WO2023214312A1 - Méthodes de traitement de la dermatite atopique par etrasimod - Google Patents

Méthodes de traitement de la dermatite atopique par etrasimod Download PDF

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Publication number
WO2023214312A1
WO2023214312A1 PCT/IB2023/054569 IB2023054569W WO2023214312A1 WO 2023214312 A1 WO2023214312 A1 WO 2023214312A1 IB 2023054569 W IB2023054569 W IB 2023054569W WO 2023214312 A1 WO2023214312 A1 WO 2023214312A1
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compound
individual
pharmaceutically acceptable
acceptable salt
weeks
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PCT/IB2023/054569
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English (en)
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Gurpreet Ahluwalia
Fiona Kuo
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Arena Pharmaceuticals, Inc.
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Publication of WO2023214312A1 publication Critical patent/WO2023214312A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • sphingosine 1 -phosphate subtype 1 S1 Pi or SIP1
  • methods useful in the treatment of sphingosine 1 -phosphate subtype 1 S1 Pi or SIP1 ) receptor-associated disorders, and more particularly atopic dermatitis.
  • AD Atopic dermatitis
  • atopic eczema Atopic dermatitis
  • AD is the most common chronic relapsing, inflammatory skin disease.
  • AD is a serious, chronic immune-mediated disease in which symptoms vary, but often include severe dry skin, itching, patches, swollen skin and raised bumps which may leak fluid.
  • the lifetime prevalence of AD is 10% to 20% in developed countries, and appears to be increasing (Weidinger 2016, Heratizadeh 2017).
  • AD can remain a chronic and lifelong condition, with prevalence in adults ranging from 7% to 10% (Boguniewicz 2017). In a clinical study population, it was found that 50% of AD patients had been living with active disease for more than 27 years (Simpson 2016b).
  • AD is characterized by systemic cutaneous inflammation and perturbed epidermal- barrier function resulting in dry, red skin and intense itch (Bieber 2008, Weidinger 2016).
  • Essential features for diagnosis of AD are pruritus, eczematous dermatitis, and a chronic or relapsing history of disease (Weidinger 2016, Boguniewicz 2017).
  • Patients with AD are more likely to have other allergic or atopic conditions.
  • 51 .3% had allergic rhinitis
  • 40.3% had asthma
  • 24.2% had allergic conjunctivitis
  • 60.5% had other allergies.
  • the disease burden of those with AD significantly impacts quality of life and patients report that their condition affects social and leisure activities (43.9%), work or studying (41 .8%), and even clothing choice (57.9%) (Simpson 2016).
  • AD Alzheimer's disease predisposition
  • pathogenesis of AD is thought to stem from the mutually reinforcing interaction between a disrupted epidermal barrier and an inappropriate immune response in the skin (Weidinger 2016, Heratizadeh 2017).
  • Epidermal barrier disruption in AD facilitates penetration by allergens, immunoglobulin E (IgE) sensitization, and bacterial colonization (particularly Staphylococcus aureus), which induce persistent type 2 helper T cell responses (Salava 2014, Zhu 2018).
  • Applicant has discovered new methods of treating moderate to severe atopic dermatitis, including methods that allow for the effective treatment of the disease with an interruption period if certain biomarkers or adverse events are observed.
  • Three S1 P modulators are approved for the treatment of relapsing forms of multiple sclerosis — fingolimod (GILENYA), siponimod (MAYZENT), and ozanimod (ZEPOSIA) (MAYZENT(siponimod) (2020) Prescribing Information.
  • GILENYA fingolimod
  • MAYZENT siponimod
  • ZEPOSIA ozanimod
  • Ozanimod is also in clinical development for ulcerative colitis and Crohn’s disease (Peyrin-Biroulet L, Christopher R, Behan D and Lassen C (2017) Modulation of sphingosine-1 -phosphate in inflammatory bowel disease. Autoimmun Rev 16:495-503).
  • Etrasimod has demonstrated efficacy in a Phase 2 clinical trial in ulcerative colitis (Sandborn WJ, Peyrin-Biroulet L, Zhang J, Chiorean M, Vermeire S, Lee SD, Kuhbacher T, Yacyshyn B, Cabell CH, Naik SU, Klassen P and Panes J (2020) Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients With Ulcerative Colitis. Gastroenterology 158:550-561 ) and is currently under Phase 3 development for ulcerative colitis and Phase 2/3 development for Crohn’s disease.
  • Described herein is the first clinical trial for an S1 P modulator in patients with the dermatological indication atopic dermatitis. Lymphocyte reduction is an on-target effect of etrasimod. During the study, some investigators discontinued etrasimod due to lymphocyte levels meeting CTCAE grade 3 criteria. Although this presented challenges for the trial, it also provided an unexpected opportunity to evaluate the effects of interrupting and reinitiating treatment with etrasimod. An analysis of the trial results revealed that the patient cohort with dose interruption showed clinical rebound (or worsening of atopic dermatitis) following withdrawal and a resumption of clinical effect following a restart of treatment with etrasimod. Further, this observation was consistent with pharmacodynamic observations in that patient cohort. Importantly, none of these patients evidenced infection that would have warranted treatment interruption.
  • a method of treating an individual with atopic dermatitis comprising: administering to the individual in need thereof a pharmaceutical dosage form comprising a therapeutically effective amount of (F?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 ,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1 ), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein prior to treatment, the individual had an inadequate response with, lost response to, or been intolerant to a conventional therapy.
  • a pharmaceutical dosage form comprising a therapeutically effective amount of (F?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 ,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1 ), or a pharmaceutically acceptable salt, solvate, or hydrate thereof,
  • the atopic dermatitis is chronic atopic dermatitis.
  • the atopic dermatitis is moderate to severe atopic dermatitis.
  • the individual had an inadequate response to conventional therapy.
  • the individual lost response to conventional therapy In some embodiments, the individual lost response to conventional therapy.
  • the individual became intolerant to conventional therapy.
  • the conventional therapy is chosen from systemic steroids, cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, dupilumab, and oral JAK inhibitors.
  • administering results in an achievement of at least 75% reduction of Eczema Area and Severity Index (EASI) from baseline.
  • EASI Eczema Area and Severity Index
  • administration of Compound 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to the individual results in an achievement of vIGA clear (0) to almost clear (1) and a reduction from baseline in Investigator’s Global Assessment (IGA) of > 2 points.
