for use in treating and / or preventing hair loss in a subject, wherein the therapeutic effect persists for at least 24 weeks or longer after the last administration of the composition. Also disclosed are kits and methods for treating and / or preventing hair loss using the compositions. [Background technology]

[0002] The hair follicle (HF) is a unique organelle that undergoes cyclical renewal throughout life. In healthy anagen HFs, the lower part (the hair bulge and hair bulb) has relative immune privilege (IP), protecting the follicle from inflammatory processes and promoting immune tolerance. These distinct HF compartments are characterized by factors that function as IP guardians to protect the HF IP (Lintzeri, 2022).

[0003] As hair follicles develop, blood vessels derived from the deep dermal vascular network surround them. These vessels nourish the follicle and support its growth by delivering nutrients, removing waste products, and promoting growth (Murphey, 2022). The vasculature supports defensive immune function by regulating the guidance of migrating immune cells, protecting the body from pathogens and other pathogens. In the event of inflammation or immune surveillance, cells lining the luminal portion of blood vessels, known as endothelial cells (ECs), attract migrating immune cells and guide them to appropriate vascular exit sites, allowing them to enter underlying tissues. Thus, "immunomodulatory ECs" (IMECs) (Amersfoort, 2022) play an important supporting role in the guidance and directional migration of migrating immune cells. During inflammation, ECs expose various adhesion molecules on their surface that slow and halt the migration of immune cells through the blood circulation. These adhesion molecules are thought to provide guidance cues for immune cells to breach the blood vessel wall through a multistep process known as transendothelial migration (TEM) or transmigration (Schimmel, 2017).

[0004] During the normal hair cycle, only scattered immune cells are found around the hair bulb in anagen HFs and occasionally within the hair bulb (Lintzeri, 2022). However, in alopecia areata (AA), genetic or extrinsic factors induce significant and unwanted transendothelial migration (TEM) of CD8+ T cells from the vasculature towards the hair follicle.

[0005] Histologically, AA lesions exhibit a characteristic, dense perifollicular and intrafollicular inflammatory cell infiltrate around the hair bulb region, resembling a bee swarm, forcing the HF into premature catagen, dystrophy, and ultimately apoptosis. CD8+ T cells are typically the first cells to invade the intrafollicular location, severely impairing the integrity of the HF (Lintzeri, 2022).

[0006] During recurrence of AA, the anagen phase of the hair cycle is significantly shortened, resulting in acute episodes of non-scarring alopecia ranging from small, localized patchy areas on the scalp to complete hair loss on the scalp and body. Although the exact pathogenesis of AA is not yet fully understood, it is recognized that IP disruption of the HF hair bulb plays an important role in the pathophysiology of this disease. The exact cause of IP disruption is not yet fully understood.

[0007] Local inflammation in AA is primarily mediated by the JAK-STAT pathway. In AA, there is an overexpression of inflammatory cytokines, which signal through receptors via the JAK-STAT pathway. This leads to JAK-mediated production of IFN-γ and IL-15, which promotes an inflammatory feedback loop that further contributes to local inflammation. Given the critical role of the JAK-STAT pathway in mediating CD8+NKG2D+ T cell responses, a major contributor to AA pathogenesis, it is not surprising that the JAK inhibitor drug class, which inhibits JAK enzymes, blocks downstream signaling of different cytokines by interfering with the JAK-STAT signaling pathway, protecting hair follicles from damage and promoting the initiation of new anagen and hair regrowth (Dillon, 2021).

[0008] The first JAK inhibitor was approved for the treatment of AA in 2022, marking the first approved treatment for a debilitating chronic autoimmune disease, with more inhibitors in development (Dillon, 2021). Since the first JAK inhibitor was approved for the treatment of rheumatoid arthritis in 2011 (Shawky, 2022), real-world evidence of serious health-related risks has been gathered (Hoisnard, 2022), leading to class-wide black box warnings for JAK inhibitors by the US Food and Drug Administration and the European Medicines Agency (Kragstrup, 2022).

[0009] The significant risks associated with immunosuppression of JAK inhibitors warrant strict adherence to drug-free periods.

