Upatinib for treating alopecia areata

Abstract

The present disclosure relates to methods of treating alopecia areata (AA) using the selective JAK1 inhibitor upatinib.

Description

Cross Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 531,443, filed August 8, 2023, which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0002] The present disclosure relates to methods of treating alopecia areata (AA) with the selective JAK1 inhibitor upadacitinib. BACKGROUND

[0003] Alopecia areata (AA) is an autoimmune disease characterized by non-scarring partial or complete hair loss on the scalp or any other body site. The extent of hair loss can range from single or multiple well-demarcated patches to involvement of the entire scalp (alopecia totalis) or the entire skin surface (universalis).

[0004] Alopecia areata has been reported to have a clinical association with atopic dermatitis (AD), with up to one-third of patients with alopecia areata also affected by AD. Both AD and alopecia areata are characterized by elevated IgE levels, high circulating eosinophil counts, and increased serum levels of Th2 cytokines. Alopecia areata increases the risk of AD, and this risk is greatest for people with early-onset alopecia (before age 10-13) and / or alopecia totalis or universalis. AD also increases the risk of severe forms of alopecia areata, with AD patients having up to 26-fold increased risk of developing alopecia areata compared to healthy controls.

[0005] Despite the prevalence of alopecia areata in patients with AD and the various approved treatment methods for AD, there are few systemic therapies currently available to treat alopecia areata, highlighting the challenge of treating this disease, especially in severe cases. Thus, the identification of new effective therapies for alopecia areata represents an unmet clinical need. SUMMARY

[0006] The present disclosure provides methods of treating alopecia areata (AA) with the selective JAK1 inhibitor upadacitinib. The methods of treatment generally comprise administering to a patient in need thereof a therapeutically effective amount of upadacitinib.

[0007] In one aspect, there is provided a method of treating a human patient having alopecia areata, the method comprising orally administering to the patient 30 mg of upadacitinib once daily.

[0008] In another aspect, there is provided a method of treating a human patient having alopecia areata, the method comprising orally administering to the patient 15 mg of upadacitinib once daily.

[0009] In some embodiments, the patient is an adult.

[0010] In another aspect, a method of treating alopecia areata in a pediatric patient is provided, the method comprising orally administering to the pediatric patient a therapeutically effective amount of upadacitinib, wherein:

[0011] In the case where the pediatric patient has a body weight in the range of about 10 kg to less than about 20 kg:

[0012] (i) upadacitinib is administered at a dose of 3 mg twice daily (3 mg BID), or

[0013] (ii) upadacitinib is administered at a dose of 6 mg twice daily (6 mg BID);

[0014] In the case where the pediatric patient has a body weight in the range of about 20 kg to less than about 30 kg:

[0015] (i) upadacitinib is administered at a dose of 4 mg twice daily (4 mg BID), or

[0016] (ii) upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID); and

[0017] In the case where the pediatric patient has a body weight of about 30 kg or greater:

[0018] (i) upadacitinib is administered at a dose of 6 mg twice daily (6 mg BID),

[0019] (ii) upadacitinib is administered at a dose of 8 mg twice daily (8 mg BID), or

[0020] (ii) upadacitinib is administered at a dose of 15 mg once daily (15 mg QD).

[0021] In some embodiments, the twice daily dose of upadacitinib is administered to the pediatric patient in the form of a stable oral pharmaceutical solution.

[0022] In some embodiments, the stable oral pharmaceutical solution comprises upadacitinib, a buffer and / or pH adjusting agent, a preservative, a sweetener, and water.

[0023] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

[0024] In some embodiments, the 15 mg once daily dose of upadacitinib is administered to the pediatric patient in the form of an extended release tablet.

[0025] In some embodiments, the method results in an AA-IGA score of 0 or 1 at 40 weeks after the first daily administration.

[0026] In some embodiments, the method results in a Severity of Alopecia Tool (SALT) score of < 20 (less than or equal to 20% scalp hair loss) at 40 weeks after the first daily administration. In some embodiments, the method results in a SALT score of < 10 at 40 weeks after the first daily administration. In some embodiments, the method results in a SALT score of 0 at 40 weeks after the first daily administration.

[0027] In some embodiments, the method results in a SALT of 50 (at least a 50% improvement [decrease] in SALT score relative to baseline) at 40 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 (at least a 75% improvement [decrease] in SALT score relative to baseline) at 40 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 (at least a 90% improvement [decrease] in SALT score relative to baseline) at 40 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 (at least a 100% improvement [decrease] in SALT score relative to baseline) at 40 weeks after the first daily administration.

[0028] In some embodiments, the method results in an AA-IGA score of 0 or 1 at 28 weeks after the first daily administration.

[0029] In some embodiments, the method results in a Severity of Alopecia Tool (SALT) score of < 20 (less than or equal to 20% scalp hair loss) at 28 weeks after the first daily administration. In some embodiments, the method results in a SALT score of < 10 at 28 weeks after the first daily administration. In some embodiments, the method results in a SALT score of 0 at 28 weeks after the first daily administration.

[0030] In some embodiments, the method results in a SALT of 50 (at least a 50% improvement [decrease] in SALT score relative to baseline) at 28 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 (at least a 75% improvement [decrease] in SALT score relative to baseline) at 28 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 (at least a 90% improvement [decrease] in SALT score relative to baseline) at 28 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 (at least a 100% improvement [decrease] in SALT score relative to baseline) at 28 weeks after the first daily administration.

[0031] In some embodiments, the method results in a Severity of Alopecia Tool (SALT) score of < 20 (less than or equal to 20% scalp hair loss) at 24 weeks after the first daily administration. In some embodiments, the method results in a SALT score of < 10 at 24 weeks after the first daily administration. In some embodiments, the method results in a SALT score of 0 at 24 weeks after the first daily administration.

[0032] In some embodiments, the method results in a SALT of 50 (at least 50% improvement [decrease] in SALT score relative to baseline) at 24 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 (at least 75% improvement [decrease] in SALT score relative to baseline) at 24 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 (at least 90% improvement [decrease] in SALT score relative to baseline) at 24 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 (at least 100% improvement [decrease] in SALT score relative to baseline) at 24 weeks after the first daily administration. In some embodiments, the method results in a Severity of Alopecia Tool (SALT) score of < 20 (less than or equal to 20% scalp hair loss) at 12 weeks after the first daily administration. In some embodiments, the method results in a SALT score of < 10 at 12 weeks after the first daily administration. In some embodiments, the method results in a SALT score of 0 at 12 weeks after the first daily administration.

[0033] In some embodiments, the method results in a SALT of 50 (at least 50% improvement [decrease] in SALT score relative to baseline) at 12 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 (at least 75% improvement [decrease] in SALT score relative to baseline) at 12 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 (at least 90% improvement [decrease] in SALT score relative to baseline) at 12 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 (at least 100% improvement [decrease] in SALT score relative to baseline) at 12 weeks after the first daily administration. In some embodiments, the method results in a Severity of Alopecia Tool (SALT) score of < 20 (less than or equal to 20% scalp hair loss) at 8 weeks after the first daily administration. In some embodiments, the method results in a SALT score of < 10 at 8 weeks after the first daily administration. In some embodiments, the method results in a SALT score of 0 at 8 weeks after the first daily administration.

[0034] In some embodiments, the method results in a SALT of 50 (at least a 50% improvement [reduction] in SALT score from baseline) at 48 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 (at least a 75% improvement [reduction] in SALT score from baseline) at 8 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 (at least a 90% improvement [reduction] in SALT score from baseline) at 8 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 (at least a 100% improvement [reduction] in SALT score from baseline) at 8 weeks after the first daily administration. In some embodiments, the method results in a Severity of Alopecia Tool (SALT) score of < 20 (less than or equal to 20% loss of scalp hair) at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT score of < 10 at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT score of 0 at 4 weeks after the first daily administration.

[0035] In some embodiments, the method results in a SALT of 50 (at least a 50% improvement [reduction] in SALT score from baseline) at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 (at least a 75% improvement [reduction] in SALT score from baseline) at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 (at least a 90% improvement [reduction] in SALT score from baseline) at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 (at least a 100% improvement [reduction] in SALT score from baseline) at 4 weeks after the first daily administration. The method results in a ClinRO measure of eyebrow hair loss of 0 or 1, an improvement of > 2 points from baseline, in subjects with a baseline score of > 2 at Week 24.

[0036] In some embodiments, the method results in a PRO of scalp hair assessment of 0 / 1, an improvement (reduction) of > 2 points from baseline, in subjects with a baseline score of > 3 at Week 24.

[0037] In some embodiments, the method results in a PaGIC score of 1 or 2 at Week 24.

[0038] In some embodiments, the method results in a Skindex-16 AA emotional domain score at Week 24.

[0039] In some embodiments, the method results in a change in Skindex-16 AA functional domain score from baseline at Week 24.

[0040] In some embodiments, the method results in a change from baseline in AASIS Interference Subscale score at Week 24.