  • administering results in improvement in itch numerical rating scale (NRS) of > 4 points.
  • NRS numerical rating scale
  • administration of Compound 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to the individual results in comparable efficacy as to the administration of Compound 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to an individual who had not had an inadequate response with, had not lost response to, or had not been intolerant to a conventional therapy.
  • the Compound 1 or pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered at a frequency of once a day during the continuation period of time.
  • the Compound 1 or pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in an amount equivalent to 2 mg of Compound 1 .
  • the Compound 1 or pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in an amount equivalent to 3 mg of Compound 1 .
  • the Compound 1 or pharmaceutically acceptable salt, solvate, or hydrate thereof, is Compound 1 .
  • a method of treating or ameliorating at least one symptom or indication of an atopic dermatitis in an individual in need thereof comprising: administering to the individual in need thereof a pharmaceutical dosage form comprising a therapeutically effective amount of (fl)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 ,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1 ), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical dosage form comprising a therapeutically effective amount of (fl)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 ,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid (Compound 1 ), or a pharmaceutically acceptable salt thereof, wherein
  • a method of treating moderate to severe atopic dermatitis includes administering etrasimod, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, identifying a threshold absolute lymphocyte count (ALC) in the patient, ceasing administration of the etrasimod, or a pharmaceutically acceptable salt thereof, for an interruption period of time, and after ceasing administration for the interruption period of time, continuing to administer the etrasimod, or a pharmaceutically acceptable salt thereof, for a continuation period of time, wherein the patient in need thereof experiences an improvement in moderate to severe atopic dermatitis.
  • the etrasimod, or a pharmaceutically acceptable salt thereof is administered at a frequency of once a day.
  • the etrasimod, or a pharmaceutically acceptable salt thereof is administered at a frequency of once a day and the improvement to moderate to severe atopic dermatitis includes an improvement in validated Investigator Global Assessment (vIGA) score.
  • the etrasimod, or a pharmaceutically acceptable salt thereof is administered at a frequency of once a day during the continuation period of time.
  • the etrasimod, or a pharmaceutically acceptable salt thereof is administered in an amount of about 2 mg.
  • the threshold ALC is less than 500/mm3 or between 0.2 x 10e9 cells/L and 0.5 x 10e9 cells/L.
  • the threshold ALC is less than 200/mm3 or less than 0.2 x 10e9 cells/L.
  • the interruption period of time is at least one week. In some embodiments, the interruption period of time is between about one week and about four weeks. In some embodiments, the continuation period of time is at least one month.
  • the patient is diagnosed with moderate atopic dermatitis and has a vIGA score of 3. In some embodiments, the patient is diagnosed with severe atopic dermatitis and has a vIGA score of 4.
  • the method further comprises the step of testing a circulating blood level of lymphocytes in the patient.
  • the method further comprises testing the circulating blood level of lymphocytes in the patient a subsequent time after the interruption period, identifying a threshold ALC in the patient, and, if the threshold is met, continuing to cease treatment.
  • the patient in need thereof exhibits a body surface area (BSA) of atopic dermatitis greater than or equal to 10%.
  • BSA body surface area
  • a method of treating moderate to severe atopic dermatitis includes administering etrasimod, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, monitoring the patient for infections, ceasing administration of the etrasimod, or a pharmaceutically acceptable salt thereof, for an interruption period of time, and after ceasing administration for the interruption period of time, continuing to administer the etrasimod, or a pharmaceutically acceptable salt thereof, for a continuation period of time, wherein the patient in need thereof experiences an improvement in moderate to severe atopic dermatitis.
  • the etrasimod, or a pharmaceutically acceptable salt thereof is administered at a frequency of once a day during the continuation period of time.
  • the etrasimod, or a pharmaceutically acceptable salt thereof is administered in an amount of about 2 mg.
  • the patient is diagnosed with moderate atopic dermatitis.
  • FIG. 1 shows the effect on Compound 1 on the primary and key secondary efficacy endpoints over time.
  • Panel Fig. 1 A shows improvement from baseline in EASI score.
  • Panel Fig. 1 B shows proportion of subjects achieving vIGA grades of clear or almost clear.
  • Panel Fig. 1C shows proportion of EASI-75 responders continuing to improve from week 6 through week 12.
  • FIG. 2 shows the proportion of subjects in prior systemic treatment failure achieving at least 75% reduction of EASI from baseline.
  • FIG. 3 shows the proportion of subjects with a vIGA of 0 or 1 and a reduction from baseline of > 2 points.
  • FIG. 4 shows the proportion of subjects achieving vIGA success for both prior systemic treatment failure subjects as non prior systemic treatment failure subjects.
  • FIG. 5 shows the proportion of subjects in prior systemic treatment failure achieving at least 75% reduction of EASI from baseline for both prior systemic treatment failure subjects as non prior systemic treatment failure subjects.
  • COMPOUND 1 As used herein, “Compound 1 ” means (P?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-1 ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid including crystalline forms thereof. (Compound 1 )
  • Compound 1 may be present as an anhydrous, nonsolvated crystalline form as described in WO 2010/011316 (incorporated by reference herein in its entirety).
  • an L-arginine salt of Compound 1 may be present as an anhydrous, non-solvated crystalline form as described in WO 2010/011316 and WO 2011/094008 (each of which is incorporated by reference herein in its entirety).
  • a calcium salt of Compound 1 may be present as a crystalline form as described in WO 2010/01 1316 (incorporated by reference herein in its entirety).
  • Compound 1 is herein also described as “etrasimod”.
  • Compound 1 is an orally administered, selective, synthetic sphingosine 1 -phosphate (S1 P) receptor 1 , 4, 5 modulator.
  • S1 P sphingosine 1 -phosphate
  • Compound 1 or a pharmaceutically acceptable salt thereof, has been found to be safe and well-tolerated in clinical trials. Its safety and tolerability have been evaluated in Phase 1 studies with healthy adult subjects at single doses up to 5 mg and repeated doses up to 4 mg once daily (QD). In a Phase 2 dose-ranging study in UC patients, treatment with 2 mg QD for 12 weeks led to clinically meaningful and statistically significant endoscopic and symptomatic improvements versus placebo. Sustained beneficial effects of were observed in a subsequent open-label extension study.
