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WO2022171654A1 - Méthode de traitement de troubles atopiques - Google Patents

Méthode de traitement de troubles atopiques Download PDF

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Publication number
WO2022171654A1
WO2022171654A1 PCT/EP2022/053093 EP2022053093W WO2022171654A1 WO 2022171654 A1 WO2022171654 A1 WO 2022171654A1 EP 2022053093 W EP2022053093 W EP 2022053093W WO 2022171654 A1 WO2022171654 A1 WO 2022171654A1
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Prior art keywords
percent
composition
score
decrease
baseline
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English (en)
Inventor
Charlotte VEDEL
Ida Blomquist CHRISTENSEN
Søren Kjærulff
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Lactobio AS
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Lactobio AS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present invention relates to the treatment and/or prevention of atopic disorders, such as atopic dermatitis, and related conditions. More specifically, the invention relates to the administration of Live Biotherapeutic Product (LBP) to treat or prevent atopic disorders, such as atopic dermatitis, in a patient in need thereof.
  • LBP Live Biotherapeutic Product
  • AD atopic dermatitis
  • atopic dermatitis is a chronically relapsing inflammatory skin disease characterized by intense pruritus (e,g,, severe itch) and by scaly and dry eczematous lesions, AD is often associated with other atopic disorders such as allergic rhinitis and asthma. Severe disease can be extremely disabling due to major psychological problems, significant sleep loss, and impaired quality of life, leading to high socioeconomic costs.
  • the pathophysiology of AD is influenced by a complex interplay between sensitization, the immune system, Staphylococcus aureus colonization and environmental factors.
  • the primary AD skin defect may be an immunological disturbance, with epithelial-barrier dysfunction that is the consequence of both genetic mutations and local inflammation, AD often begins in childhood before age 5 and may persist into adulthood.
  • Typical treatments for AD include topical lotions and moisturizers, topical corticosteroid ointments, creams or injections. Most treatment options, however, offer only temporary, incomplete, symptom relief. Moreover, many patients become resistant to treatment by topical corticosteroids, topical antibiotics or by calcineurin inhibitors. Thus, a need exists in the art for novel targeted therapies for the treatment and/or prevention of AD,
  • steroids are widely used therapeutic agents to treat atopic dermatitis lesions.
  • An overdose of steroids causes depletion of steroid binding receptors, thereby leading to tolerance, and thus forcing atopic dermatitis patients to apply medicine more frequently or use a medicine having a stronger effect.
  • the steroids are converted into peroxides on their skin and gradually aggravate the skin disease.
  • Steroids are more easily absorbed through thinner skin.
  • steroids are more easily absorbed in children, the use of steroids is restricted due to their side effects.
  • the present invention provides a method of treating an AD patient by locally administering an topical composition containing LBP as an active ingredient,
  • the present invention also provides a method of treating atopic dermatitis patient by locally administering a topical composition containing LBP as an active ingredient to replace or reduce conventional therapy
  • One aspect of the present invention provides a method of treating an AD patient by locally administering the topical composition containing LBP as an active ingredient.
  • the invention relates to a new treatment of atopic disorders, such as atopic dermatitis (AD) and related conditions. More specifically, the invention relates to the administration of Live Biotherapeutic Product (LBP) to treat or prevent atopic disorders, such as atopic dermatitis, in a patient in need thereof,
  • LBP Live Biotherapeutic Product
  • the methods of the present invention comprise administering to a subject or a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of an LBP,
  • a preferred embodiment of the invention are directed to methods for treating, reducing, ameliorating or preventing inflammation in a patient, as determined by a decrease in EASI score, comprising administration of a pharmaceutical composition comprising a therapeutically effective amount of LBP,
  • a preferred embodiment of the invention are directed to methods for treating, reducing, ameliorating or preventing pruritis in a patient, as determined by a decrease in VAS score, comprising administration of a pharmaceutical composition comprising a therapeutically effective amount of LBP,
  • An aspect of the present invention relates to a composition for use in the treatment, alleviation, suppression, prophylaxis and/or prevention of an atopic disorder in a subject, wherein the composition comprising a Live Biotherapeutic Product (LBP) by providing: (a) a decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 30 percent;
  • LBP Live Biotherapeutic Product
  • VAS Visual Analog Scale
  • an immunosuppressive effect preferably, the immunosuppressive effect of IL-4, IL-5 and/or IL-17
  • a further aspect of the present invention relates to a topical composition
  • a topical composition comprising a Live Biotherapeutic Product for use as a medicament wherein the patient following the administration of the composition exhibits an improvement in an atopic dermatitis (AD)-associated parameter, wherein the improvement in the AD-associated parameter is:
  • VAS Visual Analog Scale
  • an immunosuppressive effect preferably, the immunosuppressive effect of IL-4, IL-5 and/or IL-17
  • Yet an aspect of the present invention relates to a Live Biotherapeutic Product for use in the treatment of mild to moderate atopic dermatitis wherein topical administration of a pharmaceutical composition exhibits an improvement in an atopic dermatitis (AD)-associated parameter, wherein the improvement in the AD-associated parameter is a decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 30 percent on day 14 after administration of the first dose of the pharmaceutical composition.