[0041] In some embodiments, the method results in a change from baseline in AASIS Interference Subscale score at Week 24.

[0042] In some embodiments, the method results in a change from baseline in AASIS Interference Subscale score at Week 24.

[0043] The method results in a ClinRO measure of eyebrow hair loss of 0 or 1, an improvement of > 2 points from baseline, in subjects with a baseline score of > 2 at Week 12.

[0044] In some embodiments, the method results in a PRO of scalp hair assessment of 0 / 1, an improvement (decrease) of > 2 points from baseline, in subjects with a baseline score of > 3 at Week 12.

[0045] In some embodiments, the method results in a PaGIC score of 1 or 2 at Week 12.

[0046] In some embodiments, the method results in a Skindex-16 AA emotional domain score at Week 12.

[0047] In some embodiments, the method results in a change from baseline in Skindex-16 AA functional domain score at Week 12.

[0048] In some embodiments, the method results in a HADS-A < 8 and HADS-D < 8 at Week 12 in subjects with a HADS-A > 8 or HADS-D > 8 at baseline.

[0049] In some embodiments, the method results in a change from baseline in AASIS Interference Subscale score at Week 12.

[0050] In some embodiments, the method results in a change from baseline in AASIS Interference Subscale score at Week 12.

[0051] The method results in a ClinRO measure of eyebrow hair loss of 0 or 1, an improvement of > 2 points from baseline, in subjects with a baseline score of > 2 at Week 8.

[0052] In some embodiments, the method results in a PRO of scalp hair assessment of 0 / 1, an improvement (decrease) of > 2 points from baseline, in subjects with a baseline score of > 3 at Week 8.

[0053] In some embodiments, the method results in achieving a PaGIC score of 1 or 2 at Week 8.

[0054] In some embodiments, the method results in achieving a Skindex-16 AA emotional domain score at Week 8.

[0055] In some embodiments, the method results in a change from baseline in Skindex-16 AA functional domain score at Week 8.

[0056] In some embodiments, the method results in achieving HADS-A < 8 and HADS-D < 8 at Week 8 in subjects with HADS-A > 8 or HADS-D > 8 at baseline.

[0057] In some embodiments, the method results in a change in AASIS Interference subscale score at Week 8.

[0058] In some embodiments, the method results in a change in AASIS Symptom subscale score at Week 8.

[0059] The method results in achieving a ClinRO measure of eyebrow hair loss of 0 or 1 at Week 4, an improvement of > 2 points from baseline, in subjects with a baseline score of > 2.

[0060] In some embodiments, the method results in achieving a PRO of scalp hair assessment of 0 / 1 at Week 4, an improvement (decrease) of > 2 points from baseline, in subjects with a baseline score of > 3.

[0061] In some embodiments, the method results in achieving a PaGIC score of 1 or 2 at Week 4.

[0062] In some embodiments, the method results in achieving a Skindex-16 AA emotional domain score at Week 4.

[0063] In some embodiments, the method results in a change from baseline in Skindex-16 AA functional domain score at Week 4.

[0064] In some embodiments, the method results in achieving HADS-A < 8 and HADS-D < 8 at Week 4 in subjects with HADS-A > 8 or HADS-D > 8 at baseline.

[0065] In some embodiments, the method results in a change in AASIS Interference subscale score at Week 4.

[0066] In some embodiments, the method results in a change in AASIS Symptom subscale score at Week 4.

[0067] In some embodiments, the method results in an AA-IGA score of 0 or 1 at 16 weeks after the first daily administration.

[0068] In some embodiments, the method results in a Severity of Alopecia Tool (SALT) score of 50 at 16 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 at 16 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 at 16 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 at 16 weeks after the first daily administration.

[0069] In some embodiments, the method results in an AA-IGA score of 0 or 1 at 4 weeks after the first daily administration.

[0070] In some embodiments, the method results in a SALT of 50 at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 at 4 weeks after the first daily administration.

[0071] In some embodiments, the patient has moderate alopecia areata. In some embodiments, the patient has moderate or severe alopecia areata. In some embodiments, the patient has severe alopecia areata. In some embodiments, the patient has very severe alopecia areata.

[0072] In some embodiments, the alopecia areata is located in the frontoparietal region of the scalp and the eyebrows.

[0073] In some embodiments, the patient has a serum IgE level of > 100 IU / ml prior to starting treatment.

[0074] In some embodiments, the patient has previously received systemic agent treatment for alopecia areata. In some embodiments, the systemic agent is cyclosporine or dupilumab. In some embodiments, the systemic agent is baricitinib. BRIEF DESCRIPTION OF DRAWINGS

[0075] Figure 1 is a plot of the treatment response rate over time for patients receiving 30 mg upadacitinib per day for achieving SALT 50, SALT 75, SALT 90, and SALT 100 improvement in alopecia areata relative to baseline scores.

[0076] Figure 2 is a plot of the average SALT score over time for patients receiving 30 mg upadacitinib per day for patients exhibiting high or normal IgE serum levels prior to starting administration of upadacitinib. Detailed Implementation I. Definitions

[0077] The chapter titles used in this chapter and throughout the publication are not intended to be restrictive.

[0078] When describing a numerical range, it is explicitly assumed that each intermediate number within that range has the same precision. For example, for the range 6 to 9, the numbers 7 and 8 are assumed in addition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly assumed. In the same way, all ratios described also include all sub-ratios falling within a wider range.

[0079] Unless the context clearly indicates otherwise, the singular forms “a / kind” and “the / said” include plural referents.

[0080] The term "about" generally refers to a range of numbers that a person skilled in the art would consider equivalent to the stated value (i.e., having the same function or result). In many cases, the term "about" may include numbers rounded to the nearest significant figure.

[0081] Unless the context otherwise requires, the use of the terms “comprising,” “including,” and “containing” is based on the clear understanding that these terms will be interpreted as inclusive rather than exclusive, and that the applicant intends that these terms be interpreted in the same way in interpreting this patent (including the claims below).

[0082] The term "AUC" refers to the area under the curve. AUC is the definite integral of a curve describing the change in plasma drug concentration as a function of time.

[0083] Term "C" max "Refers to T" max The plasma concentration of the reference drug, expressed herein as ng / mL, is the result of oral administration of a single dose or an indicated number of doses of a dosage form or pharmaceutical composition (such as the dosage forms and compositions disclosed herein). Unless specifically indicated, C max This refers to the observed maximum overall concentration.

[0084] As used herein, the terms “treatment” and “therapy” are intended to include therapeutic measures for a disease or condition that produce clinically desired or beneficial effects, including but not limited to clinically significant improvements in hair regrowth over a period of time.

[0085] As used herein, the term "pediatric patient" refers to a human patient under the age of 18. The terms "patient" and "subject" are used interchangeably in this document.

[0086] "Pharmaceutically acceptable salt" refers to those salts that retain the biological effectiveness and properties of the free bases and that are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, malic acid, oxalic acid, tartaric acid (e.g., (+)-tartaric acid or (-)-tartaric acid or mixtures thereof), amino acid (e.g., (+)-amino acid or (-)-amino acid or mixtures thereof), and the like. These salts can be prepared by methods known to those skilled in the art. Examples of pharmaceutically acceptable salts of upatinib can be found in WO 2017 / 066775, which is hereby incorporated by reference in its entirety. Endpoint Definitions : Severe Alopecia Tool (SALT) Score

[0087] The Severity of Alopecia Tool (SALT) score is the sum of the percentage of hair loss in each of the four regions of the scalp (left, right, top, and back). SALT subclasses are defined according to the S1-S4 categories: • S0: no hair loss; • S1: < 25%; • S2: 25-49%; • S3: 50-74%; • S4a: 75-95%; • S4b: 96-99%; • S5 = 100% hair loss.

[0088] The SALT score is calculated by (1) multiplying the percentage of hair loss in each quadrant by the surface area of that quadrant and (2) summing the products. The score ranges from 0 to 100, reflecting 0-100% scalp hair loss. A SALT score of 1-20 indicates mild / limited alopecia areata. A SALT score of 21-49 indicates moderate alopecia areata. A SALT score of 50-94 indicates severe alopecia areata. A SALT score of 95-100 indicates very severe alopecia areata. Alopecia Areata - Investigator's Global Assessment (AA-IGA)

[0089] Alopecia Areata - Investigator's Global Assessment (AA-IGA) is a measure of alopecia areata severity that includes five grades of the extent of scalp hair loss measured using the SALT score. The AA-IGA defines alopecia areata severity as the following five grades: • 0: 0% scalp hair loss, "none" severity possible no hair loss; • 1 : 1-20%, "limited" severity, requiring further evaluation for systemic treatment benefit or potential disease control with local and / or intralesional therapy injections; • 2: 21-49%, "moderate" severity excluding 50% hair loss, which is found to be associated with severe disease; • 3: 50-95%; "severe"; • 4: 95-100%, "extremely severe", corresponding to patients with complete or almost complete hair loss, to replace the previous "totalis" and "universalis" categories. Eczema Area and Severity Index (EASI)

[0090] EASI is a tool for measuring the extent (area) and severity of atopic eczema. Area scores for each of the four regions of the body are recorded. Area scores are the percentage of skin in each body region (head and neck (face, neck, and scalp); trunk (including genital area); upper limbs; lower limbs (including buttocks)) affected by eczema. Area scores are based on the percentage of affected area, on a scale of 1 to 6 as follows: • 0: no active eczema in the region • 1 : 1-9% • 2: 10-29% • 3: 30-49% • 4: 50-69% • 5: 70-89% • 6: 90-100%: entire region affected by eczema

[0091] The severity score component is the sum of the intensity score of four signs recorded for each of the four regions of the body described above. The four signs are:

[0092] 1. Redness (erythema, inflammation)

[0093] 2. Thickening (induration, papulation, swelling - acute eczema)

[0094] 3. Scratch marks (epidermal excoriation)

[0095] 4. Lichenification (deepening of skin lines, furrowing, prurigo nodularis - chronic eczema).