  • MODERATE TO SEVERE ATOPIC DERMATITIS means that one or more of the following features are present: (1 ) a minimum involvement of 10% body surface area (BSA); (2) regardless of BSA, individual lesions with moderate-to severe-features; involvement of highly visible areas or those important for function (e.g., neck, face, genitals, palms, and/or soles); and significantly impaired quality of life.
  • BSA body surface area
  • a validated Investigator’s Global Assessment (vIGA) of 3 is considered moderate atopic dermatitis
  • vIGA of 4 is considered severe atopic dermatitis.
  • vIGA Global Assessment
  • EXTRINSIC OR ALLERGIC ATOPIC DERMATITIS Extrinsic or allergic atopic dermatitis is atopic dermatitis with high total serum IgE levels and the presence of specific IgE for environmental and food allergens.
  • vIGA Intrinsic or non-allergic atopic dermatitis is atopic dermatitis with normal total IgE values and the absence of specific IgE.
  • vIGA As used herein, “vIGA” means validated Investigator’s Global Assessment scale for AD, which is currently a five-point scale to measure disease severity.
  • the scale is further described at https://www.eczemacouncil.org/assets/docs/Validated-lnvestigator-Global-Assessment- Scale_vlGA-AD_2017.pdf/, which is incorporated by reference in its entirety herein.
  • the standards for vIGA can be apparent to those of skill in the art.
  • EASI Eczema Area and Severity Index
  • EASI is an outcome measure for the clinical signs of AD.
  • the current EASI is a composite index with scores ranging from 0 to 72.
  • the EASI scoring assessment multiplies the percentage of the affected area in 4 specific disease characteristics (erythema, thickness [induration, papulation, edema], scratching [excoriation], and lichenification), which is assessed for severity by a physician on a scale of “0” (absent) through “3” (severe).
  • the EASI Area Score can be documented for four regions of the body — Region 1 : head and neck; Region 2: trunk (including genital area); Region 3: upper limbs; and Region 4: lower limbs (including buttocks), with the area of AD involvement assessed as a percentage by body area and converted to a score of 0 to 6. In each body region, the area is expressed as 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). In some embodiments, the standards for EASI can be apparent to those of skill in the art.
  • EASI 75 As used herein, “EASI 75” means a 75% reduction of EASI from baseline.
  • EASI 50 means a 50% reduction of EASI from baseline.
  • EASI 90 means a 90% reduction of EASI from baseline.
  • PRURITUS NUMERIC RATING SCALE PRURITUS NUMERIC RATING SCALE:
  • “pruritis numeric rating scale” or “NRS” refers to an assessment tool that patients use to report the intensity of their pruritus (itch).
  • the scale for the NRS is from 0 to 10, with 0 being “no itch” and 10 being “the worst itch imaginable.” This scale is further described at http://www.pruritussymposium.de/numericalratingscale.html, which is incorporated by reference in its entirety.
  • the standards for NRS can be apparent to those of skill in the art.
  • ADMINISTERING means to provide a compound or other therapy, remedy, or treatment such that an individual internalizes a compound.
  • PRESCRIBING means to order, authorize, or recommend the use of a drug or other therapy, remedy, or treatment.
  • a health care practitioner can orally advise, recommend, or authorize the use of a compound, dosage regimen or other treatment to an individual.
  • the health care practitioner may or may not provide a prescription for the compound, dosage regimen, or treatment.
  • the health care practitioner may or may not provide the recommended compound or treatment.
  • the health care practitioner can advise the individual where to obtain the compound without providing the compound.
  • a health care practitioner can provide a prescription for the compound, dosage regimen, or treatment to the individual.
  • a health care practitioner can give a written or oral prescription to an individual.
  • a prescription can be written on paper or on electronic media such as a computer file, for example, on a hand-held computer device.
  • a health care practitioner can transform a piece of paper or electronic media with a prescription for a compound, dosage regimen, or treatment.
  • a prescription can be called in (oral), faxed in (written), or submitted electronically via the internet to a pharmacy or a dispensary.
  • a sample of the compound or treatment can be given to the individual.
  • giving a sample of a compound constitutes an implicit prescription for the compound.
  • Different health care systems around the world use different methods for prescribing and/or administering compounds or treatments and these methods are encompassed by the disclosure.
  • a prescription can include, for example, an individual’s name and/or identifying information such as date of birth.
  • a prescription can include: the medication name, medication strength, dose, frequency of administration, route of administration, number or amount to be dispensed, number of refills, physician name, physician signature, and the like.
  • a prescription can include a DEA number and/or state number.
  • a healthcare practitioner can include, for example, a physician, nurse, nurse practitioner, or other related health care professional who can prescribe or administer compounds (drugs) for the treatment of a sphingosine 1 -phosphate subtype 1 (S1 Pi) receptor-associated disorder.
  • a healthcare practitioner can include anyone who can recommend, prescribe, administer, or prevent an individual from receiving a compound or drug including, for example, an insurance provider.
  • PREVENT, PREVENTING, OR PREVENTION As used herein, the term “prevent,” “preventing”, or “prevention” such as prevention of a sphingosine 1 -phosphate subtype 1 (S1 Pi) receptor-associated disorder or the occurrence or onset of one or more symptoms associated with the particular disorder and does not necessarily mean the complete prevention of the disorder.
  • prevention means the administration of therapy on a prophylactic or preventative basis to an individual who may ultimately manifest at least one symptom of a disease or condition but who has not yet done so.
  • individuals can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease.
  • prevention therapy can be administered without prior identification of a risk factor, as a prophylactic measure. Delaying the onset of at least one symptom can also be considered prevention or prophylaxis.
  • TREAT, TREATING, OR TREATMENT means the administration of therapy to an individual who already manifests at least one symptom of a disease or condition or who has previously manifested at least one symptom of a disease or condition.
  • “treating” can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • treating in reference to a disorder means a reduction in severity of one or more symptoms associated with that particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder.
  • TOLERATE As used herein, an individual is said to “tolerate” a dose of a compound if administration of that dose to that individual does not result in an unacceptable adverse event or an unacceptable combination of adverse events.
  • tolerance is a subjective measure and that what may be tolerable to one individual may not be tolerable to a different individual. For example, one individual may not be able to tolerate headache, whereas a second individual may find headache tolerable but is not able to tolerate vomiting, whereas for a third individual, either headache alone or vomiting alone is tolerable, but the individual is not able to tolerate the combination of headache and vomiting, even if the severity of each is less than when experienced alone.
