WO2025221754A1 - Upadacitinib for use in the treatment of giant cell arteritis - Google Patents

Abstract

The present disclosure is directed to methods for treating giant cell arteritis (GCA) using upadacitinib.

Description

METHOD OF TREATING GIANT CELL ARTERITIS WITH UPADACITINIB CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to and the benefit of U.S. Provisional Application Serial No.63/635,277, filed April 17, 2024, and entitled “Method of Treating Giant Cell Arteritis With Upadacitinib”. The contents of the foregoing application are incorporated herein by reference in their entirety. FIELD OF THE DISCLOSURE [0002] The present disclosure is directed to a method for treating giant cell arteritis (GCA) with the JAK1 selective inhibitor upadacitinib. BACKGROUND OF THE DISCLOSURE [0003] Upadacitinib is a JAK1 selective inhibitor approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, ulcerative colitis, Crohn’s disease, and atopic dermatitis. [0004] Giant cell arteritis (GCA) is a type of vasculitis, which is a group of diseases whose main feature is inflammation of blood vessels. Most often, it affects the arteries in the head, and especially those in the temples. The most common symptoms of giant cell arteritis are pain and tenderness, often severe, that usually affects both temples, and may also include headaches, scalp tenderness, jaw pain, fever, fatigue, weight loss, and vision problems. Untreated GCA can lead to blindness. About 50 percent of people with giant cell arteritis also have polymyalgia rheumatica (PMR). The cause of GCA is unknown, but is believed to be of an autoimmune nature, and certain genetic and environmental factors are believed to increase susceptibility. GCA most commonly affects Caucasians in Northern Europe or of Scandinavian descent. GCA affects adults only, with most patients developing signs and symptoms between the ages of 70 and 80. Women are about twice as likely to develop the condition than men. [0005] First-line treatment for GCA is long-term administration of corticosteroids. Generally, patients taper off from corticosteroids completely after one to two years, and are susceptible to relapses following the discontinuation of treatment. Tocilizumab (Actemra®), an interleukin-6 (IL- 6) receptor antagonist, was approved by the US FDA in 2017 for the treatment of GCA in combination with a tapering course of corticosteroids and alone following discontinuation of corticosteroids. -1- ^{WBD (US) 4862-1739-3843v3} [0006] For reasons including patient convenience and compliance, particularly in long-term treatment, and to reduce or eliminate the need for corticosteroids, it would be desirable to provide an efficacious oral therapeutic for the treatment of GCA. SUMMARY OF THE DISCLOSURE [0007] The present disclosure provides a method for treating giant cell arteritis (GCA) with the selective JAK1 inhibitor, upadacitinib. The treatment method generally comprises administering to a patient in need thereof a therapeutically effective amount of upadacitinib. [0008] In one aspect is provided a method of treating GCA in a patient, the method comprising orally administering once daily to the patient 15 mg of upadacitinib. [0009] In another aspect is provided a method of inducing remission of GCA in a patient, the method comprising orally administering once daily to the patient 15 mg of upadacitinib. [0010] In some embodiments, the patient achieves remission of GCA 12 weeks following the first daily administration. In some embodiments, the patient achieves sustained remission of GCA from 12 weeks following the first daily administration through 52 weeks after the first daily administration. [0011] In one aspect is provided a method of inducing and sustaining remission of GCA in a patient, the method comprising orally administering once daily to the patient 15 mg of upadacitinib. [0012] In some embodiments, the patient achieves remission of GCA 12 weeks following the first daily administration, and remission is sustained from 12 weeks following the first daily administration through 52 weeks after the first daily administration. In some embodiments, the patient achieves glucocorticoid free sustained remission at week 52 after the first daily administration. [0013] In some embodiments, the patient achieves remission of GCA 12 weeks following the first daily administration and sustains remission of GCA through 52 weeks after the first daily administration. [0014] In one aspect is provided a method of inducing complete remission of GCA in a patient, the method comprising orally administering once daily to the patient 15 mg of upadacitinib. [0015] In some embodiments, the patient achieves complete remission of GCA 12 weeks following the first daily administration. In some embodiments, the patient achieves sustained complete remission of GCA from 12 weeks following the first daily administration through 52 weeks after the first daily administration. -2- ^{WBD (US) 4862-1739-3843v3} [0016] In one aspect is provided a method of inducing and sustaining complete remission of GCA in a patient, the method comprising orally administering once daily to the patient 15 mg of upadacitinib. [0017] In some embodiments, the patient achieves remission of GCA 12 weeks following the first daily administration, and remission is sustained from 12 weeks following the first daily administration through 52 weeks after the first daily administration. In some embodiments, the patient achieves glucocorticoid free sustained complete remission at week 52 after the first daily administration. [0018] In some embodiments, the patient achieves complete remission of GCA 12 weeks following the first daily administration and sustains complete remission of GCA through week 52 after the first daily administration. [0019] In some embodiments, the patient achieves a reduction in cumulative exposure to corticosteroids through week 52 after the first daily administration, relative to a patient that has not been treated with upadacitinib. [0020] In some embodiments, the patient achieves an increase in time to disease flare through week 52 after the first daily administration, relative to a patient that has not been treated with upadacitinib. [0021] In some embodiments, the patient achieves a reduction in a number of disease flares through week 52 after the first daily administration, relative to a patient that has not been treated with upadacitinib. [0022] In some embodiments, the patient achieves, relative to a patient that has not been treated with upadacitinib, one or more of the