[0010] However, because JAK inhibitors simply block the JAK-STAT signaling pathway, discontinuing treatment leads to systematic, rapid, and complete disease relapse within three months (Askin, 2021). Tissue-resident memory T cells (TRMs) are long-lived lymphocytes that reside in tissues and develop after the initiation of a T cell-mediated immune response. In fact, endothelial cells may promote the development of TRMs because they are essential interaction partners for T cell migration into inflamed tissues. Wienke et al. demonstrated that the interaction between T cells and activated ECs stimulates tissue residency in a coculture system of human cytokine-activated ECs and FACS-sorted T cells (Wienke, 2022). The relapse of AA, confirmation of upregulation of TRM cells, and reports of clinical benefit from JAK inhibitors during administration support the important role of TRM cells in disease development (Ryan, 2021).

[0011] Until the first drug is approved for AA, standard treatment primarily consists of the off-label use of corticosteroids in addition to older immunosuppressants (Meah, 2020). Unfortunately, corticosteroids, particularly topical corticosteroids (TCS), have been reported to cause potential local side effects, such as impaired epidermal barrier function and skin atrophy (Wollenberg, 2018). Additionally, percutaneous absorption of TCS through disrupted skin can lead to systemic exposure and subsequent growth disorders (Coureau, 2008). As a result of both actual and perceived side effects and potential long-term toxicity, "corticosteroid phobia" often leads to poor adherence to TCS (Stalder, 2017).

[0012] Similarly, the significant risks associated with corticosteroids warrant strict adherence to drug-free periods. However, as with JAK inhibitors, disease relapse is common when treatment is discontinued (Lintzeri, 2021).

[0013] Systemic disease recurrence after treatment cessation turns AA patients' lives into a debilitating "emotional roller coaster" that rhythmically cycles between periods of potential hair growth during treatment followed by periods of hair loss after treatment cessation (McGettigan, 2013).

[0014] There is a high unmet medical need for treatments that are not only safe, but also do not require a drug holiday and have sustained efficacy after treatment is discontinued. Summary of the Invention

[0015] This object is achieved by providing a composition for use in treating and / or preventing alopecia in a subject, comprising an effective amount of an extract of Allium spp., an extract of Citrus spp., an extract of Paulinia spp. and an extract of Theobrama spp. as active ingredients, the composition is topically administered for a period of time necessary to detect one or more therapeutic effects, including slowing hair loss, stimulating hair growth, and / or increasing hair density; The one or more therapeutic effects persist for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or more after the last administration of the composition, as evidenced by measurement of the Alopecia Severity Assessment Tool (SALT) score.

[0016] It is a further object of the present invention to provide a method for treating and / or preventing alopecia in a subject, the method comprising administering a composition comprising an effective amount of an extract of Allium spp., an extract of Citrus spp., an extract of Paulinia spp. and an extract of Theobrama spp. as active ingredients; the composition is topically administered for a period of time necessary to detect one or more therapeutic effects, including slowing hair loss, stimulating hair growth, and / or increasing hair density; The one or more therapeutic effects persist for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or more after the last administration of the composition, as evidenced by measurement of the Alopecia Severity Assessment Tool (SALT) score.

[0017] A further object of the present invention is to provide the use of a composition of the present invention in the manufacture of a medicament for the treatment and / or prevention of alopecia in a subject.

[0018] A further object of the present invention is to provide a kit for the treatment and / or prevention of alopecia, comprising the composition or compositions used according to the present invention. [Brief explanation of the drawings]

[0019] [Figure 1] An example of SALT scoring (Olsen, ed., 2004). [Figure 2] The SALT scores of patients treated with the composition continue to improve, and the changes in SALT scores are sustained throughout the follow-up period and are statistically significantly superior to placebo. DETAILED DESCRIPTION OF THE INVENTION

[0020] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Additionally, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0021] In case of conflict, the present specification, including definitions, will control. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this specification belongs. As used herein, the following definitions are provided to facilitate understanding of the present invention.