  • an individual is said to be “intolerant” of a dose of a compound if administration of that dose to that individual results in an unacceptable adverse event or an unacceptable combination of adverse events.
  • ADVERSE EVENT As used herein, an “adverse event” is an untoward medical occurrence that is associated with treatment with Compound 1 or a pharmaceutically acceptable salt thereof.
  • INFECTION As used herein, “infection” refers to the invasion and multiplication of microorganisms such as bacteria, viruses, and parasites that are not normally present within the body. An infection may cause no symptoms and be subclinical, or it may cause symptoms and be clinically apparent. An infection may remain localized, or it may spread through the blood or lymphatic vessels to become systemic (body wide). Infections may include, but are not limited to urinary tract infection, common cold, diptheria, E.
  • coli giardiasis, HIV/AIDS, mononucleosis, influenza, lyme disease, measles, meningitis, mumps, pneumonia, salmonella infections, respiratory infections, shingles, herpes, tuberculosis, viral hepatitis, COVID-19, and those recognized by those of skill in the art.
  • in need of treatment and “in need thereof” when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g., physician, nurse, nurse practitioner, etc.) that an individual requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver’s expertise, but that includes the knowledge that the individual is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.
  • INDIVIDUAL As used herein, “individual” means a human. In some embodiments, an individual is referred to a “subject” or “patient.”
  • DOSE As used herein, “dose” means a quantity of Compound 1 , or a pharmaceutically acceptable salt thereof, given to the individual for treating or preventing the disease or disorder at one specific time.
  • therapeutically effective amount of an agent, compound, drug, composition or combination is an amount which is nontoxic and effective for producing some desired therapeutic effect upon administration to a subject or patient .
  • the precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art.
  • the effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.
  • the therapeutically effective amount is the standard dose.
  • PHARMACEUTICAL COMPOSITION means a composition comprising at least one active ingredient, such as Compound 1 ; including but not limited to salts of Compound 1 , whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • a mammal for example, without limitation, a human.
  • Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.
  • agonist means a moiety that interacts with and activates a G-protein-coupled receptor, such as the S1 Pi receptor, such as can thereby initiate a physiological or pharmacological response characteristic of that receptor.
  • a G-protein-coupled receptor such as the S1 Pi receptor
  • an agonist activates an intracellular response upon binding to the receptor, or enhances GTP binding to a membrane.
  • an agonist of the invention is an S1 Pi receptor agonist that is capable of facilitating sustained S1 Pi receptor internalization (see e.g., Matloubian etal., Nature, 427, 355, 2004).
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric, oxalic, p- toluenesulfonic and the like, such as those pharmaceutically acceptable salts listed by Berge et al., Journal of Pharmaceutical Sciences, 66:1 -19 (1977), incorporated herein by reference in its entirety.
  • the individual has had an inadequate response with, lost response to, been intolerant to, or demonstrated dependence on another agent for the treatment of the SIP1 receptor-associated disorder. In some embodiments, the individual has had an inadequate response with the other agent for the treatment of the SIP1 receptor-associated disorder. In some embodiments, the individual has lost response to another agent for the treatment of the SIP1 receptor-associated disorder. In some embodiments, the individual was intolerant to another agent for the treatment of the SIP1 receptor-associated disorder.
  • Also provided is a method of treating an individual with atopic dermatitis comprising: administering to the individual in need thereof a pharmaceutical dosage form comprising a therapeutically effective amount of (F?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 ,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1 ), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein prior to treatment, the individual had an inadequate response with, lost response to, or been intolerant to a conventional therapy.
  • a pharmaceutical dosage form comprising a therapeutically effective amount of (F?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1 ,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1 ), or a pharmaceutically acceptable salt, solvate, or
  • the individual had become intolerant to conventional therapy.
  • the individual had an inadequate response to conventional therapy.
  • the individual lost response to conventional therapy as a prior treatment the individual lost response to conventional therapy as a prior treatment.
  • the prior treatment is chosen from systemic steroids, cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, dupilumab, and oral JAK inhibitors.
  • administration of Compound 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to an individual who had an inadequate response with, lost response to, or been intolerant to a conventional therapy results in an achievement of at least 75% reduction of Eczema Area and Severity Index (EASI) from baseline.
  • EASI Eczema Area and Severity Index
  • administration of Compound 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to an individual who had an inadequate response with, lost response to, or been intolerant to a conventional therapy results in an achievement of vIGA clear (0) to almost clear (1 ) and a reduction from baseline in Investigator’s Global Assessment (IGA) of > 2 points.
  • itch numerical rating scale (NRS) of > 4 points.
  • the itch NRS is comprised of one item and represents the numbers 0 (“no itch”) to 10 (“worst imaginable itch”). Subjects are asked to rate the intensity of their itch using this scale.
  • administration of Compound 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to an individual who had an inadequate response with, lost response to, or been intolerant to a conventional therapy results in comparable efficacy as to the administration of Compound 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to an individual who had not had an inadequate response with, had not lost response to, or had not been intolerant to a conventional therapy.
  • the Compound 1 is administered orally.
  • the Compound 1 is formulated as a capsule or tablet suitable for oral administration.
  • the Compound 1 , or a pharmaceutically acceptable salt thereof is selected from: Compound 1 ; a calcium salt of Compound 1 ; and an L-arginine salt of Compound 1 .
  • the Compound 1 , or a pharmaceutically acceptable salt thereof is an L-arginine salt of Compound 1 .
  • the Compound 1 , or a pharmaceutically acceptable salt, thereof is an anhydrous, non-solvated crystalline form of an L-arginine salt of Compound 1 .
  • the Compound 1 , or a pharmaceutically acceptable salt thereof is an anhydrous, non-solvated crystalline form of Compound 1 .
  • compositions comprising a standard dose of Compound 1 , or a pharmaceutically acceptable salt thereof, and, optionally, one or more pharmaceutically acceptable carriers.
  • pharmaceutical compositions comprising Compound 1 , or a pharmaceutically acceptable salt thereof, optionally, one or more pharmaceutically acceptable carriers.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.
  • Compound 1 is administered as a raw or pure chemical, for example as a powder in capsule formulation.
  • Compound 1 is formulated as a pharmaceutical composition further comprising one or more pharmaceutically acceptable carriers.
  • compositions may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, forming the resulting mixture into a desired shape.