[0096] The average intensity of each sign in each body region was assessed as: none (0), mild (1), moderate (2), and severe (3). For each region, the intensity of each of the four signs was recorded and used to calculate a severity score as follows: Severity Score = Intensity of Redness + Intensity of Thickening + Intensity of Scratch Marks + Intensity of Pseudofolliculitis. To calculate the EASI score, for each region, the severity score was multiplied by the area score and by a multiplier. The multiplier is different for each body site. • Head and neck: Severity Score x Area Score x 0.1 (x 0.2 for children 0-7 years) • Trunk: Severity Score x Area Score x 0.3 • Upper limbs: Severity Score x Area Score x 0.2 • Lower limbs: Severity Score x Area Score x 0.4 (x 0.3 for children 0-7 years)

[0097] The total score for each region was added to determine the final EASI score. The minimum EASI score is 0 and the maximum EASI score is 72. Clinician Reported Outcomes (ClinRO)

[0098] The Clinician Reported Outcome (ClinRO) is a scale used to assess the severity of alopecia in the eyebrows and eyelashes. The ClinRO score ranges from 0 (no involvement) to 3 (complete loss). A score of 0 / 1 indicates full coverage or minimal defects, while a score of 2 / 3 indicates significant defects or no obvious hair. Patient Reported Outcomes (PRO)

[0099] The Patient Reported Outcome (PRO) hair loss score is a five-point response scale that patients use to rate their loss of scalp hair. The ratings are as follows: • None: 0% • Limited: 1-20% • Moderate: 21-49% • Severe: 50-94% • Almost all or all: 95-100% Patient Global Impression of Change (PaGIC)

[0100] The Patient Global Impression of Change (PaGIC) scale is a self- assessment questionnaire that asks the subject to rate the change in their condition since a certain point in time. The PaGIC uses a seven-point scale, ranging from significant worsening to significant improvement. Skindex-16 AA

[0101] Skindex-16 AA is a 16-item questionnaire that reports scores in three domains: Emotions (7 items), Symptoms (4 items), and Function (5 items). Scores range from 0 to 100, with higher scores indicating worse QOL. Hospital Anxiety and Depression Scale (HADS)

[0102] The Hospital Anxiety and Depression Scale (HADS) is a 14-item self-report rating scale using a 4-point Likert scale (range 0-3). It was designed to measure anxiety (A) and depression (D) in subjects. A total score of 0-7 indicates normal levels of anxiety or depression, while a score of 8-10 is a borderline level, and a score of 11-21 is an abnormal level. Alopecia Areata Symptom Impact Scale (AASIS)

[0103] The Alopecia Areata Symptom Impact Scale (AASIS) is a questionnaire that assesses the severity of alopecia areata-related symptoms and the impact of these symptoms on daily functioning. The AASIS asks AA patients about the severity of their AA in 13 items, each of which is scored on a 0-10 scale (where 0 is not present and 10 is the worst imaginable). II. JAK1 Inhibition

[0104] Upadacitinib ((3S,4R)-3-ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3- e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide) or a pharmaceutically acceptable salt or solid state form thereof is an oral Janus kinase (JAK) inhibitor that exhibits unique selectivity against the JAK1 receptor. Upadacitinib has the structure shown below:

[0105]

[0106] The dosage strengths of upadacitinib described in this application are based on the weight of anhydrous free base upadacitinib present in the active ingredient delivered to the patient. For example, “15 mg upadacitinib” or “UPA 15 MG” refers to a 15 mg amount of neutral upadacitinib free base present in the active ingredient, exclusive of any coformers (e.g., solvent or water molecules) of solvates or hydrates (including hemihydrates) or counterions of pharmaceutically acceptable salts that can also be present in the active ingredient. Thus, for example, administration of “15 mg upadacitinib” includes administration of 15.4 mg of crystalline upadacitinib free base hemihydrate (containing ½ water coformer molecule per upadacitinib free base molecule) that delivers 15 mg of anhydrous free base upadacitinib to the patient. III. Treatment of Alopecia Areata (AA) with Upadacitinib

[0107] The present disclosure generally provides methods for treating a human patient having alopecia areata (AA), the method comprising administering to the patient a selective JAK1 inhibitor, upadacitinib. The disclosed methods generally comprise orally administering upadacitinib to the patient. Upadacitinib is administered in a therapeutically effective amount. The disclosed methods generally comprise orally administering upadacitinib to the patient daily for a period of time.

[0108] As described herein in Example 1, it has been found that upadacitinib provides effective and safe treatment of AD and concomitant alopecia areata in a patient group treated with 30 mg upadacitinib once daily. The study of Example 1 highlights rapid and extensive hair regrowth in AD patients treated with upadacitinib, particularly in those patients with high serum IgE levels or with a personal history of atopic comorbidities. Surprisingly, in this study, despite the high severity of alopecia areata in the patient population, clinically meaningful hair regrowth (achieving at least a SALT 50 response) was detected in about 16% of patients after only 4 weeks of treatment. A. Adult Patients

[0109] Thus, in one aspect, there is provided a method of treating a human patient having systemic alopecia areata (AA), the method comprising orally administering 30 mg upadacitinib to the patient once daily.

[0110] In another aspect, there is provided a method of treating a human patient having systemic alopecia areata (AA), the method comprising orally administering 15 mg upadacitinib to the patient once daily.

[0111] The patient’s age can vary. In some embodiments, the patient is an adult patient (e.g., at least 18 years old).

[0112] The method comprises orally administering upadacitinib to the patient daily for a period of time. The period of time can vary. In some embodiments, the period of time is at least 4 weeks. In some embodiments, the period of time is up to 52 weeks. In some embodiments, the period of time is at least 16 weeks, such as 16 weeks, 20 weeks, 24 weeks, 28 weeks, 36 weeks, 44 weeks, 52 weeks, 64 weeks, 76 weeks, 88 weeks, 100 weeks, or 104 weeks.

[0113] In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 4 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 8 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 12 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 14 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 16 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 20 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 24 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 28 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 36 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 44 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 52 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 64 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 76 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 88 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 100 weeks. In some embodiments, the method comprises orally administering to the patient upatinib daily for up to 104 weeks.

[0114] In some embodiments, the method comprises orally administering to the patient an induction dose of upatinib once daily, followed by orally administering to the patient a maintenance dose of upatinib once daily. Thus, in some embodiments, the method comprises orally administering to the patient a 45 mg induction dose of upatinib once daily, followed by orally administering to the patient a 15 mg maintenance dose of upatinib once daily. Thus, in some embodiments, the method comprises orally administering to the patient a 45 mg induction dose of upatinib once daily, followed by orally administering to the patient a 30 mg maintenance dose of upatinib once daily. Thus, in some embodiments, the method comprises orally administering to the patient a 30 mg induction dose of upatinib once daily, followed by orally administering to the patient a 15 mg maintenance dose of upatinib once daily.

[0115] In some embodiments, the method results in an alopecia areata- Investigator's Global Assessment (AA-IGA) score of 0 or 1 within 40 weeks of the first daily administration, such as within 28 weeks, 16 weeks, or 4 weeks.

[0116] In some embodiments, the method results in a Severity of Alopecia Tool (SALT) 50 within 40 weeks of the first daily administration, such as within 28 weeks, 16 weeks, or 4 weeks.

[0117] In some embodiments, the method produces a Severity of Alopecia Tool (SALT) 75 within 40 weeks of the first daily administration, such as within 28 weeks, 16 weeks, or 4 weeks.

[0118] In some embodiments, the method produces a Severity of Alopecia Tool (SALT) 90 within 40 weeks of the first daily administration, such as within 28 weeks, 16 weeks, or 4 weeks.

[0119] In some embodiments, the method produces a Severity of Alopecia Tool (SALT) 100 within 40 weeks of the first daily administration, such as within 28 weeks, 16 weeks, or 4 weeks.

[0120] The severity of alopecia can differ before treatment is initiated. In some embodiments, the patient has moderate alopecia areata. In some embodiments, the patient has moderate or severe alopecia areata. In some embodiments, the patient has severe alopecia areata. In some embodiments, the patient has very severe alopecia areata.