[0022] The term "comprises" is generally used in the sense of include / including, i.e., permitting the presence of one or more features or components. The terms "comprise(s)" and "comprising" also encompass the more limited terms "consist(s)," "consisting," and "consist / consisting essentially of," respectively.

[0023] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0024] As used herein, the terms "subject" / "subject in need thereof," or "patient" / "patient in need thereof," are well known in the art and are used interchangeably herein, and refer to mammals, including dogs, cats, rats, mice, monkeys, cows, horses, goats, sheep, pigs, camels, and most preferably humans. In some cases, the subject is a subject in need of treatment or a subject with a disease or disorder. However, in other embodiments, the subject may be a normal subject. The term does not denote a particular age or sex. Thus, adult and neonatal subjects, both male and female, are intended to be subjects. Preferably, the subject is a human, most preferably a human suffering from or at risk of suffering from alopecia.

[0025] The term "about," particularly in relation to a given amount, number, or percentage, is meant to encompass a deviation of plus or minus 10% (±10). For example, about 5% encompasses any value between 4.5% and 5.5%, such as 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, or 5.5.

[0026] As used herein, "at least one" means "one or more," "two or more," "three or more," etc. For example, "at least eight weeks" means eight weeks or more, i.e., nine weeks, ten weeks, eleven weeks, etc.

[0027] In one aspect, the present invention provides a composition for use in treating and / or preventing alopecia in a subject, said composition comprising an effective amount of an extract of Allium species, an extract of Citrus species, an extract of Paullinia species and an extract of Theobroma species as active ingredients; The composition is topically administered for a period of time necessary to detect one or more therapeutic effects, including slowing hair loss, stimulating hair growth, and / or increasing hair density; The one or more therapeutic effects persist after the last administration of the composition, as evidenced by measurement of the Alopecia Severity Assessment Tool (SALT) score.

[0028] In one embodiment, one or more therapeutic effects last for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or more.

[0029] The terms "treatment" or "treating" refer to administering to a subject a composition, pharmaceutical composition, therapeutic agent, active ingredient, compound, etc. of the present disclosure to: (i) inhibiting the disease, i.e., preventing the onset of clinical symptoms; (ii) reverse the disease; and / or (iii) Relieving the disease, i.e., causing regression of clinical symptoms.

[0030] As used herein, the terms "prevention" or "preventing" refer to the administration of a composition, pharmaceutical composition, therapeutic agent, active ingredient, compound, etc. of the present disclosure to a subject for the purpose of preventing disease, i.e., preventing the development of clinical symptoms and signs of disease.

[0031] In the context of the present invention, the disease is alopecia. In one embodiment, the alopecia is an immune-mediated disease, preferably an autoimmune disease. More preferably, the autoimmune disease is alopecia areata.

[0032] Alopecia areata (AA) is an immune-mediated, autoimmune, and inflammatory hair disease affecting both pediatric and adult patients. Immune-inflammatory attack on scalp hair follicles aborts the normal hair cycle, causing them to prematurely enter telogen phase and alopecia. The disease begins with the development of perifollicular inflammation and infiltration of immune-inflammatory cells around the anagen hair bulb, leading to disruption of HF immune privilege, tissue dystrophy, HF cell death, and hair shaft shedding (Lintzeri, 2022). A central role is played by NKG2D-positive T cells, natural killer (NK) cells, and autoreactive CD8-positive T lymphocytes, which recognize self-antigens upon exposure to MHC class I and class II expression on hair follicle cells. T cell activation is accompanied by increased IFN-γ secretion, which recruits or activates more inflammatory cells, such as macrophages, mast cells, and dendritic cells, thereby accelerating cell death and apoptosis of hair follicle cells (Bertolini, M, 2020).

[0033] The initial clinical manifestation of AA manifests as random, patchy hair loss - which can result in hair loss over the entire scalp (alopecia totalis) or may be generalized to all parts of the body (alopecia universalis). AA affects patients of all ethnicities, but similar clinical symptoms affect women more than men. Most importantly, when AA begins early in infancy, the prognosis is usually more severe, with a higher frequency of unpredictable recurrences in adulthood (Villasante Fricke, AC, 2015).