  • the pharmaceutical composition may be in the form of, for example, a tablet or capsule.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are capsules, tablets, powders, granules or suspensions, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desired shape and size.
  • the powders and tablets may contain varying percentage amounts of the active compound.
  • a representative amount in a powder or tablet may be from 0.5 to about 90 percent of the active compound.
  • Suitable carriers for powders and tablets include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like.
  • the term “preparation” includes the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets or capsules.
  • the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any of these in packaged form.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • the pharmaceutical dosage form is administered once daily to the individual.
  • the individual is administered an amount equivalent to about 0.5 to about 5.0 mg of Compound 1 . In some embodiments, the individual is administered an amount equivalent to 1 mg of Compound 1 . In some embodiments, the individual is administered an amount equivalent to 2 mg of Compound 1 . In some embodiments, a patient is administered an amount equivalent to more than 2 mg of Compound 1 . In some embodiments, a patient is administered an amount equivalent to more than 2.5 mg of Compound 1 . In some embodiments, the individual is administered an amount equivalent to 2.25 mg of Compound 1 . In some embodiments, the individual is administered an amount equivalent to 2.5 mg of Compound 1 . In some embodiments, the individual is administered an amount equivalent to 2.75 mg of Compound 1 .
  • the individual is administered an amount equivalent to 3 mg of Compound 1 .
  • a patient is administered an amount equivalent to, or of about, 2.1 , 2.2, 2.25, 2.3, 2.4, 2.5, 2.6, 2.7, 2.75, 2.8. 2.9, or 3.0 mg of Compound 1 .
  • a patient is administered more than, or more than about, 2 mg of Compound 1 for greater efficacy than may be achieved with 2 mg of Compound 1 .
  • a patient is administered more than, or more than about, 2 mg of Compound 1 to maximize EASI change from baseline at week 12.
  • the individual is administered an amount equivalent to 1 mg of Compound 1 for a first time period and subsequently an amount equivalent to 2 mg of Compound 1 for a second time period.
  • the first time period is at least one month, such as one month, two months, three months, four months, etc.
  • the first time period is at least one week, such as one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, thirteen weeks, fourteen weeks, fifteen weeks, etc.
  • the second time period is at least one month, such as one month, two months, three months, four months, etc.
  • the second time period is at least one week, such as one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, thirteen weeks, fourteen weeks, fifteen weeks, etc.
  • the second time period is indefinite, e.g., chronic administration.
  • the standard dose is administered without titration. In some embodiments, the standard dose is administered without titration; and the individual does not experience a severe related adverse event. In some embodiments, the standard dose is administered without requiring titration to avoid first-dose effect seen with other S1 P receptor modulators.
  • the dosage form is administered under fasted conditions. In some embodiments, the dosage form is administered under fed conditions.
  • the method is non-gender specific.
  • Compound 1 is administered in combination with a second therapeutic agent or therapy, wherein the second therapeutic agent or therapy is selected from an IL-1 beta inhibitor, an IL-5 inhibitor, an IL-9 inhibitor, an IL-13 inhibitor, an IL-17 inhibitor, an IL-25 inhibitor, a TNFa inhibitor, an eotaxin-3 inhibitor, an IgE inhibitor, a prostaglandin D2 inhibitor, an immunosuppressant, a glucocorticoid, a proton pump inhibitor, a NSAID, allergen removal and diet management.
  • the second therapeutic agent or therapy is selected from an IL-1 beta inhibitor, an IL-5 inhibitor, an IL-9 inhibitor, an IL-13 inhibitor, an IL-17 inhibitor, an IL-25 inhibitor, a TNFa inhibitor, an eotaxin-3 inhibitor, an IgE inhibitor, a prostaglandin D2 inhibitor, an immunosuppressant, a glucocorticoid, a proton pump inhibitor, a NSAID, allergen removal and diet management.
  • Compound 1 was previously administered at least one therapeutic agent or therapy, wherein the therapeutic agent or therapy is selected from an IL-1 beta inhibitor, an IL-5 inhibitor, an IL-9 inhibitor, an IL- 13 inhibitor, an IL-17 inhibitor, an IL-25 inhibitor, a TNFa inhibitor, an eotaxin-3 inhibitor, an IgE inhibitor, a prostaglandin D2 inhibitor, an immunosuppressant, a glucocorticoid, a proton pump inhibitor, a NSAID, allergen removal and diet management.
  • the therapeutic agent or therapy is selected from an IL-1 beta inhibitor, an IL-5 inhibitor, an IL-9 inhibitor, an IL- 13 inhibitor, an IL-17 inhibitor, an IL-25 inhibitor, a TNFa inhibitor, an eotaxin-3 inhibitor, an IgE inhibitor, a prostaglandin D2 inhibitor, an immunosuppressant, a glucocorticoid, a proton pump inhibitor, a NSAID, allergen removal and diet management.
  • the individual is, or was, treated with an IL-1 beta inhibitor.
  • the IL-1 beta inhibitor is anakinra, rilonacept, or canakinumab.
  • the individual is, or was, treated with an IL-5 inhibitor.
  • the IL-5 inhibitor is benralizumab, mepolizumab or reslizumab.
  • the individual is treated with an IL-9 inhibitor.
  • the individual is, or was, treated with an IL-13 inhibitor.
  • the IL-13 inhibitor is lebrikizumab, RPC4046, or tralokinumab.
  • the individual is, or was, treated with an IL-17 inhibitor.
  • the IL-17 inhibitor is ixekizumab or brodalumab.
  • the individual is, or was, treated with an IL-25 inhibitor.
  • the individual is, or was, treated with a TNFa inhibitor.
  • the TNFa inhibitor is SIMPONI® (golimumab), REMICADE® (infliximab), HUMIRA® (adalimumab), or CIMZIA® (certolizumab pegol).
  • the individual is, or was, treated with an eotaxin-3 inhibitor.
  • the individual is, or was, treated with an IgE inhibitor.
  • the IgE inhibitor is omalizumab.
  • the individual is, or was, treated with a prostaglandin D2 inhibitor.
  • the individual is, or was, treated with an immunosuppressant.
  • the immunosuppressant is AZASAN® (azathioprine), IMURAN® (azathioprine), GENGRAF® (cyclosporine), NEORAL® (cyclosporine), or SANDIMMUNE® (cyclosporine).
  • Immunosuppressants also may be referred to as immunosuppressives or immunosuppressive agents.
  • the individual is, or was, treated with a glucocorticoid.