  • AD atopic dermatitis
  • EASI Eczema Area and Severity Index
  • An even further aspect of the present invention relates to a Live Biotherapeutic Product for use in the treatment of mild to moderate atopic dermatitis wherein topical administration of a pharmaceutical composition exhibits an improvement in an atopic dermatitis (AD)-associated parameter, wherein the improvement in the AD-associated parameter is a decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 30 percent on day 14 after administration of the first dose of the pharmaceutical composition and wherein the improvement is observed in at least 60% of patients
  • AD atopic dermatitis
  • EASI Eczema Area and Severity Index
  • a further aspect of the present invention relates to a Live Biotherapeutic Product for use in the treatment of mild to moderate atopic dermatitis wherein topical administration of a pharmaceutical composition exhibits an improvement in an atopic dermatitis (AD)-associated parameter, wherein the improvement in the AD-associated parameter is a decrease from baseline in Visual Analog Scale (VAS) score of at least 60 percent on day 14 after administration of the first dose of the pharmaceutical composition.
  • AD atopic dermatitis
  • VAS Visual Analog Scale
  • Yet an aspect of the present invention relates to a Live Biotherapeutic Product for use in the treatment of mild to moderate atopic dermatitis wherein topical administration of a pharmaceutical composition exhibits an improvement in an atopic dermatitis (AD)-associated parameter, wherein the improvement in the AD-associated parameter is a decrease from baseline in Visual Analog Scale (VAS) score of at least 60 percent on day 14 after administration of the first dose of the pharmaceutical composition and wherein the improvement is observed in at least 75% of patients.
  • AD atopic dermatitis
  • VAS Visual Analog Scale
  • Some embodiments of the invention are directed to methods for treating, reducing, ameliorating or preventing pruritus, itching or inflammation in a patient, comprising administration of a pharmaceutical composition comprising a therapeutically effective amount of LBP.
  • Figure 1 shows the distribition of the EASI Score (Value) over time from treating 24 subjects, 21 females and 3 males, age between 18 years and 67 old and with a Caucasian skin type (photype I-IV) and presenting atopic dermatitis on the face and/or body as well as pruritus.
  • the subjects were treated with a cream comprising live Lactiplantibacillus plantarum strain LB244R (DSM32996), lyophilized and formulated in the concentration of 10 7 CFU /gram in a carrier composition of almond oil, Shea butter, jojoba oil, beeswax.
  • the cream was applied 2 times per day, one time in the morning and one time in the evening.
  • FIG. 1 A first analysis was performed at the start of the experiment, at day 0 (DO), and repeated again after 14 days of treatment (D14).
  • the effect of the treatment using the composition according to the present invention are demonstrated by D14-D0;
  • Figure 2 shows the EASI Score represented by a graph based on the same data as presented in figure 1.
  • the graph of the EASI Score in figure 2 demonstrates a strong anti inflammatory effect where a significant decrease of the EASI Score, an average decrease of 48% after 14 days treatment may be obtained. Improvements in the EASI Score have been demonstrated in 67% of the subjects;
  • Figure 3 shows the distribution of the VAS Score (Value) of pruritus over time from treating 24 subjects, 21 female and 3 male, age between 18 years and 67 old and with a Caucasian skin type (photype I-IV) and presenting atopic dermatitis on the face and/or body as well as pruritus.
  • the subjects were treated with a cream comprising live Lactiplantibacillus plantarum strain LB244R (DS 32996), lyophilized and formulated in the concentration of 10 7 CFU /gram in a carrier composition of almond oil, Shea butter, jojoba oil, beeswax.
  • the cream was applied 2 times per day, one time in the morning and one time in the evening.
  • a first analysis was performed at the start of the experiment, at day 0 (DO), and repeated again after 14 days of treatment (D14). The effect of the treatment using the composition according to the present invention are demonstrated by D14-D0;
  • FIG 4 shows VAS Score represented by a graph based on the same data as presented in figure 3.
  • the graph of the VAS Score in figure 4 demonstrates an antipruritic effect where a significant decrease of the VAS Score, an average decrease of 82% after 14 days treatment was obtained. Improvements in the VAS Score have been demonstrated in 96% of the subjects;
  • Figure 5 shows the results from a dermatologist on 10 different parameters (parameter A- J) in evaluating the cream used in Example 1.
  • the parameters are: A: “It leaves the skin soft”, ⁇ B: “It leaves the skin moisturized”, ⁇ C: “It leaves the skin supple”, ⁇ D: “It improves the skin texture” ; E: “It leaves the skin smoothed”, ⁇ F: “It leaves the skin comfortable”, ⁇ G: “It reduces discomfort sensations”, ⁇ FI: “It reduces pruritus”, ⁇ I: “It protects the skin from external aggression”, ⁇ and J: “It leaves the skin nourished”, ⁇
  • Figure 6 shows the effect on expression of the cytokine IL-4 (interleukin 4) from treating fresh PBMCs with LB244R in a concentration of 10 11 CFU /g added to PBMCs.