[0034] In one embodiment, a subject in need thereof is a subject suffering from mild AA (SALT score <25), moderate AA (SALT score between 25 and 50), or severe AA (SALT score between 50 and 95). Preferably, a subject suffering from alopecia totalis / universalis (SALT score >95) is not a subject in need thereof according to the present invention, and the compositions of the present invention are not intended for use in treating such alopecia totalis / universalis.

[0035] As used herein, the term "effective amount" means a therapeutically effective amount of a composition, pharmaceutical composition, therapeutic agent, active ingredient, compound, etc. of the present disclosure that is high enough to significantly positively modify the symptoms and / or condition being treated, yet low enough to avoid serious side effects (a reasonable risk / benefit ratio), within the scope of sound medical judgment.

[0036] In the context of the present invention, the composition of the present invention comprises as active ingredients effective amounts of an extract of an Allium species, an extract of a Citrus species, an extract of a Paullinia species and an extract of a Theobroma species.

[0037] The term "extract or hydroalcoholic extract of Allium species" refers in particular to hydroalcoholic extracts and natural extracts obtained from all species of the Allium genus (Liliaceae), in particular from onion (Allium cepa).

[0038] The term "extract or hydroalcoholic extract of Citrus species" refers in particular to hydroalcoholic extracts and natural extracts obtained from all species of the genus Citrus (Rutaceae), in particular Citrus lemon.

[0039] The term "extract (atomized or non-atomized) or hydroalcoholic extract of Paullinia spp." refers in particular to hydroalcoholic extracts and natural extracts obtained from all species of the genus Paullinia spp. (Sapindaceae), in particular from guarana (Paullinia cupana).

[0040] The term "extract (atomized or non-atomized) or hydroalcoholic extract of Theobrama species" refers in particular to hydroalcoholic extracts and natural extracts obtained from all species of the genus Theobrama (Malvaceae), in particular from cocoa (Theobroma cacao).

[0041] In one aspect of the invention, the compositions of the invention or used compositions are typically administered topically to the external skin surface of the skull for a period of time necessary to detect one or more therapeutic effects, including slowing hair loss, stimulating hair growth, and / or increasing hair density.

[0042] The period required to detect one or more therapeutic effects is usually about 16 to about 48 weeks, preferably about 20 to about 40 weeks, more preferably about 20 to about 32 weeks, and even more preferably about 24 weeks.

[0043] Any method known in the art can be used to detect, monitor, and / or reveal one or more therapeutic effects, including slowing hair loss, stimulating hair growth, and / or increasing hair density.

[0044] In one embodiment, one or more therapeutic effects are detected, monitored and / or revealed by measuring the Alopecia Severity Assessment Tool (SALT) score.

[0045] SALT scoring is a calculation based on a scoring system. The scalp is divided into four regions: the left side of the scalp, which represents 18% of the scalp surface area; the right side of the scalp, which represents 18% of the scalp surface area; the vertex, which represents 40% of the scalp surface area; and the occipital region, which represents 24% of the scalp surface area. The hair loss rate in each of the four scalp regions is measured independently by multiplying it by its respective coefficient (left and right: 0.18, vertex: 0.40, occipital: 0.24). The coefficient for each region varies depending on the location. The hair loss rates obtained for all four regions are then summed to calculate the final total hair loss rate (called the SALT score).

[0046] Olsen et al. also described a SALT score assessment that is more suitable for clinical trials. As shown in Figure 1, each region is further subdivided into four quadrants (5% + 4% + 4% + 5%, 10% + 10% + 10% + 10%, or 6% + 6% + 6% + 6%) according to scalp area.

[0047] The hair loss rate of each quadrant is measured independently by multiplying it by a coefficient (0.04, 0.05, 0.06, or 0.1). The coefficient for each quadrant varies depending on the location (Figure 1). The hair loss rates of all four areas (16 quadrants) are then summed to calculate the final total hair loss rate (called the SALT score).

[0048] Because numerous calculations are performed to obtain a final SALT score, and because coefficients vary depending on the region, manual SALT scoring can be prone to error. Therefore, in one embodiment, SALT scoring is performed by computer. In a preferred embodiment, the SALT score assessment described by Olsen is used to detect, monitor, and / or characterize one or more therapeutic effects.