  • the glucocorticoid is UCERIS® (budesonide); DELTASONE® (prednisone), MEDROL® (methylprednisolone), or hydrocortisone.
  • Glucocorticosteroids also may be referred to as glucocorticoid or corticosteroids.
  • the individual is, or was, treated with a NSAID.
  • the NSAID is aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, or tolmetin.
  • the individual is, or was treated with DUPIXENT® (dupilumab).
  • the treatment is for inducing clinical remission. In some embodiments, the treatment is for maintaining clinical remission. In some embodiments, the treatment is for inducing and maintaining clinical remission.
  • the treatment is for inducing clinical response. In some embodiments, the treatment is for maintaining clinical response. In some embodiments, the treatment is for inducing and maintaining clinical response.
  • atopic dermatitis is moderate to severe atopic dermatitis. In some embodiments, the atopic dermatitis is moderate atopic dermatitis. In some embodiments, the atopic dermatitis is severe atopic dermatitis. In some embodiments, the atopic dermatitis is chronic atopic dermatitis. In some embodiments, the individual with atopic dermatitis is inadequately controlled by or intolerant to topical therapy. In some embodiments, the individual with atopic dermatitis is inadequately controlled by or intolerant to biologies. In some embodiments, the individual with atopic dermatitis is inadequately controlled by or intolerant to dupilumab.
  • a method of treating an individual with pruritis comprising administering to the individual in need thereof a therapeutically effective amount of etrasimod, or a pharmaceutically acceptable salt thereof.
  • the pruritis is moderate to severe pruritis. In some embodiments, the pruritis is moderate pruritis. In some embodiments, the pruritis is severe pruritis.
  • the methods described herein achieve a therapeutic effect.
  • the method is therapeutically effective to improve EASI from baseline, to achieve EASI-75, to achieve a vIGA 0 to 1 (on a 5-point scale) score, to reduce a patient’s peak pruritus NRS, to reduce the percent BSA AD involvement from baseline, to achieve EASI-50, defined as a > 50% reduction of EASI from baseline, or to achieve EASI-90 (defined as a > 90% reduction of EASI from baseline).
  • the therapeutic effect is observed in, or in about, four weeks, five weeks, six weeks, seven weeks, eight weeks, ten weeks, twelve weeks, or sixteen weeks. In some embodiments, the therapeutic effect is observed in, or in about, four weeks, five weeks, six weeks, seven weeks, eight weeks, ten weeks, twelve weeks, or sixteen weeks of initiating treatment. In some embodiments, the therapeutic effect is observed in, or in about, four weeks, five weeks, six weeks, seven weeks, eight weeks, ten weeks, twelve weeks, or sixteen weeks of reinitiating treatment. In some embodiments, the method is effective to treat pruritis in a patient diagnosed with AD in, or in about, four weeks. In some embodiments, the method is effective to demonstrate a statistically significant improvement in EASI from baseline in four weeks.
  • the improvement in moderate to severe atopic dermatitis comprises an improvement in a patient-reported outcome assessed using the Dermatology Life Quality Index (DLQI), Patient Oriented Eczema Measure (POEM), or Patient Global Assessment (PGA).
  • DLQI Dermatology Life Quality Index
  • POEM Patient Oriented Eczema Measure
  • PGA Patient Global Assessment
  • the improvement to moderate to severe atopic dermatitis comprises an improvement in pruritus.
  • a method of treatment includes monitoring the circulating blood lymphocyte levels of a patient suffering from atopic dermatitis and adjusting the treatment if the absolute lymphocyte count (ALC) levels are below an identified threshold.
  • the threshold is ALC less than, or less than about, 500/mm 3 .
  • the threshold is ALC less than, or less than about, 500/mm 3 , 450/mm 3 , 400/mm 3 , 350/mm 3 , 300/mm 3 , 250/mm 3 , or 200/mm 3 .
  • the ALC is between, or between about, 0.2 x 10e9 cells/L and 0.5 x 10e9 cells/L.
  • the ALC is less than, or less than about, 0.5 x 10e9 cells/L, 0.45 x 10e9 cells/L, 0.4 x 10e9 cells/L, 0.35 x 10e9 cells/L, 0.3 x 10e9 cells/L, 0.25 x 10e9 cells/L, or 0.2 x 10e9 cells/L.
  • the threshold is an ALC that meets grade 3 criteria as defined by the Common Terminology Criteria for Adverse Events (CTCAE), as described at https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R eference_8.5x11 .pdf (lymphocyte count decreased), which is herein incorporated by reference in its entirety.
  • CTCAE Common Terminology Criteria for Adverse Events
  • the threshold is an ALC that meets grade 4 criteria as defined by the CTCAE.
  • the threshold is ALC less than 200/mm 3 .
  • the threshold is ALC less than, or less than about, 0.2 x 10e9 cells/L.
  • the patient is monitored or screened for infection during treatment.
  • An infection may be identified by diagnosis by a physician based on physical signs and symptoms.
  • a patient may be tested for certain infections based on known diagnostic tests.
  • an interruption period of time is initiated and treatment is ceased (the patient does not receive etrasimod during the interruption period).
  • the interruption period is between one day and two months. In some embodiments, the interruption period is between one week and six weeks. In some embodiments, the interruption period is between one week and four weeks. In some embodiments, the interruption period is between one week and three weeks. In some embodiments, the interruption period is one day, two days, three days, four days, five days, six days, seven days (one week), ten days, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, or thirteen weeks.
  • the serum levels of ALC in the patient can be retested, and if the ALC levels are above the threshold, then the patient can continue to receive etrasimod in a continuation period of time.
  • the serum levels of ALC in the patient can be retested, and if the ALC levels are below the threshold level, then the patient can enter a subsequent interruption period.
  • the subsequent interruption period is between one day and two months. In some embodiments, the subsequent interruption period is between one week and six weeks. In some embodiments, the subsequent interruption period is between one week and four weeks. In some embodiments, the subsequent interruption period is between one week and three weeks.
  • the subsequent interruption period is one day, two days, three days, four days, five days, six days, seven days (one week), ten days, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, or thirteen weeks.
  • the serum levels of ALC in the patient can be retested, and if the ALC level are above the threshold, then the patient can continue to receive etrasimod in a continuation period of time.
  • the serum levels of ALC in the patient can be retested, and if the ALC levels are below the threshold, then the patient can enter another subsequent interruption period.