[0121] The area of the patient affected by alopecia areata can differ. In some embodiments, the alopecia areata is located in the frontoparietal region of the scalp and the eyebrows.

[0122] In some embodiments, the patient has a serum IgE level of > 100 IU / ml before treatment is initiated.

[0123] In some embodiments, the patient has previously received systemic agent treatment for alopecia areata. In some embodiments, the systemic agent is cyclosporine or dupilumab. In some embodiments, the systemic agent is baricitinib. B. Pediatric Patients

[0124] In some embodiments, the patient with alopecia areata is a pediatric human patient (i.e., less than about 18 years old). In some embodiments, the dose administered to a pediatric patient can differ from the dose of an adult human patient.

[0125] Accordingly, in another aspect, methods of treating alopecia areata in a pediatric human patient are provided. The methods generally include administering upadacitinib to a pediatric patient in the form of a stable oral pharmaceutical formulation or a sustained release tablet, wherein the dosing is based on body weight. The amount of upadacitinib administered, the oral dosage form, and the frequency of dosing (e.g., once daily or twice daily) will vary depending on the body weight of the patient. Examples of sustained release tablets comprising upadacitinib can be found in International Patent Application Publication No. WO 2017 / 066775, which is hereby incorporated by reference in its entirety.

[0126] In some embodiments, the pediatric patient has an age of less than 18 years. In some embodiments, the pediatric patient has an age of less than 12 years. In some embodiments, the pediatric patient has an age of less than 6 years. In some embodiments, the pediatric patient has an age in a range of about 2 years to less than about 6 years, about 6 years to less than about 12 years, or about 12 years to less than about 18 years. In some embodiments, the pediatric patient has an age in a range of about 2 years to about 18 years, such as about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, or about 18 years.

[0127] In some embodiments, the pediatric patient has a body weight of at least about 10 kg. In some embodiments, the pediatric patient has a body weight in a range of about 10 kg to less than about 30 kg, such as about 20 kg to less than about 20 kg, or about 20 kg to less than about 30 kg. In some embodiments, the pediatric patient has a body weight of 30 kg or greater.

[0128] In some embodiments, the pediatric patient has a body weight in a range of about 10 kg to less than about 20 kg, the method comprises administering 3 mg of upadacitinib twice daily in the form of an oral solution (3 mg BID).

[0129] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg / mL, such as about 0.8 mg / mL, 0.9 mg / mL, or about 1.0 mg / mL to about 1.1 mg / mL or about 1.2 mg / mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of 1.0 mg / mL.

[0130] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg / mL, and the 3 mg dose is provided in the form of about 3 mL of the about 1 mg / mL solution BID.

[0131] In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg / mL, such as about 0.3 mg / mL, 0.4 mg / mL, or about 0.5 mg / mL to about 0.6 mg / mL or about 0.7 mg / mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of 0.5 mg / mL

[0132] In some embodiments, the oral solution comprises uparitnib at a concentration of about 0.5 mg / mL, and a 6 mg dose is provided BID as about 6 mL of the about 0.5 mg / mL solution.

[0133] In some embodiments, the pediatric patient has a body weight in the range of about 10 kg to less than about 20 kg, and the method comprises administering 6 mg of uparitnib twice daily (6 mg BID) in the form of an oral solution.

[0134] In some embodiments, the oral solution comprises uparitnib at a concentration of about 1 mg / mL, such as about 0.8 mg / mL, 0.9 mg / mL, or about 1.0 mg / mL to about 1.1 mg / mL or about 1.2 mg / mL. In some embodiments, the oral solution comprises uparitnib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution comprises uparitnib at a concentration of 1.0 mg / mL.

[0135] In some embodiments, the oral solution comprises uparitnib at a concentration of about 1 mg / mL, and a 6 mg dose is provided BID as about 6 mL of the about 1 mg / mL solution.

[0136] In some embodiments, the oral solution comprises uparitnib at a concentration of about 0.5 mg / mL, such as about 0.3 mg / mL, 0.4 mg / mL, or about 0.5 mg / mL to about 0.6 mg / mL or about 0.7 mg / mL. In some embodiments, the oral solution comprises uparitnib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution comprises uparitnib at a concentration of 0.5 mg / mL

[0137] In some embodiments, the oral solution comprises uparitnib at a concentration of about 0.5 mg / mL, and a 6 mg dose is provided BID as about 12 mL of the about 0.5 mg / mL solution.

[0138] In some embodiments, the pediatric patient has a body weight in the range of about 20 kg to less than about 30 kg, and the method comprises administering 4 mg of uparitnib twice daily (4 mg BID) in the form of an oral solution. In some embodiments, the pediatric patient has a body weight in the range of about 20 kg to less than about 30 kg, and the method comprises administering 8 mg of uparitnib twice daily (8 mg BID) in the form of an oral solution.

[0139] In some embodiments, the oral solution comprises upatinib at a concentration of about 1 mg / mL, such as about 0.8 mg / mL, 0.9 mg / mL, or about 1.0 mg / mL to about 1.1 mg / mL or about 1.2 mg / mL. In some embodiments, the oral solution comprises upatinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution comprises upatinib at a concentration of 1.0 mg / mL.

[0140] In some embodiments, the oral solution comprises upatinib at a concentration of about 1 mg / mL and the 8 mg dose is provided as about 8 mL of the about 1 mg / mL solution BID.

[0141] In some embodiments, the oral solution comprises upatinib at a concentration of about 0.5 mg / mL, such as about 0.3 mg / mL, 0.4 mg / mL, or about 0.5 mg / mL to about 0.6 mg / mL or about 0.7 mg / mL. In some embodiments, the oral solution comprises upatinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution comprises upatinib at a concentration of 0.5 mg / mL

[0142] In some embodiments, the oral solution comprises upatinib at a concentration of about 0.5 mg / mL and the 8 mg dose is provided as about 16 mL of the about 0.5 mg / mL solution BID.

[0143] In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, the method comprises administering 6 mg of upatinib per day twice in the form of an oral solution (6 mg BID).

[0144] In some embodiments, the oral solution comprises upatinib at a concentration of about 1 mg / mL, such as about 0.8 mg / mL, 0.9 mg / mL, or about 1.0 mg / mL to about 1.1 mg / mL or about 1.2 mg / mL. In some embodiments, the oral solution comprises upatinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution comprises upatinib at a concentration of 1.0 mg / mL.

[0145] In some embodiments, the oral solution comprises upatinib at a concentration of about 1 mg / mL and the 6 mg dose is provided as about 6 mL of the about 1 mg / mL solution BID.

[0146] In some embodiments, the oral solution comprises uparitnib at a concentration of about 0.5 mg / mL, such as about 0.3 mg / mL, 0.4 mg / mL, or about 0.5 mg / mL to about 0.6 mg / mL or about 0.7 mg / mL. In some embodiments, the oral solution comprises uparitnib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution comprises uparitnib at a concentration of 0.5 mg / mL

[0147] In some embodiments, the oral solution comprises uparitnib at a concentration of about 0.5 mg / mL, and a 6 mg dose is provided as about 12 mL of about 0.5 mg / mL solution BID.

[0148] In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, and the method comprises administering 15 mg of uparitnib once daily (15 mg QD) in the form of an extended release formulation.

[0149] In some embodiments, the pediatric patient has a body weight of about 30 kg or greater, and the method comprises administering 8 mg of uparitnib twice daily (8 mg BID) in the form of an oral solution.

[0150] In some embodiments, the oral solution comprises uparitnib at a concentration of about 1 mg / mL, such as about 0.8 mg / mL, 0.9 mg / mL, or about 1.0 mg / mL to about 1.1 mg / mL or about 1.2 mg / mL. In some embodiments, the oral solution comprises uparitnib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution comprises uparitnib at a concentration of 1.0 mg / mL.

[0151] In some embodiments, the oral solution comprises uparitnib at a concentration of about 1 mg / mL, and an 8 mg dose is provided as about 8 mL of about 1 mg / mL solution BID.

[0152] In some embodiments, the oral solution comprises uparitnib at a concentration of about 0.5 mg / mL, such as about 0.3 mg / mL, 0.4 mg / mL, or about 0.5 mg / mL to about 0.6 mg / mL or about 0.7 mg / mL. In some embodiments, the oral solution comprises uparitnib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution comprises uparitnib at a concentration of 0.5 mg / mL

[0153] In some embodiments, the oral solution comprises uparitnib at a concentration of about 0.5 mg / mL, and an 8 mg dose is provided as about 16 mL of about 0.5 mg / mL solution BID.

[0154] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in the form of a sustained-release formulation.

[0155] The maximum concentration (C) achieved by the above-mentioned administration max The dosage can vary depending on factors such as dosage, patient weight, and individual patient metabolism of utpatinib.