  • cytokine IL-4 interleukin 4
  • Two groups of PBMCs cells are tested, either stimulated with anti-CD3/anti-CD28 (figure 6a) or unstimulated cells (figure 6b);
  • Figure 7 shows the effect on expression of the cytokine IL-5 (interleukin 5) from treating fresh PBMCs with LB244R in a concentration of 10 11 CFU /g added to PBMCs.
  • cytokine IL-5 interleukin 5
  • Two groups of PBMCs cells are tested, either stimulated with anti-CD3/anti-CD28 (figure 7a) or unstimulated cells (figure 7b);
  • Figure 8 shows the effect on expression of the cytokine IL-17 (interleukin 17) from treating fresh PBMCs with LB244R in a concentration of 10 11 CFU/g added to PBMCs.
  • Two groups of PBMCs cells are tested, either stimulated with anti-CD3/anti-CD28 (figure 8a) or unstimulated cells (figure 8b).
  • Atopic dermatitis patient refers to a patient diagnosed with atopic dermatitis, and atopic dermatitis is usually diagnosed based on clinical symptoms since there are no specific methods or examination methods.
  • atopic dermatitis may be diagnosed according to diagnostic criteria for atopic dermatitis of Hanifin and Rajka (Hanifin JM, Rajka G, Disgnostic features of atopic dermatitis, Acta Derm Venereol Suppl 1980; 92: 44- 47,),
  • prevention of inflammation includes, for example, reducing the EASI score in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable lesions in a treated population versus an untreated control population, e.g,, by a statistically and/or clinically significant amount.
  • treating includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilize a subject's condition.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i,e,, not worsening) state of disease, prevention of disease, delay or slowing of disease progression, and/or amelioration or palliation of the disease state.
  • the decrease can be a 10 percent, 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 65 percent, 70 percent, 75 percent, 80 percent, 85 percent, 90 percent, 95 percent, or 100% decrease in severity of complications or symptoms.
  • An embodiment of the present invention relates to a composition comprising LBP according to the present invention for use in treating; alleviating; suppressing; prophylaxis; and/or preventing AD,
  • a “decrease” from baseline may be “statistically significant” as compared to the baseline at before applying the treatment or using the method of the present invention, and may include a 10 percent, 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 65 percent, 70 percent, 75 percent, 80 percent, 85 percent, 90 percent, 95 percent, or 100 percent decrease,
  • a preferred embodiment of the present invention relates to a composition for use in the treatment, alleviation, suppression, prophylaxis and/or prevention of an atopic disorder in a subject, wherein the composition comprising a Live Biotherapeutic Product (LBP) by providing decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 30 percent.
  • a further preferred embodiment of the present invention relates to a composition for use in the treatment, alleviation, suppression, prophylaxis and/or prevention of an atopic disorder in a subject, wherein the composition comprising a Live Biotherapeutic Product (LBP) by providing a decrease from baseline in pruritus Visual Analog Scale (VAS) score of at least 60 percent,
  • An even further preferred embodiment of the present invention relates to a composition for use in the treatment, alleviation, suppression, prophylaxis and/or prevention of an atopic disorder in a subject, wherein the composition comprising a Live Biotherapeutic Product (LBP) by providing an immunosuppressive effect, preferably, the immunosuppressive effect of IL-4, IL-5 and/or IL- 17,
  • LBP Live Biotherapeutic Product
  • composition for use in the treatment, alleviation, suppression, prophylaxis and/or prevention of an atopic disorder in a subject, wherein the composition comprising a Live Biotherapeutic Product (LBP) by providing:
  • LBP Live Biotherapeutic Product
  • Atopic disorder may relate to a series of monogenic diseases that have allergy- or atopic effector-related symptoms as a substantial feature.
  • Atopic disorders may affect the nose, eyes, skin, and lungs. These disorders include conjunctivitis, atopic dermatitis, immune- mediated urticaria, immune-mediated angioedema, acute latex allergy, some allergic lung disorders (e,g, allergic asthma, IgE-mediated components of allergic bronchopulmonary aspergillosis, allergic rhinitis, and allergic reactions to venomous stings,
  • the atopic disorder may be selected from atopic dermatitis, allergic rhinitis or asthma.
  • the atopic disorder may be atopic dermatitis.
  • the decrease from baseline may be determined as a decrease from baseline of at least 25 percent.
  • the decrease from baseline is determined as a decrease from baseline of at least 30 percent, more preferably the decrease from baseline is determined as a decrease from baseline of at least 40 percent, more preferably the decrease from baseline is determined as a decrease from baseline of at least 50 percent, more preferably the decrease from baseline is determined as a decrease from baseline of at least 60 percent, more preferably the decrease from baseline is determined as a decrease from baseline of at least 70 percent.
  • AD-associated parameters include, e,g,, a decrease in Investigator's Global Assessment (IGA) score; a decrease in Body Surface Area Involvement of Atopic Dermatitis (BSA) score; a decrease in Eczema Area and Severity Index (EASI) score; a decrease in SCORAD score; a decrease in Visual Analogue Scale (VAS) score; and/or a decrease in Pruritus Numeric Rating Scale (NRS) score.