  • an interruption period of time is initiated and treatment is ceased (the patient does not receive etrasimod during the interruption period).
  • the interruption period is between one day and two months. In some embodiments, the interruption period is between one week and six weeks. In some embodiments, the interruption period is between one week and four weeks. In some embodiments, the interruption period is between one week and three weeks. In some embodiments, the interruption period is one day, two days, three days, four days, five days, six days, seven days (one week), ten days, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, or thirteen weeks.
  • the patient can be screened again for an infection and if an infection is not identified, then the patient can continue to receive etrasimod in a continuation period of time.
  • the patient can be screened again for an infection and if an infection is identified, then the patient can enter a subsequent interruption period.
  • the subsequent interruption period is between one day and two months.
  • the subsequent interruption period is between one week and six weeks.
  • the subsequent interruption period is between one week and four weeks.
  • the subsequent interruption period is between one week and three weeks.
  • the subsequent interruption period is one day, two days, three days, four days, five days, six days, seven days (one week), ten days, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, or thirteen weeks.
  • the patient can be screened again for an infection and if an infection is not identified, then the patient can continue to receive etrasimod in a continuation period of time.
  • the patient can be screened again for an infection and if an infection is identified, then the patient can enter another subsequent interruption period.
  • a patient reinitiates treatment with etrasimod, or a pharmaceutically acceptable salt thereof.
  • the continuation period is between one day and two months. In some embodiments, the continuation period is between one week and six weeks. In some embodiments, the continuation period is between one month and two years. In some embodiments, the continuation period is until the AD substantially resolves (e.g., a vIGA score of 0 or 1 ). In some embodiments, the continuation period is between one week and one year. In some embodiments, the continuation period is between one week and four weeks. In some embodiments, the continuation period is between one week and two weeks.
  • the continuation period is at least one week, one month, two months, three months, four months, five months, six months, seven months, ten months, eleven months, twelve months, thirteen months, fifteen months, twenty months or twenty-four months.
  • the patient can be administered etrasimod or a pharmaceutically acceptable salt thereof at a frequency of once a day.
  • the patient can be administered etrasimod or a pharmaceutically acceptable salt thereof in an amount equivalent to 1 mg or 2 mg or 3 mg of etrasimod a day.
  • the patient can be administered etrasimod or a pharmaceutically acceptable salt thereof in an amount equivalent to 2 mg of etrasimod a day.
  • the methods described herein achieve a therapeutic effect during the continuation period of time.
  • the method is therapeutically effective to improve EASI from baseline, to achieve EASI-75, to achieve a vIGA 0 to 1 (on a 5- point scale) score, to reduce a patient’s vIGA by at least 1 point, to reduce a patient’s peak pruritus NRS, to reduce the percent BSA AD involvement from baseline, to achieve EASI-50, defined as a > 50% reduction of EASI from baseline, or to achieve EASI-90, defined as a > 90% reduction of EASI from baseline during the continuation period of time.
  • the patient experiences an improvement in EASI score that is equal to or within 25% of the EASI score if the patient had not experienced an interruption period. In some embodiments, after treatment is reinitiated, the patient experiences an improvement in vIGA score that is equal to or within 25% of the vIGA score if the patient had not experienced an interruption period. In some embodiments, after treatment is reinitiated, the patient experiences an improvement in pruritis that is equal to or within 25% of the treatment effect for pruritis if the patient had not experienced an interruption period.
  • a rapid recapture of therapeutic effect is achieved.
  • the patient when a rapid recapture occurs, the patient can exhibit a therapeutic effect equal to or better than the patient’s measurement of the effect immediately before the interruption period began.
  • the patient achieves a vIGA score equal to or better than the patient’s measurement of the effect immediately before the interruption period began.
  • the patient achieves an EASI equal to or better than the patient’s measurement of the effect immediately before the interruption period began.
  • the patient achieves an NRC equal to or better than the patient’s measurement of the effect immediately before the interruption period began.
  • the recapture of therapeutic effect occurs within one day, two days, three days, four days, five days, six days, seven days (one week), ten days, two weeks, three weeks, or one month of the start of the continuation period.
  • a lymphocyte level in a patient is used as a biomarker.
  • ALC in a patient is used as a biomarker.
  • the biomarker is used to determine dose and/or frequency of administration for the patient.
  • the biomarker is used to determine whether treatment should be interrupted.
  • the biomarker is used to reinitiate treatment following interruption.
  • the biomarker is used to expedite reinitiation of treatment following interruption.
  • the biomarker is a lymphocyte count that meets grade 3 criteria as defined CTCAE.
  • the biomarker is a lymphocyte count that meets grade 4 criteria as defined CTCAE.
  • the biomarker is an ALC that meets grade
  • the biomarker is an ALC that meets grade
  • Formulations composed of immediate-release tablets containing an L-arginine salt of
  • Compound 1 were prepared as shown in Table 1 .
  • the primary endpoint measured was percent change in Eczema Area and Severity Index (EASI) from baseline to week 12, followed by a 4-week follow-up observation period. Secondary endpoints include the proportion of participants achieving EASI-75, proportion of participants with a validated Investigator Global Assessment (vIGA) 0 to 1 , and percent change in peak pruritis.
  • the trial enrolled approximately 140 patients and was conducted in study sites across the United States, Canada and Australia. An open-label extension of the trial is ongoing.
  • Subjects with chronic AD for at least one year (as defined by Hanifin and Rajka criteria (Hanifin 1980)) despite optimized skin care (e.g., use of emollients, avoidance of irritants) whose disease is not adequately controlled with topical therapies, or for whom those therapies are not advisable, were equally randomized (1 :1 :1 ratio) to receive etrasimod (1 or 2 mg) or placebo.
  • Etrasimod 1 or 2 mg tablets or matching placebo tablets were taken orally once daily during the double-blind treatment period.
  • Etrasimod 2 mg tablets are taken orally once daily during the open-label extension period. There was no reference therapy (no placebo) during the open-label extension period.
  • EASI Eczema Area and Severity Index
  • BSA Body surface area
  • systemic immunosuppressive/immunomodulating drugs e.g., methotrexate, cyclosporine
  • JNK Janus kinase
  • systemic glucocorticoids excludedes topical, inhaled, or intranasal delivery that are considered topical for any reason
  • immunoglobulin or blood products e.g., methotrexate, cyclosporine
  • Phototherapy for AD or artificial tanning (beds, booths, or lamps) within 4 weeks prior to screening or during screening.