[0156] In some implementations, when utpatinib was administered by BID to pediatric subjects with an immediate-release oral solution as described herein, an average C10 concentration was achieved in the range of approximately 20 g / mL to approximately 160 ng / mL. max .

[0157] In some implementations, when utpatinib was administered twice daily in pediatric subjects at a dose of 3 mg or 4 mg each time (3 mg or 4 mg BID), an average C10 concentration was achieved in the range of approximately 25 ng / mL to approximately 50 ng / mL. max Such as about 25 ng / mL to about 35 ng / mL, about 25 ng / mL to about 33 ng / mL, about 25 ng / mL to about 31 ng / mL, about 25 ng / mL to about 29 ng / mL or about 25 ng / mL to about 27 ng / mL.

[0158] In some implementations, when utpatinib was administered twice daily in pediatric subjects at a dose of 6 mg or 8 mg (6 mg or 8 mg BID), an average C10 concentration was achieved in the range of approximately 40 ng / mL to approximately 100 ng / mL. max Such as about 40 ng / mL to about 95 ng / mL, about 40 ng / mL to about 90 ng / mL, about 40 ng / mL to about 85 ng / mL, about 40 ng / mL to about 80 ng / mL, about 40 ng / mL to about 75 ng / mL, about 40 ng / mL to about 70 ng / mL, about 40 ng / mL to about 65 ng / mL, about 40 ng / mL to about 60 ng / mL, about 40 ng / mL to about 55 ng / mL, about 40 ng / mL to about 50 ng / mL, or about 40 ng / mL to about 45 ng / mL.

[0159] In some implementations, when 15 mg extended-release tablets (15 mg QD) as described herein were administered once daily to pediatric subjects, an average C-level of utpatinib was achieved in the range of approximately 45 ng / mL to approximately 50 ng / mL. max Such as about 45 ng / mL to about 49 ng / mL, about 45 ng / mL to about 48 ng / mL, about 45 ng / mL to about 46 ng / mL, or about 45 ng / mL to about 46 ng / mL.

[0160] The average 24-hour exposure (AUC 0-24 ) achieved by the above administration can vary depending on, for example, the dose, patient weight, fed versus fasted conditions, and individual patient’s upatinib metabolism.

[0161] In some embodiments, when a pediatric subject is administered a rapid release oral solution as described herein BID, an average AUC 0-24 of upatinib ranging from about 200 ng-h / mL to about 700 ng-h / mL is achieved.

[0162] In some embodiments, when a pediatric subject is administered a rapid release oral solution as described herein BID, an average AUC 0-24 of upatinib ranging from about 200 ng-h / mL to about 700 ng-h / mL is achieved.

[0163] In some embodiments, when a pediatric subject is administered a rapid release oral solution as described herein BID, an average AUC 0-24 of upatinib ranging from about 200 ng-h / mL to about 700 ng-h / mL is achieved.such as about 340 ng h / mL to about 580 ng h / mL, about 340 ng h / mL to about 570 ng h / mL, about 340 ng h / mL to about 560 ng h / mL, about 340 ng h / mL to about 550 ng h / mL, about 340 ng h / mL to about 540 ng h / mL, about 340 ng h / mL to about 530 ng h / mL, about 340 ng h / mL to about 520 ng h / mL, about 340 ng h / mL to about 510 ng h / mL, about 340 ng h / mL to about 500 ng h / mL, about 340 ng h / mL to about 490 ng h / mL, about 340 ng h / mL to about 480 ng h / mL, about 340 ng h / mL to about 470 ng h / mL, about 340 ng h / mL to about 460 ng h / mL, about 340 ng h / mL to about 450 ng h / mL, about 340 ng h / mL to about 440 ng h / mL, about 340 ng h / mL to about 430 ng h / mL, about 340 ng h / mL to about 420 ng h / mL, about 340 ng h / mL to about 410 ng h / mL, about 340 ng h / mL to about 400 ng h / mL, about 340 ng h / mL to about 390 ng h / mL, about 340 ng h / mL to about 380 ng h / mL, about 340 ng h / mL to about 370 ng h / mL, about 340 ng h / mL to about 360 ng h / mL, about 340 ng h / mL to about 350 ng h / mL, or about 340 ng h / mL to about 345 ng h / mL. In some embodiments, a mean AUC of upatinib ranging from about 570 ng h / mL to about 590 ng h / mL is achieved when the sustained release 15 mg tablet as described herein (15 mg QD) is administered to a pediatric subject once daily 0-24 such as about 570 ng h / mL to about 590 ng h / mL, about 570 ng h / mL to about 588 ng h / mL, about 570 ng h / mL to about 586 ng h / mL, about 570 ng h / mL to about 584 ng h / mL, about 570 ng h / mL to about 582 ng h / mL, or about 570 ng h / mL to about 580 ng h / mL.

[0164] In some embodiments, a mean AUC of upatinib ranging from about 45 ng h / mL to about 50 ng h / mL is achieved when the sustained release 15 mg tablet as described herein (15 mg QD) is administered to a pediatric subject once daily 0-24such as about 45 ng h / mL to about 49 ng h / mL, about 46 ng h / mL to about 48 ng h / mL, or about 47 ng h / mL to about 48 ng h / mL.

[0165] In some embodiments, the method results in an AA-IGA score of 0 or 1 at 40 weeks after the first daily administration.

[0166] In some embodiments, the method results in a Severity of Alopecia Tool (SALT) score of < 20 (less than or equal to 20% scalp hair loss) at 40 weeks after the first daily administration. In some embodiments, the method results in a SALT score of < 10 at 40 weeks after the first daily administration. In some embodiments, the method results in a SALT score of 0 at 40 weeks after the first daily administration.

[0167] In some embodiments, the method results in a SALT of 50 (at least 50% improvement [reduction] in SALT score from baseline) at 40 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 (at least 75% improvement [reduction] in SALT score from baseline) at 40 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 (at least 90% improvement [reduction] in SALT score from baseline) at 40 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 (at least 100% improvement [reduction] in SALT score from baseline) at 40 weeks after the first daily administration.

[0168] In some embodiments, the method results in an AA-IGA score of 0 or 1 at 28 weeks after the first daily administration.

[0169] In some embodiments, the method results in a Severity of Alopecia Tool (SALT) score of < 20 (less than or equal to 20% scalp hair loss) at 28 weeks after the first daily administration. In some embodiments, the method results in a SALT score of < 10 at 28 weeks after the first daily administration. In some embodiments, the method results in a SALT score of 0 at 28 weeks after the first daily administration.

[0170] In some embodiments, the method results in a SALT of 50 (at least a 50% improvement [reduction] in SALT score from baseline) at 28 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 (at least a 75% improvement [reduction] in SALT score from baseline) at 28 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 (at least a 90% improvement [reduction] in SALT score from baseline) at 28 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 (at least a 100% improvement [reduction] in SALT score from baseline) at 28 weeks after the first daily administration.

[0171] In some embodiments, the method results in a Severity of Alopecia Tool (SALT) score of < 20 (less than or equal to 20% loss of scalp hair) at 24 weeks after the first daily administration. In some embodiments, the method results in a SALT score of < 10 at 24 weeks after the first daily administration. In some embodiments, the method results in a SALT score of 0 at 24 weeks after the first daily administration.

[0172] In some embodiments, the method results in a SALT of 50 (at least a 50% improvement [reduction] in SALT score from baseline) at 24 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 (at least a 75% improvement [reduction] in SALT score from baseline) at 24 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 (at least a 90% improvement [reduction] in SALT score from baseline) at 24 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 (at least a 100% improvement [reduction] in SALT score from baseline) at 24 weeks after the first daily administration. In some embodiments, the method results in a Severity of Alopecia Tool (SALT) score of < 20 (less than or equal to 20% loss of scalp hair) at 12 weeks after the first daily administration. In some embodiments, the method results in a SALT score of < 10 at 12 weeks after the first daily administration. In some embodiments, the method results in a SALT score of 0 at 12 weeks after the first daily administration.

[0173] In some embodiments, the method results in a SALT of 50 (at least a 50% improvement [reduction] in SALT score from baseline) at 12 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 (at least a 75% improvement [reduction] in SALT score from baseline) at 12 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 (at least a 90% improvement [reduction] in SALT score from baseline) at 12 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 (at least a 100% improvement [reduction] in SALT score from baseline) at 12 weeks after the first daily administration. In some embodiments, the method results in a Severity of Alopecia Tool (SALT) score of < 20 (less than or equal to 20% loss of scalp hair) at 8 weeks after the first daily administration. In some embodiments, the method results in a SALT score of < 10 at 8 weeks after the first daily administration. In some embodiments, the method results in a SALT score of 0 at 8 weeks after the first daily administration.

[0174] In some embodiments, the method results in a SALT of 50 (at least a 50% improvement [reduction] in SALT score from baseline) at 48 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 (at least a 75% improvement [reduction] in SALT score from baseline) at 8 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 (at least a 90% improvement [reduction] in SALT score from baseline) at 8 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 (at least a 100% improvement [reduction] in SALT score from baseline) at 8 weeks after the first daily administration. In some embodiments, the method results in a Severity of Alopecia Tool (SALT) score of < 20 (less than or equal to 20% loss of scalp hair) at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT score of < 10 at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT score of 0 at 4 weeks after the first daily administration.