  • IGA Investigator's Global Assessment
  • BSA Body Surface Area Involvement of Atopic Dermatitis
  • EASI Eczema Area and Severity Index
  • SCORAD a decrease in Visual Analogue Scale (VAS) score
  • PIS Pruritus Numeric Rating Scale
  • composition consists essentially of a Live Biotherapeutic Product (LBP),
  • the term “comprising” or “comprises” may be used interchangeably, may be synonymous with the terms “including”, “containing” or “characterized by”, and relates to an inclusive or open-ended listing of features and does not exclude additional, unrecited features or method steps.
  • the term “comprising” leaves the claim open for the inclusion of unspecified ingredients even in major amounts.
  • the patient suffers from AD
  • the patient suffering from AD is resistant to treatment by conventional therapies or suffers from significant side-effects of conventional therapy.
  • atopic dermatitis including mild to moderate and moderate to severe AD
  • Certain embodiments of the invention pertain to methods for treating, ameliorating or preventing AD in a patient who is resistant to treatment by a topical corticosteroid or a calcineurin inhibitor.
  • the improvement in an AD-associated parameter is selected from the group consisting of: (i) a decrease from baseline in EASI score of at least 30 percent; (ii) a decrease from baseline in Pruritus VAS score of at least 60 percent; (iii) an immunosuppressive effect, preferably, the immunosuppressive effect of IL-4, IL-5 and/or IL-17; and (iv) percent responders with greater than or equal to 50 percent improvement in EASI (EASI50),
  • the improvement in an AD-associated parameter is selected from the group consisting of: (i) a decrease from baseline in EASI score of at least 40 percent; (ii) a decrease from baseline in Pruritus VAS score of at least 65 percent; (iii) an immunosuppressive effect, preferably, the immunosuppressive effect of IL-4, IL-5 and/or IL-17; and (iv) percent responders with greater than or equal to 50 percent improvement in EASI (EASI50),
  • the improvement in an AD-associated parameter comprises a decrease from baseline in EASI score of at least 30 percent on day 14 after daily administration of the composition comprising LBP
  • the improvement in an AD-associated parameter comprises a decrease from baseline in EASI score of at least 30 percent on day 14 in at least 50 percent of subjects administered with the composition comprising LBP
  • the improvement in an AD-associated parameter comprises a decrease from baseline in VAS score of at least 60 percent at the end of week 2 after daily administration of the composition comprising LBP
  • the present invention includes methods for long term management of AD in a patient.
  • the methods comprise administering a LBP concomitantly with a conventional therapeutic agent such as a topical corticosteroid (TCS), immunoregulator, antihistamine or an antibody treatment.
  • a conventional therapeutic agent such as a topical corticosteroid (TCS), immunoregulator, antihistamine or an antibody treatment.
  • live biotherapeutic product refers to a product candidate(s) containing live bacteria, yeast, and/or other microorganisms
  • LBP Live Biotherapeutic Products
  • LBP are defined as biological products that: 1) contain live organisms, such as bacteria; 2) are applicable to the prevention, treatment, or cure of a disease or condition of human beings; and 3) are not vaccines.
  • the LBP of the present invention may be a procaryote, more preferred a bacteria.
  • the LBP of the present invention may be a bacteria in the taxonomic order Lactobacillales
  • the LBP of the present invention may be a bacteria in the taxonomic family Lactobacillaceae
  • the LBP of the present invention may be a lactic acid bacteria.
  • the LBP is an isolated microorganism with anti inflammatory activity.
  • the LBP is an isolated microorganism with anti microbial activity. In a preferred embodiment of the invention the LBP is an isolated bacteriocin producing microorganism.
  • the LBP is an isolated bacteriocin producing microorganism with anti-inflammatory activity.
  • the LBP is an isolated bacteriocin producing microorganism with anti-inflammatory activity, producing at least one type of antimicrobial peptide. In a further preferred embodiment, the LBP produces at least two different antimicrobial peptides.
  • the lactic acid bacteria may be a lactiplantibacillus plantarum.
  • the lactic acid bacteria may be a lactiplantibacillus plantarum, even more preferably, the lactiplantibacillus plantarum may be the lactiplantibacillus plantarum strain LB244R (DSM32996)
  • the LBP is an isolated wildtype microorganism, wherein the microorganism has not been genetically modified.
  • the number of live microorganisms is measured as Colony Forming Units CFU/gram
  • the LBP according to the present invention may preferably be in isolated form, where the term "isolated” means in particular that the live microorganism is derived from their culture medium including their natural medium, for example isolated from other species.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more LBP together with a pharmaceutically acceptable carrier and/or diluent.
  • compositions comprising one or more LBP together with a cosmetical acceptable carrier and/or diluent.
  • Another aspect of the present invention relates to a medical device composition
  • a medical device composition comprising one or more LBP together with an acceptable carrier and/or diluent useful for topical application.
  • compositions comprising 10 3 to 10 13 colony forming units of LBP per gram. More specifically a pharmaceutical composition comprising 10 4 to 10 12 colony forming units of lactic acid bacteria per gram. More specifically a pharmaceutical composition comprising 10 s to 10 10 colony forming units of LBP per gram.
  • the formulation is a topical formulation.