[0049] Typically, a subject's baseline SALT score is measured before starting administration of the compositions of the invention.

[0050] In one embodiment, a decrease in the SALT score of at least about 2% or more, at least about 5% or more, at least about 10% or more, at least about 15% or more, at least about 20% or more, at least about 30% or more, at least about 40% or more, or at least about 50% or more is detected compared to the subject's baseline SALT score, indicating that one or more therapeutic effects have been detected and that administration of the compositions of the invention is effective.

[0051] A decrease in SALT score of at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, at least about 40%, or at least about 50% is detected, compared to the subject's SALT score measured after the last administration of the composition, indicating that one or more therapeutic effects have been detected and persist after the topical administration has ceased. In some embodiments, one or more therapeutic effects persist or are even improved.

[0052] Typically, the compositions of the present invention are administered topically, preferably to the external skin surface of the skull, at least once daily, at least twice daily, or more than once daily.

[0053] Typically, about 0.5 ml to 2.5 ml of the composition is applied at least once a day, at least twice a day, or more often to cover the subject's entire scalp.

[0054] In one embodiment, the composition of the present invention or composition for use comprises about 65% to about 93% by weight of a hydroalcoholic extract of Allium spp., about 5% to about 33% by weight of a hydroalcoholic extract of Citrus spp., about 0.25% to about 2.5% by weight of a hydroalcoholic extract of Paulinia spp., and about 0.25% to about 2.5% by weight of a hydroalcoholic extract of Theobroma spp.

[0055] In a preferred embodiment, the composition of the present invention or the composition used comprises from about 65% to about 93% by weight of a hydroalcoholic extract of onion, from about 5% to about 33% by weight of a hydroalcoholic extract of citrus lemon, from about 0.25% to about 2.5% by weight of a hydroalcoholic extract of guarana, and from about 0.25% to about 2.5% by weight of a hydroalcoholic extract of cocoa.

[0056] In an even more preferred embodiment, the composition of the present invention or the composition used comprises about 87% by weight of a hydroalcoholic extract of onion, about 12% by weight of a hydroalcoholic extract of citrus lemon, about 0.67% by weight of a hydroalcoholic extract of guarana, and about 0.67% by weight of a hydroalcoholic extract of cocoa.

[0057] In one embodiment, the composition of the present invention or the composition for use further comprises, as an excipient, about 0.05% to about 8.0% by weight of sodium chloride and about 1% to about 40% by weight of glycerin, based on the total weight of the composition.

[0058] In one embodiment, the composition of the present invention or the composition used comprises about 0.05% to about 8.0% by weight, preferably about 0.1% to about 7.0% by weight, more preferably about 0.4% to about 6.0% by weight, and even more preferably about 0.9% to about 3% by weight of sodium chloride, based on the total weight of the composition.

[0059] In one embodiment, the composition of the present invention or the composition used comprises from about 1% to about 20% by weight, preferably from about 1.2% to about 15% by weight, more preferably from about 1.8% to about 10% by weight, and even more preferably from about 2% to about 5% by weight of glycerin, based on the total weight of the composition.

[0060] Compositions of the present invention suitable for topical administration include liquid or semi-liquid formulations suitable for skin penetration, such as solutions, lotions, shake lotions, creams, ointments, gels, foams, transdermal patches, powders, solids, sponges, tapes, vapors, pastes, tinctures, microparticles, microcapsules, nanoparticles, liposomes, emulsions, etc. Preferably, compositions of the present invention suitable for topical administration are in the form of a solution or lotion.

[0061] The present invention further contemplates a method for treating and / or preventing alopecia in a subject.

[0062] In one aspect, a method for treating and / or preventing alopecia in a subject comprises administering to a subject a composition comprising an effective amount of an extract of Allium spp., an extract of Citrus spp., an extract of Paulinia spp., and an extract of Theobrama spp. as active ingredients; The composition is topically administered for a period of time necessary to detect one or more therapeutic effects, including slowing hair loss, stimulating hair growth, and / or increasing hair density; The one or more therapeutic effects persist for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or more after the last administration of the composition, as evidenced by measurement of the Severity of Alopecia Tool (SALT) score.