[0175] In some embodiments, the method results in a SALT of 50 (at least a 50% improvement [reduction] in SALT score from baseline) at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 (at least a 75% improvement [reduction] in SALT score from baseline) at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 (at least a 90% improvement [reduction] in SALT score from baseline) at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 (at least a 100% improvement [reduction] in SALT score from baseline) at 4 weeks after the first daily administration. The method results in achieving a ClinRO measure of eyebrow hair loss of 0 or 1 at Week 24, an improvement of > 2 points from baseline, in subjects with a baseline score of > 2.

[0176] In some embodiments, the method results in achieving a PRO of scalp hair assessment of 0 / 1 at Week 24, an improvement (reduction) of > 2 points from baseline, in subjects with a baseline score of > 3.

[0177] In some embodiments, the method results in achieving a PaGIC score of 1 or 2 at Week 24.

[0178] In some embodiments, the method results in achieving a Skindex-16 AA emotional domain score at Week 24.

[0179] In some embodiments, the method results in a change in Skindex-16 AA functional domain score from baseline at Week 24.

[0180] In some embodiments, the method results in achieving HADS-A < 8 and HADS-D < 8 at Week 24 in subjects with HADS-A > 8 or HADS-D > 8 at baseline.

[0181] In some embodiments, the method results in a change in AASIS Interference subscale score at Week 24.

[0182] In some embodiments, the method results in a change in AASIS Symptom subscale score at Week 24.

[0183] The method results in achieving a ClinRO measure of eyebrow hair loss of 0 or 1 at Week 12, an improvement of > 2 points from baseline, in subjects with a baseline score of > 2.

[0184] In some embodiments, the method results in achieving a PRO of scalp hair assessment of 0 / 1 at Week 12, an improvement (reduction) of > 2 points from baseline, in subjects with a baseline score of > 3.

[0185] In some embodiments, the method results in achieving a PaGIC score of 1 or 2 at Week 12.

[0186] In some embodiments, the method results in achieving a Skindex-16 AA emotional domain score at Week 12.

[0187] In some embodiments, the method results in a change from baseline in Skindex-16 AA functional domain score at Week 12.

[0188] In some embodiments, the method results in achieving HADS-A < 8 and HADS-D < 8 at Week 8 in subjects with HADS-A > 8 or HADS-D > 8 at baseline.

[0189] In some embodiments, the method results in a change in AASIS Interference subscale score at Week 8.

[0190] In some embodiments, the method results in a change in AASIS Symptom subscale score at Week 8.

[0191] The method results in achieving a ClinRO measure of eyebrow hair loss of 0 or 1 at Week 8, an improvement of > 2 points from baseline, in subjects with a baseline score of > 2.

[0192] In some embodiments, the method results in achieving a PRO of scalp hair assessment of 0 / 1 at Week 8, an improvement (decrease) of > 2 points from baseline, in subjects with a baseline score of > 3.

[0193] In some embodiments, the method results in achieving a PaGIC score of 1 or 2 at Week 8.

[0194] In some embodiments, the method results in achieving a Skindex-16 AA emotional domain score at Week 8.

[0195] In some embodiments, the method results in a change from baseline in Skindex-16 AA functional domain score at Week 8.

[0196] In some embodiments, the method results in achieving HADS-A < 8 and HADS-D < 8 at Week 8 in subjects with HADS-A > 8 or HADS-D > 8 at baseline.

[0197] In some embodiments, the method results in a change in AASIS Interference subscale score at Week 8.

[0198] In some embodiments, the method results in a change in AASIS Symptom subscale score at Week 8.

[0199] The method results in a ClinRO measure of eyebrow hair loss of 0 or 1 at Week 4, an improvement of > 2 points from baseline, in subjects with a baseline score of > 2.

[0200] In some embodiments, the method results in a PRO of scalp hair assessment of 0 / 1 at Week 4, an improvement (decrease) of > 2 points from baseline, in subjects with a baseline score of > 3.

[0201] In some embodiments, the method results in a PaGIC score of 1 or 2 at Week 4.

[0202] In some embodiments, the method results in a Skindex-16 AA emotional domain score at Week 4.

[0203] In some embodiments, the method results in a change in Skindex-16 AA functional domain score at Week 4 from baseline.

[0204] In some embodiments, the method results in HADS-A < 8 and HADS-D < 8 at Week 4 in subjects with HADS-A > 8 or HADS-D > 8 at baseline.

[0205] In some embodiments, the method results in a change at Week 4.

[0206] In some embodiments, the method results in a change in AASIS symptom subscale score at Week 4.

[0207] In some embodiments, the method results in an AA-IGA score of 0 or 1 at 16 weeks after the first daily administration.

[0208] In some embodiments, the method results in a Severity of Alopecia Tool (SALT) of 50 at 16 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 at 16 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 at 16 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 at 16 weeks after the first daily administration.

[0209] In some embodiments, the method results in an AA-IGA score of 0 or 1 at 4 weeks after the first daily administration.

[0210] In some embodiments, the method results in a SALT of 50 at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT of 75 at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT of 90 at 4 weeks after the first daily administration. In some embodiments, the method results in a SALT of 100 at 4 weeks after the first daily administration.

[0211] In some embodiments, the patient has moderate alopecia areata. In some embodiments, the patient has moderate or severe alopecia areata. In some embodiments, the patient has severe alopecia areata. In some embodiments, the patient has very severe alopecia areata.

[0212] In some embodiments, the alopecia areata is located in the frontoparietal region of the scalp and the eyebrows.

[0213] In some embodiments, the patient has a serum IgE level of > 100 IU / ml prior to starting treatment.

[0214] In some embodiments, the patient has previously received systemic agent treatment for alopecia areata. In some embodiments, the systemic agent is cyclosporine or dupilumab. In some embodiments, the systemic agent is baricitinib. IV. Pharmaceutical Compositions and Routes of Administration

[0215] Upadacitinib can be administered to a human patient by itself or in the form of a pharmaceutical composition wherein upadacitinib is mixed with a biologically suitable carrier or excipient at dosages effective for treating or ameliorating diseases or conditions as described herein. Mixtures of these compounds can also be administered to a patient as simple mixtures or as suitable formulated pharmaceutical compositions.

[0216] The pharmaceutical compositions of the present disclosure can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0217] Pharmaceutical compositions for use in accordance with the present disclosure thus can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent on the chosen route of administration.

[0218] In some embodiments, the pharmaceutical composition is a tablet dosage form. In some embodiments, the tablet is a controlled release formulation, such as a sustained release tablet dosage form (also referred to herein as a modified release or sustained release formulation). Examples of solid dosage forms comprising upadacitinib can be found in International Patent Application Publication No. WO 2017 / 066775, which is hereby incorporated by reference in its entirety.

[0219] In some embodiments, the composition is a stable liquid pharmaceutical composition. In some embodiments, the stable liquid pharmaceutical composition is a stable oral solution. In some embodiments, the stable liquid pharmaceutical composition is a stable oral suspension. Suitable stable liquid pharmaceutical compositions comprise upadacitinib or a pharmaceutically acceptable salt or solid form thereof, and excipients such as buffers, preservatives, sweeteners, flavorings, pH adjusting agents, solvents, and the like. In some embodiments, the stable liquid pharmaceutical composition is a stable oral pharmaceutical solution comprising upadacitinib, a buffer and / or pH adjusting agent, a preservative, a sweetener, and water. In some embodiments, the stable liquid pharmaceutical composition is a stable oral pharmaceutical suspension comprising upadacitinib, a buffer and / or pH adjusting agent, a preservative, a sweetener, and water.

[0220] The concentration of upadacitinib in the stable liquid pharmaceutical composition can vary. Upadacitinib is typically present at about 1 mg / mL or less for palatability reasons as it is difficult to mask the bitter taste of upadacitinib at higher concentrations (see, e.g., Example 5). In some embodiments, the stable pharmaceutical composition is an oral solution comprising: upadacitinib at a concentration ranging from about 0.3 mg / mL to about 1.2 mg / mL, such as about 0.3 mg / mL to about 0.7 mg / mL, or about 0.8 mg / mL to about 1.2 mg / mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 1 mg / mL, such as about 0.8 mg / mL, 0.9 mg / mL, or about 1.0 mg / mL to about 1.1 mg / mL or about 1.2 mg / mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of 1.0 mg / mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.5 mg / mL, such as about 0.3 mg / mL, 0.4 mg / mL, or about 0.5 mg / mL to about 0.6 mg / mL or about 0.7 mg / mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution comprises upadacitinib at a concentration of 0.5 mg / mL

[0221] In particular embodiments, the oral solution has a formulation as provided in Table 1. Table 1. Example Formulation of Upadacitinib Oral Solution

[0222] Example Example 1: Efficacy and Safety of Upadacitinib in Alopecia Areata (AA) Study Design

[0223] This study included AD patients with alopecia areata who had been treated with utpatinib for at least 4 weeks at baseline visits. All AD patients with alopecia areata at baseline visits were identified based on data reported by each investigator in their patient clinical report forms. Medical records included demographic characteristics such as age, sex, occupation, smoking habits (smoker, former smoker, or non-smoker), AD history and severity, alopecia areata history and severity, previous treatments, atopic and non-atopic comorbidities, serum IgE levels, and concomitant therapies.