  • the topical formulation for use in the present invention can be in any form suitable for application to the body surface, such as a cream, a lotion, a spray, a solution, a gel, an ointment, a fat, an oil, a paste, a plaster, a paint, a bioadhesive, a suspensions, an emulsions, or the like, and/or can be prepared so as to contain liposomes, micelles, microcapsules and/or microspheres.
  • Such a formulation can be used in combination with an occlusive overlayer so that moisture evaporating from the body surface is maintained within the formulation upon application to the body surface and thereafter.
  • the formulation can include a living biotherapeutic composition and can comprise at least one microorganism, e.g , an bacterial strain. This living biotherapeutic composition can deliver the LBP directly to the skin for treating or preventing skin conditions, and/or skin diseases (e.g , inflammatory skin diseases).
  • the formulation can be either formulated for stabilization of the LBP or the formulation can be composed before topical application to facilitate application of LBP
  • the composition is a live bacterial product, live biotherapeutic product or a probiotic composition.
  • the at least one isolated or purified population of bacteria or the at least two isolated or purified populations of bacteria are provided as a lyophilizate.
  • the LBP is preferably stabilized in freeze dried, lyophilized and/ or microencapsulated forms and may be prepared according to conventional methods.
  • the LBP can be provided by lyophilising bacteria alone or in combination with one or more excipients to produce a lyophilizate.
  • the excipient/s provided in the process of the invention can be comprised in the lyophilizate, and / or be separate from the lyophilizate.
  • the LBP is stabilized by formulation of the lyophilizate in a pharmaceutical composition for topical application.
  • a two-phase system E.g small bottles with reservoirs containing the lyophilized microorganisms, to be dissolved before use in a suitable liquid carrier contained in the bottles.
  • the LBP are stabilized in the formulation.
  • the formulation is mixed with the stabilized LBP before application.
  • This can e.g be by mixing a sachet with lyophilizate into a topical composition, and then applying the mixture on skin.
  • conventional therapeutic agent refers to therapeutic agents and drugs commonly or routinely used to treat AD in patients.
  • Conventional therapeutic agents include systemic as well as topical therapeutics.
  • the most commonly or frequently prescribed drugs are the topical corticosteroids (TCS)
  • TCS topical corticosteroids
  • Other examples of such agents include, but are not limited to, topical calcineurin inhibitors, anti-histamines, oral immunosuppressants, and glucocorticoids, antibodies, systemic immunosuppressants such as methotrexate, cyclosporine, and azathioprine.
  • Conventional therapeutic agents are used to relieve the symptoms of AD; however have numerous and considerable adverse side effects including diabetes, hypertension, osteoporosis, myelosuppression, nephrotoxicity, hepatotoxicity, leucopenia, an increased risk of microbial infections.
  • Topical agents such as corticosteroids and calcineurin inhibitors are not recommended for long-term application due to the risk of irreversible skin atrophy, dyspigmentation, acneiform eruptions and risks associated with systemic absorption including skin malignancies and lymphomas. Also repetitive application of any topical therapies over a long period of time can erode patient compliance.
  • the administration regimen and dosage of the LBP is adjusted or varied such that one or more AD-associated parameters is significantly improved as well as the toxicity due to the reduction or elimination of conventional therapy is prevented or minimized.
  • the LBP may be administered in higher loading doses for significant improvement in an AD-associated parameter followed by lower regular doses to sustain or maintain the improvement.
  • LBP is combined with conventional therapy e.g TCS
  • TCS may be administered at a reduced dose, typically reduced by about 20 percent, about 30 percent, about 40 percent, about 50 percent or about 60 percent as compared to a patient not treated with LBP
  • the present invention includes methods to reduce dependence on TCS in a patient with AD
  • topical composition comprising LBP replaces conventional therapy.
  • the present invention includes methods for a safer and/or more effective therapy in management of AD in patients.
  • the term "safer and/or more effective therapy”, as used herein, refers to methods of treatment comprising administering LBP to replace conventional therapy or LBP in combination with a conventional therapeutic agent such that one or more AD- associated parameters is significantly improved as well as the side effects and toxicity due to the conventional agent is minimized or prevented.
  • the improvement in an AD-associated parameter is selected from the group consisting of: (a) a decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 30 percent; (b) a decrease from baseline in VAS score of at least 60 percent; and/or (c) an immunosuppressive effect, preferably, the immunosuppressive effect of IL-4, IL-5 and/or IL-17 In certain embodiments, the improvement in an AD-associated parameter is a decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 30 percent.
  • EASI Eczema Area and Severity Index
  • the improvement in an AD-associated parameter is a decrease from baseline in VAS score of at least 60 percent.
  • the improvement in an AD-associated parameter is a decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 30 percent and a decrease from baseline in VAS score of at least 60 percent.