  • Any cell-depleting agents including but not limited to rituximab, within 6 months prior to the baseline visit or until lymphocyte count returns to normal, whichever is longer.
  • dupilumab within 8 weeks prior to screening or during screening. 7. Use of any biological agents other than dupilumab (e.g., adalimumab, ustekinumab, secukinumab) regardless of indication, within 5 half-lives (if known) or 16 weeks prior to screening, whichever is longer, or during screening.
  • any biological agents other than dupilumab e.g., adalimumab, ustekinumab, secukinumab
  • cytochrome P450 cytochrome P450
  • CYP2C8 and CYP2C9 cytochrome P4502C8 and CYP2C9
  • clopidogrel, gemfibrozil, fluconazole, and carbamazepine cytochrome P450 during screening (this includes St. John’s Wort).
  • carbamazepine cytochrome P450
  • a. Primary or secondary immunodeficiency syndromes e.g., hereditary immunodeficiency syndrome, acquired immunodeficiency syndrome, drug-induced immune deficiency
  • c. History of an opportunistic infection e.g., pneumocystis jirovecii pneumonia, cryptococcal meningitis, progressive multifocal leukoencephalopathy [PML]
  • PML progressive multifocal leukoencephalopathy
  • IGRA interferon-gamma release assay
  • Those with known history of active TB or with positive test for latent TB at Screening may be included if 1 of the following are documented: Subjects with latent TB, who have been ruled out for active TB according to local country guidelines, (e.g., chest X-ray), have completed an appropriate course of TB prophylaxis treatment, and have not had recent close contact with a person with active TB are eligible to enroll in the study. It is the responsibility of the investigator to verify the adequacy of previous TB treatment and provide appropriate documentation; subjects diagnosed with latent TB at screening, ruled out for active TB, and who received at least 4 weeks of an appropriate TB prophylaxis regimen may be rescreened for enrollment.
  • local country guidelines e.g., chest X-ray
  • Active severe pulmonary disease e.g., chronic obstructive pulmonary disease, pulmonary fibrosis
  • chronic pulmonary disease requiring intravenous corticosteroid treatment or hospitalization ⁇ 12 months prior to screening or during screening.
  • Exclusionary criteria related to test or laboratory results (performed by central laboratory) Note: A confirmed result means there have been two consecutive assessments showing a consistent abnormal, clinically relevant result.
  • liver function test values during Screening • Aspartate aminotransferase (AST) > 2 x the upper limit of normal (ULN) • Alanine aminotransferase (ALT) > 2 x ULN • Direct (conjugated) bilirubin that is > 1 .5 x ULN, unless in the context of Gilbert’s syndrome.
  • a female who is not of childbearing potential must meet one of the following: postmenopausal, defined as no menses for 12 months without an alternative medical cause; permanent sterilization procedure, such as hysterectomy, bilateral salpingectomy, or bilateral oophorectomy; b.
  • a female who is of childbearing potential must agree to using a highly effective contraception method during treatment and for 4 weeks following treatment that can achieve a failure rate of less than 1% per year when used consistently and correctly.
  • the following are considered highly effective birth control methods: Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, which may be oral, intravaginal, or transdermal; progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injected, or implanted; intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner; sexual abstinence (complete sexual abstinence defined as refraining from heterosexual intercourse for the entire period of risk associated with study treatments).
  • Efficacy was assessed by changes in AD severity using EASI, vIGA, SCORing Atopic Dermatitis (SCORAD), and BSA. Symptoms of itch were assessed using the pruritus numeric rating scale (NRS). Patient-reported outcomes will also be assessed using the Dermatology Life Quality Index (DLQI), Patient Oriented Eczema Measure (POEM), and Patient Global Assessment (PGA).
  • DLQI Dermatology Life Quality Index
  • POEM Patient Oriented Eczema Measure
  • PGA Patient Global Assessment
  • etrasimod plasma concentrations and a complete blood count (CBC) including lymphocyte count were assessed on day 1 and before dosing at subsequent study visits. Study visits occurred at baseline, week 1 , week 2, week 4, week 6, week 8, week 12, at the end of treatment, and at the week 16 follow-up visit.
  • the absolute lymphocyte count (ALC) was included as part of the assessment.
  • vIGA moderate atopic dermatitis
  • Treatment with 2 mg etrasimod improved patient-reported outcomes and clinician- assessed outcomes versus placebo over 12 weeks.
  • Treatment with 2 mg etrasimod resulted in significantly greater proportions of patients achieving a vIGA score of 0 or 1 , DLQI, and POEM at week 12 compared to placebo.
  • the data showed a dose-dependent numerical decrease (improvement) in pruritus greater than or equal to 4 points.
  • the pruritis score decreased in patients receiving 1 mg and 2 mg of etrasimod over 12 weeks of treatment. There was an early and significant effect through week 6 with continued improvement through week 12. A statistically significant improvement in pruritis was observed at week 4 in 2 mg etrasimod dose group.
  • Etrasimod 1 mg and 2 mg were shown to be well tolerated. There were no cases of macular edema, there was one case of dyspnea in the placebo group, and one case in the 2 mg etrasimod treatment group. There were no adverse events related to heart rate. There were no reports of conjunctivitis, acne, venous thromboembolic events, and no opportunistic or serious infections.
  • Prior systemic treatment failure was defined as documented prior failed (e.g., lack of efficacy or discontinue due to side effects) systemic treatments for atopic dermatitis, including conventional systemic treatments (e.g., oral steroid and cyclosporine), biologies (e.g., dupilumab), or oral JAK inhibitor (e.g., baricitinib).
  • conventional systemic treatments e.g., oral steroid and cyclosporine
  • biologies e.g., dupilumab
  • oral JAK inhibitor e.g., baricitinib
  • One patient can have more than one prior failed systemic therapy for AD ⁇ documented ineffective or stopped treatment due to side effect

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  • Immunology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes de traitement de la dermatite atopique permettant de traiter efficacement la maladie avec une période d'interruption si certains événements indésirables sont observés. De plus, l'invention concerne de nouvelles méthodes de traitement de dermatite atopique modérée à sévère.
PCT/IB2023/054569 2022-05-06 2023-05-02 Méthodes de traitement de la dermatite atopique par etrasimod WO2023214312A1 (fr)

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