[0224] Eligible patients are aged 18 to 75 years and have completed pre-specified washout of prior systemic immunomodulatory therapy, according to the criteria used for the utpatinib trial.

[0225] Patients were treated with 15 mg or 30 mg utpatinib once daily (QD). The choice of 15 mg or 30 mg utpatinib daily was based on the physician's decision. All patients were initially treated with 30 mg utpatinib daily and maintained at that dose, except for two patients who reduced their daily dose to 15 mg. No patients discontinued utpatinib treatment throughout the observation period.

[0226] Patients were evaluated at baseline and followed up 4 weeks after baseline and every 12 weeks thereafter. The severity of alopecia areata (AD) was assessed at baseline and at each follow-up visit using the Eczema Area and Severity Index (EASI) and other tools. To assess the severity of alopecia areata and treatment response, the Alopecia Area and Severity Tool (SALT) and the Alopecia Area and Investigator Global Assessment (AA-IGA), commonly used in routine practice, were used. Mean SALT scores were measured at baseline and at weeks 4, 16, 28, and 40 during utpatinib treatment. The clinical course of alopecia areata was defined as SALT scores of 50, 75, 90, and 100 (resulting in 50%, 75%, 90%, and 100% hair regrowth compared to baseline SALT scores) achieved at weeks 4, 16, 28, and 40 during utpatinib administration. SALT changes throughout the observation period were recorded as the difference between the baseline SALT score and the SALT score calculated at each follow-up visit (ΔSALT). Statistical Analysis

[0227] Qualitative and quantitative variables were described as relative frequencies (%), mean and standard deviation (or median and interquartile range [IR], as appropriate). SALT 50, 75, 90, 100 achieved at week 4, 16, 28 and 40 during upadacitinib administration were analyzed according to the clinical demographic characteristics of the patients using Fisher's exact test or Mann-Whitney test, as appropriate. Pearson correlation analysis was performed to assess the correlation between ASALT and i) baseline SALT score, ii) age at onset of alopecia, iii) and / or mean time of alopecia duration until upadacitinib administration. Multivariate regression models were established to study the relationship between ASALT and IgE levels (considered as a categorical variable: high levels before treatment initiation vs normal levels) and baseline SALT score (considered as a continuous variable), considering gender and age at onset of alopecia as potential confounders. Statistical analysis was performed using STATA 17 / BE software (StataCorp, Texas) and p values < 0.05 were considered statistically significant. Data were reported and analyzed "as observed". Therefore, no missing imputation was performed. Results Demographics

[0228] Among the 118 AD patients charts treated with upadacitinib and included in the database, 19 also had concomitant alopecia areata (16.1%). Most of them were female subjects (12 / 19, 63.1%) with a mean age of 36 years (Table 2). Concomitant autoimmune diseases were observed in 6 / 19 (31.6%) patients, while atopic comorbidities were reported in 8 / 19 (42.1%) cases (Table 2). High serum IgE levels (>100 IU / ml) were detected in 6 / 19 (31.6%) patients. Most of the patients were previously treated with systemic agents, including cyclosporine (12 / 19, 63.2%) and dupilumab (8 / 19, 42.1%). The mean duration of alopecia areata was 119.8 ± 100.1 months (median [IQR]= 92.7 [26.3-224.9]).

[0229] Alopecia areata was located in the frontoparietal region of the scalp in all cases and in the eyebrow in 18 / 19 (94.7%) cases. Universalis alopecia was observed in 14 / 19 (68.4%) cases (Table 2). The diagnosis of AD occurred before the onset of alopecia areata. The mean interval (years) between AD diagnosis and alopecia areata onset was defined and it was found that the interval was significantly shorter for the onset of universalis alopecia areata compared to other clinical variants of alopecia areata (14.8 ± 9.5 vs 32.5 ± 62.8 p=0.04).

[0230] According to the SALT subcategory, the baseline severity of alopecia areata was defined as s3 in 1 / 19 (5.3%) cases, s4a in 4 / 19 (21.0%) cases, s4b in 3 / 19 (15.8%) cases, and s5 in 11 / 19 (57.9%) cases. Based on the AA-IGA scale, 4 / 19 (21.0%) and 11 / 19 (79.0%) of patients were classified as severe and very severe, respectively. Table 2. Baseline Demographics and Clinical Characteristics of Patients with AD and concomitant AA (N=19)

[0231]

[0232]

[0233] a Range quartile

[0234] b BMI: body mass index

[0235] c Sum does not match total number of patients due to missing data

[0236] d Standard deviation

[0237] e Sum does not match total due to concomitant multiple drug administration

[0238] n. Number of cases: number of patients Efficacy

[0239] A positive effect of upadacitinib on alopecia areata severity was observed in terms of AA-IGA reduction, with an increasing number of patients achieving AA-IGA 0-1 (2 / 19 [10.5%] at Week 4, 9 / 17 [52.9%] at Week 16, 9 / 14 [64.3%] at Week 28, and 6 / 9 [66.7%] at Week 40; Table 3).

[0240] A significant reduction in mean baseline SALT score (94.9 ± 9.8) was detected as early as 4 weeks after treatment initiation (76.4 ± 28.5, p = 0.0087), with incremental reductions observed over time at 16, 28, 40, and 40 weeks after treatment (Table 3). The improvement in SALT score was also measured as the difference in SALT score between each follow-up visit and baseline (ASALT), revealing a mean SALT score reduction of 18.4 ± 26.4 points after 4 weeks, with greater reductions at subsequent time points (Table 3). Table 3. Evaluation of Alopecia Severity, Clinical Improvement, and Treatment Response During Upadacitinib Administration

[0241]

[0242] * P-value = 0.0087 for comparison between Week 4 and baseline; ** P-value < 0.0001 for comparison between Week 16 and baseline;*** P value <0.0001 for comparison between Week 28 and baseline; **** P value <0.0009 for comparison between Week 40 and baseline.

[0243] a Standard deviation

[0244] A surprising proportion of patients (3 / 19, 15.8%) achieved clinical treatment targets (SALT 50, 75, 90, and 100 responses) after only 4 weeks of treatment, and this percentage increased significantly after 16 weeks of treatment. At Week 16, treatment responses were even more impressive, with over 50% of patients achieving an AA-IGA score of 0-1, which reflects a significant reduction in SALT change or average SALT score. Indeed, by Week 16, over 50% of cases achieved a high rate of SALT 50 and SALT 75 (10 / 17, 58.8%). In Figure 1 a graph of SALT 75 and SALT 100 responses over time is provided. Referring to Figure 1 , at Week 16, 52.9% (9 / 17) and 29.4% (5 / 17) of treated patients achieved SALT 75 and SALT 100 responses, respectively. Among patients who achieved a SALT 50 response during the first 16 weeks of treatment, further improvement was observed at Weeks 28 and 40, with SALT 90 and 100 responses obtained in most patients.

[0245] After 16 weeks of treatment, there were 7 / 17 (41.2%) non-responders (<SALT 50). In these patients, no meaningful improvement was detected thereafter.

[0246] Notably, SALT 50 and SALT 75 were observed more frequently at Week 16 (p=0.012 for SALT 50; and p=0.046 for SALT 75) and Week 40 (p=0.028 for all clinical endpoints) in patients with a personal history of atopic comorbidities.

[0247] A slight positive correlation between the change in SALT score throughout upadacitinib treatment and the age at which the patient experienced alopecia areata was found and confirmed by multivariate regression analysis (Pearson correlation coefficient r=0.48, p=0.0446), revealing that for each 1-unit increase in age at which alopecia areata was experienced, a 2.1-point decrease in SALT was predicted (p=0.025) independent of baseline SALT score and gender (Prob>F=0.04; adjusted R 2 =0.34). Furthermore, a significantly greater reduction in SALT score (by 39.0 points) was found in patients with high IgE serum levels (p=0.03). AsFigure 2 Patients with high IgE levels had a greater improvement in SALT score compared to patients with normal serum IgE levels (mean delta SALT: -82.3 ± 12.56 vs -44.38 ± 11.12, p = 0.05). In contrast, baseline SALT score (p = 0.447) and duration of alopecia areata (p = 0.378) were not significantly associated with the change in SALT score that occurred during the observation period (Table 4). Table 4. Multivariable Linear Regression Models for Understanding Whether AA Improvement During Upadacitinib Administration Can be Predicted Based on Age at Onset of Alopecia, Baseline Serum IgE, and Baseline SALT Score ​ .