  • EASI Eczema Area and Severity Index
  • the improvement in an AD-associated parameter may be an immunosuppressive effect, e,g, an immunosuppressive effect of IL-4, IL-5, IL-17 or a combination of IL-4 and IL-5; IL-4 and IL-17; IL-5 and IL-17; or IL-4, IL-5 and IL-17,
  • an immunosuppressive effect e,g, an immunosuppressive effect of IL-4, IL-5, IL-17 or a combination of IL-4 and IL-5; IL-4 and IL-17; IL-5 and IL-17; or IL-4, IL-5 and IL-17,
  • the immunosuppressive effect may be an immunosuppressive effect of IL-4 or IL-5, even more preferably, the immunosuppressive effect may be an immunosuppressive effect of IL- 4,
  • composition according to the present invention provides an immunosuppressive effect on IL-4 of at least 10%, such as at least 20%, e,g, at least 30%, such as at least 40%, e,g, at least 50%, such as at least 60%, e.g, at least 70%, such as at least 60%, e,g, at least 90%, such as at least 95%, e.g, at least 98%,
  • the immunosuppressive effect on IL-4 may be provided within 72 hours, such as 48 hours, e.g, within 24 hours.
  • composition according to the present invention provides an immunosuppressive effect on IL-5 of at least 10%, such as at least 20%, e.g, at least 30%, such as at least 40%, e.g, at least 50%, such as at least 60%, e.g, at least 70%, such as at least 60%, e.g, at least 90%, such as at least 95%, e.g, at least 98%,
  • the immunosuppressive effect on IL-5 may be provided within 72 hours, such as 48 hours, e.g, within 24 hours.
  • composition according to the present invention provides an immunosuppressive effect on IL-17 of at least 10%, such as at least 20%, e.g, at least 30%, such as at least 40%, e.g, at least 50%, such as at least 60%, e.g, at least 70%, such as at least 60%, e.g, at least 90%, such as at least 95%, e.g, at least 98%,
  • the immunosuppressive effect on IL-17 may be provided within 72 hours, such as 48 hours, e.g, within 24 hours.
  • the composition according to the present invention may provide an immunosuppressive effect on each of the combination of IL-4 and IL-5; IL-4 and IL-17; IL-5 and IL-17; or IL-4, IL-5 and IL- 17, of at least 10%, such as at least 20%, e.g at least 30%, such as at least 40%, e.g at least 50%, such as at least 60%, e.g at least 70%, such as at least 60%, e.g at least 90%, such as at least 95%, e.g. at least 98%.
  • IL-4"; IL-5"; and IL-17 relate to interleukin- 4; interleukin-5; and interleukin-17, respectively.
  • LBP replaces conventional therapy in the management of AD in patients.
  • composition according to the present invention may be suitable for the treatment, alleviation, suppression, prophylaxis and/or prevention of an atopic disorder in a mammal.
  • composition according to the present invention may be suitable for the treatment, alleviation, suppression, prophylaxis and/or prevention of an atopic disorder in children, toddlers, and/or babies.
  • LBP replaces conventional therapy in the management of AD in children, toddlers or babies.
  • the dosage of the conventional agent is reduced or lowered to minimize the adverse side effects.
  • the methods of treatment as described herein may reduce or eliminate the risk of rebound after steroid reduction or discontinuation.
  • the present invention includes methods for more effective and safer therapy in management of AD in patients including in babies, toddlers, children or young adults who may be more susceptible or sensitive to a conventional therapeutic agent.
  • methods for reducing or eliminating an AD patient's dependence on conventional therapeutics such as TCS during the treatment of AD comprise: selecting a patient with AD that is uncontrolled or partially controlled with a background therapy; administering to the patient a topical composition comprising LBP.
  • methods of treating AD comprising an add-on therapy to conventional therapy.
  • the combined treatment of topical LBP and conventional therapy, the conventional therapy may be reduced by about 5 percent, about 10 percent, about 20 percent, about 30 percent, about 40 percent, about 50 percent, about 60 percent, about 70 percent or by more.
  • the present invention provides a method of treating a atopic dermatitis patient using an topical composition containing viable microorganisms as an active ingredient
  • Atopic dermatitis means an inflammatory skin disease characterized by intense pruritus (e g , severe itch) and by scaly and dry eczematous lesions.
  • the term "atopic dermatitis” includes, but is not limited to, AD caused by or associated with epidermal barrier dysfunction, allergy (e.g , allergy to certain foods, pollen, mold, dust mite, animals, etc ), radiation exposure, and/or asthma.
  • the present disclosure encompasses methods to treat patients with mild, mild-to-moderate, moderate-to-severe or severe AD
  • the present disclosure includes methods to treat both the extrinsic and the intrinsic forms of AD
  • a subject in need thereof means a human or non human animal that exhibits one or more symptoms or indicia of an atopic disorder, such as atopic dermatitis, and/or who has been diagnosed with an atopic disorder, such as atopic dermatitis.
  • a subject in need thereof may include, e.g , subjects who, prior to treatment, exhibit (or have exhibited) one or more AD-associated parameters such as, e.g , elevated EASI and/or VAS score.
  • a subject in need thereof may include a subset of population which is more susceptible to AD or may show an elevated level of an AD- associated biomarker.
  • the term "subject in need thereof includes patients with AD who have been administered one or more topical corticosteroids (TCS) for more than 6 months, more than 1 year, more than 2 years, more than about 5 years, more than about 7 years, or more than about 10 years.
  • TCS topical corticosteroids
  • topical corticosteroids includes group I, group II, group III and group IV topical corticosteroids.