[0063] The present invention further contemplates the use of the composition of the present invention in the manufacture of a medicament for the treatment and / or prevention of alopecia in a subject, said use comprising administering a medicament comprising an effective amount of an Allium spp. extract, a Citrus spp. extract, a Paulinia spp. extract and a Theobrama spp. extract as active ingredients; The agent is administered topically for a period of time necessary to detect one or more therapeutic effects, including slowing hair loss, stimulating hair growth, and / or increasing hair density; The one or more therapeutic effects persist for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or more after the last administration of the composition, as evidenced by measurement of the Severity of Alopecia Tool (SALT) score.

[0064] The present invention also contemplates kits for the treatment and / or prevention of alopecia as described herein. In one aspect of the invention, the kit comprises a composition of the invention or a composition for use.

[0065] The kit of the present invention may also include a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, dispensers, spray applicators, etc. The container can be formed from a variety of materials, such as glass or plastic.

[0066] A label or package insert may include instructions for its use. The included instructions may be affixed to the packaging material or included as a package insert. The instructions are typically, but are not limited to, written or printed material. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this disclosure.

[0067] The present disclosure is to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein. [Example]

[0068] Materials and Methods The composition (22.25%) was evaluated in a clinical trial evaluating the safety and efficacy of the composition in subjects with AA (RAAINBOW study, ClinicalTrials.gov identifier: NCT03240627). Approximately 1 mL of the composition was applied to the entire scalp twice daily, approximately 12 hours apart (e.g., in the morning and evening).

[0069] The RAAINBOW study was a double-blind, randomized, multicenter, placebo-controlled study. 107 subjects (male and female) were enrolled and safety analyses were performed. Of these subjects, 62 met the inclusion criteria (i.e., moderate to severe AA) and represented the full analysis set (FAS). Efficacy analyses were performed on these 62 subjects.

[0070] result The safety analysis is outlined below.

[0071] [Table 1]

[0072] No subjects in the composition group experienced serious adverse events (AEs). Only 5.6% of subjects treated with the composition experienced AEs that were possibly drug-related (vs. 11.1% in the placebo group). One AE was severe, consisting of severe scalp and facial eczema. However, eczema is the most common comorbidity in AA, and AA patients are more likely to suffer from atopic dermatitis and eczema (17.4% vs. 2.2% in controls) (Conic, 2020). All other AEs were mild, moderate, localized, and transient.

[0073] This study did not report any side effects observed with JAK inhibitors and corticosteroids. This composition is so safe in treating AA that it does not require a treatment withdrawal period. Therefore, this composition can be used chronically without discontinuation and without risk to the user's health or disease recurrence.

[0074] Additionally, the RAAINBOW study was specifically designed to evaluate not only the effectiveness of the composition against AA after 6 months of treatment, but also the likelihood of potential disease recurrence after treatment cessation, measured 6 months after treatment cessation.

[0075] AA was assessed using the scalp alopecia areata severity score, known as the SALT (Alopecia Severity Tool) score, based on global standardized scalp photographs. The SALT score was developed by Olsen in 2004 "to facilitate well-controlled clinical trials in alopecia areata" (Olsen, 2004). It is a standardized method for assessing the extent of alopecia, with a SALT score of 100% indicating complete hair loss. It is based on a scoring system based on four photographs, in which each side of the head is divided into four quadrants and scored accordingly by the investigator (see Figure 1). The SALT score is a standardized measurement endpoint and is used in all trials evaluating the effectiveness of new treatments for AA. An example is shown below.

[0076] In the RAAINBOW study, SALT scores (Figure 1) were measured at baseline (V1), after 3 months of treatment (V2), and after 6 months of treatment (V3). Treatment was then discontinued, and patients' AA was reassessed after 3 months of treatment-free follow-up (V4) and after 6 months of treatment-free follow-up (V5).