[0248]

[0249] * Normal serum IgE levels were considered the reference.

[0250] ** Female patients were considered the reference

[0251] a Standard error

[0252] b Confidence interval

Claims

1. A method of treating a human patient having alopecia areata, the method comprising orally administering 30 mg of upadacitinib to the patient once daily.

2. A method of treating a human patient having alopecia areata, the method comprising orally administering 15 mg of upadacitinib to the patient once daily.

3. The method of claim 1 or 2, wherein the patient is an adult.

4. The method of any one of claims 1 to 3, wherein the method results in an AA-IGA score of 0 or 1 at 40 weeks after the first daily administration.

5. The method of any one of claims 1 to 4, wherein the method results in a Severity of Alopecia Tool (SALT) of 50 at 40 weeks after the first daily administration.

6. The method of any one of claims 1 to 4, wherein the method results in a SALT of 75 at 40 weeks after the first daily administration.

7. The method of any one of claims 1 to 4, wherein the method results in a SALT of 90 at 40 weeks after the first daily administration.

8. The method of any one of claims 1 to 4, wherein the method results in a SALT of 100 at 40 weeks after the first daily administration.

9. The method of any one of claims 1 to 3, wherein the method results in an AA-IGA score of 0 or 1 at 28 weeks after the first daily administration.

10. The method of any one of claims 1 to 4, wherein the method results in a Severity of Alopecia Tool (SALT) of 50 at 28 weeks after the first daily administration.

11. The method of any one of claims 1 to 4, wherein the method results in a SALT of 75 at 28 weeks after the first daily administration.

12. The method of any one of claims 1 to 4, wherein the method results in a SALT of 90 at 28 weeks after the first daily administration.

13. The method of any one of claims 1 to 4, wherein the method results in a SALT of 100 at 28 weeks after the first daily administration.

14. The method of any one of claims 1 to 3, wherein the method results in an AA-IGA score of 0 or 1 at 16 weeks after the first daily administration.

15. The method of any one of claims 1 to 4, wherein the method results in a Severity of Alopecia Tool (SALT) score of < 20 at 24 weeks after the first daily administration.

16. The method of any one of claims 1 to 4, wherein the method results in a Severity of Alopecia Tool (SALT) of 50 at 16 weeks after the first daily administration.

17. The method of any one of claims 1 to 4, wherein the method results in a SALT of 75 at 16 weeks after the first daily administration.

18. The method of any one of claims 1 to 4, wherein the method results in a SALT of 90 at 16 weeks after the first daily administration.

19. The method of any one of claims 1 to 4, wherein the method results in a SALT of 100 at 16 weeks after the first daily administration.

20. The method of any one of claims 1 to 3, wherein the method results in an AA-IGA score of 0 or 1 at 4 weeks after the first daily administration.

21. The method of any one of claims 1 to 4, wherein the method results in a SALT of 50 at 4 weeks after the first daily administration.

22. The method of any one of claims 1 to 4, wherein the method results in a SALT of 75 at 4 weeks after the first daily administration.

23. The method of any one of claims 1 to 4, wherein the method results in a SALT of 90 at 4 weeks after the first daily administration.

24. The method of any one of claims 1 to 4, wherein the method results in a SALT of 100 at 4 weeks after the first daily administration.

25. The method of any one of claims 1 to 24, wherein the patient has moderate or severe alopecia areata.

26. The method of any one of claims 1 to 24, wherein the patient has severe alopecia areata.

27. The method of any one of claims 1 to 26, wherein the alopecia areata is located in the frontoparietal region of the scalp and the eyebrows.

28. The method of any one of claims 1 to 27, wherein the patient has a serum IgE level of >100 IU / ml prior to starting treatment.

29. The method of any one of claims 1 to 28, wherein the patient has previously received systemic agent treatment for alopecia areata.

30. The method of claim 29, wherein the systemic agent is cyclosporine or dupilumab.

31. The method of claim 29, wherein the systemic agent is baricitinib.

32. A method of treating alopecia areata in a pediatric human patient, the method comprising orally administering to the pediatric patient a therapeutically effective amount of upadacitinib, wherein: in the case that the pediatric patient weighs in a range of about 10 kg to less than about 20 kg: (i) the upadacitinib is administered at a dose of 3 mg per dose twice daily (3 mg BID), or (ii) the upadacitinib is administered at a dose of 6 mg per dose twice daily (6 mg BID); in the case that the pediatric patient weighs in a range of about 20 kg to less than about 30 kg: (i) the upadacitinib is administered at a dose of 4 mg per dose twice daily (4 mg BID), or (ii) the upadacitinib is administered at a dose of 8 mg per dose twice daily (8 mg BID); and in the case that the pediatric patient weighs about 30 kg or more: (i) the upadacitinib is administered at a dose of 6 mg per dose twice daily (6 mg BID), (ii) the upadacitinib is administered at a dose of 8 mg per dose twice daily (8 mg BID), or (ii) the upadacitinib is administered at a dose of 15 mg per dose once daily (15 mg QD). ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 33. The method of claim 32, wherein a twice daily dose of umbralisib is administered to the pediatric patient as a stable oral pharmaceutical solution.

34. The method of claim 32 or 33, wherein the stable oral pharmaceutical solution comprises umbralisib, a buffering and / or pH adjusting agent, a preservative, a sweetener, and water.

35. The method of any one of claims 32 to 34, wherein the oral solution comprises umbralisib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

36. The method of any one of claims 32 to 35, wherein a once daily dose of umbralisib is administered to the pediatric patient as a tablet.

37. The method of any one of claims 32 to 36, wherein the method results in an AA-IGA score of 0 or 1 at 40 weeks after the first daily administration.

38. The method of any one of claims 32 to 37, wherein the method results in a Severity of Alopecia Tool (SALT) of 50 at 40 weeks after the first daily administration.

39. The method of any one of claims 32 to 37, wherein the method results in a SALT of 75 at 40 weeks after the first daily administration.

40. The method of any one of claims 32 to 37, wherein the method results in a SALT of 90 at 40 weeks after the first daily administration.

41. The method of any one of claims 32 to 37, wherein the method results in a SALT of 100 at 40 weeks after the first daily administration.

42. The method of any one of claims 32 to 36, wherein the method results in an AA-IGA score of 0 or 1 at 28 weeks after the first daily administration.

43. The method of any one of claims 32 to 36 or 42, wherein the method results in a Severity of Alopecia Tool (SALT) of 50 at 28 weeks after the first daily administration.

44. The method of any one of claims 32 to 36 or 42, wherein the method results in a SALT of 75 at 28 weeks after the first daily administration.

45. The method of any one of claims 32 to 36 or 42, wherein the method results in a SALT of 90 at 28 weeks after the first daily administration.

46. The method of any one of claims 32 to 36 or 42, wherein the method results in a SALT of 100 at 28 weeks after the first daily administration.

47. The method of any one of claims 32 to 36, wherein the method results in an AA-IGA score of 0 or 1 at 16 weeks after the first daily administration.

48. The method of any one of claims 32 to 36, wherein the method results in a Severity of Alopecia Tool (SALT) score of < 20 at 24 weeks after the first daily administration.

49. The method of any one of claims 32-36 or 47, wherein the method results in a Severity of Alopecia Tool (SALT) of 50 at 16 weeks after the first daily administration.

50. The method of any one of claims 32-36 or 47, wherein the method results in a SALT of 75 at 16 weeks after the first daily administration.

51. The method of any one of claims 32-36 or 47, wherein the method results in a SALT of 90 at 16 weeks after the first daily administration.

52. The method of any one of claims 32-36 or 47, wherein the method results in a SALT of 100 at 16 weeks after the first daily administration.

53. The method of any one of claims 32-36, wherein the method results in an AA-IGA score of 0 or 1 at 4 weeks after the first daily administration.

54. The method of any one of claims 32-36 or 53, wherein the method results in a SALT of 50 at 4 weeks after the first daily administration.

55. The method of any one of claims 32-36 or 53, wherein the method results in a SALT of 75 at 4 weeks after the first daily administration.

56. The method of any one of claims 32-36 or 53, wherein the method results in a SALT of 90 at 4 weeks after the first daily administration.

57. The method of any one of claims 32-36 or 53, wherein the method results in a SALT of 100 at 4 weeks after the first daily administration.

58. The method of any one of claims 1-57, wherein the patient has moderate or severe alopecia areata.

59. The method of any one of claims 1-57, wherein the patient has severe alopecia areata.

60. The method of any one of claims 1-59, wherein the alopecia areata is in the frontoparietal region of the scalp and the eyebrows.

61. The method of any one of claims 1-60, wherein the patient has a serum IgE level of >100 IU / ml prior to starting treatment.

62. The method of any one of claims 1-61, wherein the patient has previously received systemic agent treatment for alopecia areata.

63. The method of claim 62, wherein the systemic agent is cyclosporine or dupilumab.

64. The method of claim 62, wherein the systemic agent is baricitinib.

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