  • group I the corticosteroids are classified as weak (group I), moderately potent (Group II) and potent (Group III) and very potent (Group IV), based on their activity as compared to hydrocortisone.
  • Group IV TCS very potent are up to 600 times as potent as hydrocortisone and include clobetasol propionate and halcinonide.
  • Group III TCS are 50 to 100 times as potent as hydrocortisone and include, but are not limited to, betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone- 17-butyrate, mometasone furoate, and methylprednisolone aceponate.
  • Group II TCS are 2 to 25 times as potent as hydrocortisone and include, but are not limited to, clobetasone butyrate, and triamcinolone acetonide.
  • Group I TCS includes hydrocortisone.
  • the phrase "pharmaceutically acceptable” refers to those active compounds, materials, LBPs, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • EASI Eczema Area and Severity Index
  • the EASI is a validated measure used in clinical settings to assess the severity and extent of AD, (Hanifin et al, 2001, The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis, EASI Evaluator Group, Exp, Dermatol, 70:1 1 -18, DOI: 10, 1034/i, 1600-0625,2001,100102.x),
  • EASI score is indicative to anti-inflammatory efficacy of a treatment.
  • AD disease characteristics are assessed for severity by a physician or other qualified medical professional on a scale of 0 (absent) through 3 (severe).
  • area of AD involvement is assessed as a percentage by body area of head, trunk, arms and legs and converted to a score of 0 to 6,
  • administration of the LBP to a patient result in a decrease in EASI score.
  • the present disclosure includes therapeutic methods which result in a decrease from baseline in EASI score of at least about 10 percent, 15 percent, 20 percent, 25 percent, 30 percent, 35 percent, 40 percent, 45 percent, 50 percent, 55 percent, 60 percent, 65 percent, 70 percent, 75 percent or more at week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or later following administration of the LBP,
  • VAS Visual Pruritus Numeric Rating Scale
  • TIMs topical immunomodulators
  • NSAID anti-inflammatory
  • corticosteroids corticosteroids
  • antihistaminics antibiotics or antiseptics treatments applied on lesion(s) within 7 days before the inclusion or required during the study.
  • GCP Good Clinical Practice
  • Evaluation criteria and endpoints measured were EASI score, VAS score, Nikon ® D90 illustrations, Subjective evaluation questionnaire and Clinical examination by the dermatologist. Patients were evaluated at day 0 (DO) and after 14 days (D14), LBP was administered as a cream 2 times per day (morning and evening).
  • the statistical software used was SAS Enterprise Guide v9,4.
  • the studied product was tested on 24 included subjects, 21 female and 3 male, aged 18 years old to 67, with Caucasian skin type (photype I-IV) and presenting atopic dermatitis on the face and/or body as well as pruritus.
  • photype I-IV Caucasian skin type
  • the LBP was Live Lactiplantibacillus plantarum strain LB244R (DSM32996), lyophilized and formulatedin the concentration of 10 7 CFU/gram in a carrier composition of almond oil, Shea butter, jojoba oil, beeswax. Composition available by Lactobio ApS as Bak Concentrated serum for dry skin.
  • EASI Eczema Area Severity Index
  • Soothing efficacy was evaluated by the subjects themselves under dermatological control using a Visual Analogue Scale from 0 (no pruritus) to 10 (severe pruritus) after 14 days of use with structured scale from 0 to 10
  • the cutaneous acceptability of the product was assessed by taking into account the relevant elements reported by the subject (functional and physical signs) as well as those noted during the examination (clinical signs) The confrontation of these signs was used to conclude the final cutaneous acceptability of the study product.
  • Figure 1 shows the distribution of the EASI score over time
  • Figure 2 the graph of the EASI score.
  • the data showed a statistically significant decrease in the EASI score at D14 from the baseline value (DO) for the product (p ⁇ ,0001). Furthermore, the data demonstrates a strong anti inflammatory effect where a significant decrease of the EASI Score, an average decrease, of 48% after 14 days treatment may be obtained. The improvements in the EASI Score have been demonstrated in 67% of the subjects.
  • the figure 3 shows the distribution of the VAS score of pruritus over time, and figure 4 the graph of the VAS score.
  • the table below summarizes the changes from the baseline value (DO) for the time point (D14), The data showed a statistically significant decrease in the VAS score of pruritus at D14 from the baseline value (DO) for the product (p ⁇ ,0001). Furthermore, the data demonstrates a strong anti-inflammatory effect where a significant decrease of the VAS Score, an average decrease, of 82% after 14 days treatment may be obtained. The improvements in the EASI Score have been demonstrated in 96% of the subjects.
  • Fresh PBMCs from three human donors (obtained from the Blood Bank, Rigshospitalet, Copenhagen, Denmark) were seeded as 0.3 x 10 s cells and co-cultured with 3 bacterial strains in 2 concentrations (1:1 and 1: 10 PBMC to bacteria ratio)
  • Freeze-dried probiotic strains were reconstituted in cell culture medium before addition to PBMC culture. Medium was prepared in absence of pen/strep. The assay was performed on both unstimulated PBMCs and anti-CD3/anti-CD28 stimulated PBMCs.