[0077] After testing the normality assumption of the data (using both QQ plots and Shapiro-Wilk tests), a generalized linear model (GLIMMIX procedure in SAS) was preferred over MMRM. The GLIMMIX model had rank of relative change from baseline in SALT score as the dependent variable, treatment, visit, and treatment-by-visit interaction as fixed effects, and baseline severity based on SALT score as a covariate.

[0078] There was a statistically significant difference between the LH-8 and placebo groups in terms of relative and absolute changes in SALT scores from baseline to week 24, with the LH-8 group showing a higher change, thus meeting the planned primary endpoint (p-value <0.0001).

[0079] Of subjects treated with the composition who improved over the 6-month treatment period (V1 through V3), only 4% experienced disease recurrence after treatment discontinuation, as measured after a 6-month treatment-free period (V5). 96% of subjects who responded to treatment did not relapse after treatment cessation. Furthermore, as shown in Figure 2, SALT scores in patients treated with the composition continued to improve, and the change in SALT score was sustained throughout the follow-up period and statistically significantly superior to placebo.

[0080] In chronic diseases, a 6-month period is considered representative of disease progression (Ostbye, 2005). Therefore, a 6-month treatment-free follow-up period is considered representative of the long-term progression of the disease (Figure 2).

[0081] In this case, it can be concluded that discontinuation of treatment with the composition did not lead to disease recurrence in all but 4% of cases. Therefore, unlike treatment with JAK inhibitors and corticosteroids, treatment with the composition does not require discontinuation for safety reasons and can be discontinued without risk of disease recurrence. While AA is a chronic disease requiring chronic treatment, the composition allows the disease to be treated only until it is controlled, rather than chronically, and then treatment can be safely discontinued. This represents a new method for treating AA.

[0082] References Table 2

Claims

1. 1. Use of a composition in the manufacture of a medicament for the treatment and / or prevention of alopecia in a subject, comprising: The composition comprises, as active ingredients, about 87% by weight of a hydroalcoholic extract of onion, about 12% by weight of a hydroalcoholic extract of citrus lemon, about 0.67% by weight of a hydroalcoholic extract of guarana, and about 0.67% by weight of a hydroalcoholic extract of cocoa; The alopecia is an immune-mediated disease, the composition is topically administered for 16 to 48 weeks, which is the period necessary to detect one or more therapeutic effects, including slowing hair loss, stimulating hair growth, and / or increasing hair density; The use, wherein the one or more therapeutic effects persist for at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks or more after the last administration of the composition, as evidenced by measurement of the Alopecia Severity Assessment Tool (SALT) score.

2. The use according to claim 1 , wherein the immune-mediated disease is an autoimmune disease.

3. The use according to claim 2, wherein the autoimmune disease is alopecia areata.

4. The use according to any one of claims 1 to 3, wherein a decrease in SALT score of at least about 2% or more, at least about 5% or more, at least about 10% or more, at least about 15% or more, at least about 20% or more, at least about 30% or more, at least about 40% or more, or at least about 50% or more is detected in the subject compared to the subject's baseline SALT score measured before administration of the composition was initiated.

5. The use according to any one of claims 1 to 3, wherein a decrease in the SALT score of at least about 2% or more, at least about 5% or more, at least about 10% or more, at least about 15% or more, at least about 20% or more, at least about 30% or more, at least about 40% or more, or at least about 50% or more is detected compared to the subject's SALT score measured after the last administration of the composition.

6. The use according to any one of claims 1 to 3, wherein the composition further comprises about 0.05 wt% to about 8.0 wt% sodium chloride and about 1 wt% to about 40 wt% glycerin as excipients, based on the total weight of the composition.

7. 7. The use according to claim 6, wherein the composition comprises from about 0.05% to about 8.0% by weight, preferably from about 0.1% to about 7.0% by weight, more preferably from about 0.4% to about 6.0% by weight, and even more preferably from about 0.9% to about 3% by weight of sodium chloride, based on the total weight of the composition.

8. 7. The use according to claim 6, wherein the composition comprises from about 1% to about 20%, preferably from about 1.2% to about 15%, more preferably from about 1.8% to about 10%, and even more preferably from about 2% to about 5% by weight of glycerin, based on the total weight of the composition.

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