  • PBMCs donors (Obtained from the blood bank, Rigshospitalet, Copenhagen, Denmark), were purified from three different donors by density gradient centrifugation using 50 ml Lecosep tubes with lymphoprep density gradient medium.
  • Bacterial strain LB244R in the concentration of 10 11 CFU/g was added to PBMCs 1:1 which were stimulated sub-optimally with anti-CD3/anti-CD28 or left unstimulated, for 24 h or 72 h
  • PBMCs (10 6 cells/ml) were seeded into well cell culture plates (5x 10 s cells/well) at 37°C After 2 h, PBMCs were stimulated with CD3/CD28 (eBioscience, clones OKT3, CD28.2) (100 ng/ml) Dexamethasone was used as positive control for immunosuppression and shows a suppressive effect on most of the cytokines, as expected.
  • CD3/CD28 eBioscience, clones OKT3, CD28.2
  • Dexamethasone was used as positive control for immunosuppression and shows a suppressive effect on most of the cytokines, as expected.
  • strain LB244R shows a convincing immunosuppressive effect on IL-4 (figure 6), IL-5 (figure 7) and IL-17 (figure 8), both before and after anti-CD3/anti-CD28 stimulation (marked with (a) or (b) respectively).
  • the suppressed expression of IL-4, IL-5 and IL-17 demonstrates the superior and convincing immunosuppressive effect of the strain LB244R on atopic disorder, such as atopic dermatitis, allergic rhinitis and asthma.

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Abstract

La présente invention se rapporte à une composition destinée à être utilisée dans le traitement, le soulagement, la suppression, la prophylaxie et/ou la prévention d'un trouble atopique chez un sujet, la composition comprenant un produit biothérapeutique vivant (LBP), fournissant (a) une diminution de la ligne de base dans le score d'indice de surface et de gravité de l'eczéma (EASI) d'au moins 30 pour cent ; (b) une diminution de la ligne de base dans le score d'échelle analogique visuelle (VAS) du prurit d'au moins 60 pour cent ; et/ou (c) un effet immunosuppresseur, de préférence, l'effet immunosuppresseur de l'IL-4, de l'IL-5 et/ou de l'IL-17.
PCT/EP2022/053093 2021-02-09 2022-02-09 Méthode de traitement de troubles atopiques Ceased WO2022171654A1 (fr)

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Citations (7)

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Publication number Priority date Publication date Assignee Title
WO2007108763A1 (fr) * 2006-03-17 2007-09-27 Probac Ab Utilisation de souches de lactobacillus permettant de favoriser l'immunotolérance dans une maladie autoimmune
WO2017085655A1 (fr) * 2015-11-18 2017-05-26 Probiotical S.P.A. Compositions présentant une action synergique entre un complexe gélifiant mucoadhésif contre le passage d'antigènes, et des bactéries anti-il7 immunomodulatrices, destinées à être utilisées dans le traitement de maladies auto-immunes et neurodégénératives non apparentées.
CA3052134A1 (fr) * 2017-01-31 2018-08-09 University-Industry Cooperation Group Of Kyung Hee University Nouvelles bacteries lactiques et leur utilisation
US20190030097A1 (en) * 2015-09-15 2019-01-31 University-Industry Cooperation Group Of Kyung Hee University Novel Lactobacillus Having Various Functions, and Use Thereof
WO2020098988A1 (fr) * 2019-01-04 2020-05-22 Lactobio Aps Souches , composition et procédé d'utilisation
WO2020127637A1 (fr) * 2018-12-21 2020-06-25 Lactobio Aps Composition topique comprenant des microorganismes viables
WO2020249734A1 (fr) * 2019-06-13 2020-12-17 Lactobio Aps Composition de gel comprenant des micro-organismes viables

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Publication number Priority date Publication date Assignee Title
WO2007108763A1 (fr) * 2006-03-17 2007-09-27 Probac Ab Utilisation de souches de lactobacillus permettant de favoriser l'immunotolérance dans une maladie autoimmune
US20190030097A1 (en) * 2015-09-15 2019-01-31 University-Industry Cooperation Group Of Kyung Hee University Novel Lactobacillus Having Various Functions, and Use Thereof
WO2017085655A1 (fr) * 2015-11-18 2017-05-26 Probiotical S.P.A. Compositions présentant une action synergique entre un complexe gélifiant mucoadhésif contre le passage d'antigènes, et des bactéries anti-il7 immunomodulatrices, destinées à être utilisées dans le traitement de maladies auto-immunes et neurodégénératives non apparentées.
CA3052134A1 (fr) * 2017-01-31 2018-08-09 University-Industry Cooperation Group Of Kyung Hee University Nouvelles bacteries lactiques et leur utilisation
WO2020127637A1 (fr) * 2018-12-21 2020-06-25 Lactobio Aps Composition topique comprenant des microorganismes viables
WO2020098988A1 (fr) * 2019-01-04 2020-05-22 Lactobio Aps Souches , composition et procédé d'utilisation
WO2020249734A1 (fr) * 2019-06-13 2020-12-17 Lactobio Aps Composition de gel comprenant des micro-organismes viables

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