following: a positive change from baseline in a 36-item Short Form Quality of Life Questionnaire (SF- 36) Physical Component Score (PCS); a positive change from baseline in a Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-Fatigue); a positive change from baseline in an Assessment of Treatment Satisfaction Questionnaire for Medication (TSQM) Patient Global Satisfaction Subscale. [0023] In some embodiments, the patient is currently receiving a tapering course of glucocorticoids. [0024] In some embodiments, the patient is currently receiving at least 20 mg oral corticosteroid once daily at the time of the first daily administration. [0025] In some embodiments, the method further comprises tapering a dose of the oral corticosteroid over a period of 26 weeks. -3- ^{WBD (US) 4862-1739-3843v3} [0026] In some embodiments, the patient has: a history of erythrocyte sedimentation rate (ESR) >= 50 mm/hour or high sensitivity C- reactive protein (hsCRP)/CRP >=1.0 mg/dL; unequivocal cranial symptoms of GCA, unequivocal symptoms of polymyalgia rheumatica (PMR), or both; a temporal artery biopsy revealing features of GCA, evidence of large vessel vasculitis by angiography or cross-sectional imaging, or both; active GCA, either new onset or relapsing, within 8 weeks prior to the first administration; and clinically stable GCA. [0027] In some embodiments, the patient has not received any Janus Kinase (JAK) inhibitor within 4 weeks prior to initiating the method. Examples of JAK inhibitors include, but are not limited to, upadacitinib, tofacitinib, baricitinib, delgocitinib, pacritinib, fedratinib, ritlecitinib, ruxolitinib, and abrocitinib. [0028] In some embodiments, the patient has not received any interleukin-6 (IL-6) inhibitor within 4 weeks prior to initiating the treatment or has not had a disease flare during prior treatment with an IL-6 inhibitor. [0029] In some embodiments, the patient has not received: anakinra within 1 week prior to initiating the treatment; methotrexate, hydroxychloroquine, cyclosporine, azathioprine, or mycophenolate within 4 weeks prior to initiating the treatment; greater than or equal to 8 weeks for leflunomide if no elimination procedure was followed; and cell-depleting agents or alkylating agents including cyclophosphamide within 6 months prior to initiating the treatment. [0030] In some embodiments, the patient is 50 years of age or older. In some embodiments, the patient is 50 years of age or older with new-onset or relapsing GCA. [0031] In some embodiments, the patient does not have and has not previously had herpes zoster, herpes simplex, or human immunodeficiency virus (HIV). [0032] In some embodiments, the patient does not have active tuberculosis, an active or chronic recurring infection, or active hepatitis B or C. BRIEF DESCRIPTION OF THE DRAWINGS -4- ^{WBD (US) 4862-1739-3843v3} [0033] FIG. 1 is a schematic illustration of a clinical study according to a non-limiting embodiment of the disclosure, as described in Example 1. [0034] FIG. 2 is a graphical depiction of efficacy over time according to the primary endpoint of sustained remission in the clinical study of Example 1. [0035] FIG.3 is a graphical depiction of efficacy over time according to the secondary endpoint of sustained complete remission in the clinical study of Example 1. [0036] FIG. 4A is a graphical depiction of the proportion of patients achieving sustained remission from week 12 to week 52 in the clinical study of Example 1 (Quartile plot). [0037] FIG. 4B is a graphical depiction of the proportion of patients achieving sustained remission from week 12 to week 52 in the clinical study of Example 1 (Logistic regression model). [0038] FIG. 5A is a graphical depiction of the proportion of patients achieving sustained complete remission from week 12 to week 52 in the clinical study of Example 1 (Quartile plot). [0039] FIG. 5B is a graphical depiction of the proportion of patients achieving sustained complete remission from week 12 to week 52 in the clinical study of Example 1 (Logistic regression model). [0040] FIG. 6 is a graphical depiction of cumulative exposure through week 52 in the clinical study of Example 1. [0041] FIG.7 is a graphical depiction of time to first disease flare through week 52 in the clinical study of Example 1. DETAILED DESCRIPTION OF THE DISCLOSURE I. Definitions [0042] Section headings as used in this section and the entire disclosure are not intended to be limiting. [0043] Where a numeric range is recited, each intervening number within the range is explicitly contemplated with the same degree of precision. For example, for the range 6 to 9, the numbers 7 and 8 are contemplated 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 contemplated. In the same manner, all recited ratios also include all sub-ratios falling within the broader ratio. [0044] The singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. [0045] The term "about" generally refers to a range of numbers that one of skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many instances, the term "about" may include numbers that are rounded to the nearest significant figure. -5- ^{WBD (US) 4862-1739-3843v3} [0046] Unless the context requires otherwise, the terms "comprise," "comprises," and "comprising" are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicant intends each of those words to be so interpreted in construing this patent, including the claims below. [0047] The term “remission” is defined as having all of the following: • Absence of GCA signs and symptoms; and • Adherence to the 26-week CS taper regimen in Table 1 below. [0048] The term “sustained remission” is defined as having all of the following: • Absence of GCA signs and symptoms over a period of time; • Adherence to the 26-week CS taper regimen in Table 1 below. [0049] The term “complete remission” is defined as having all of the following: • Absence of GCA signs and symptoms; • Normalization of ESR (to < 30 mm/hr); if ESR ≥ 30 mm/hr and elevation is not attributable to GCA, this criterion can still be met; • Normalization of hsCRP (to < 1 mg/dL without elevation [on 2 consecutive visits] to ≥ 1 mg/dL); and • Adherence to the 26-week CS taper regimen in Table 1 below. [0050] The term “sustained complete remission” is defined as having all of the following: • Absence of GCA signs and symptoms over a period of time; • Normalization of ESR (to < 30 mm/hr) over a period of time; if ESR ≥ 30 mm/hr and elevation is not attributable to GCA, this criterion can still be met; • Normalization of hsCRP (to < 1 mg/dL without elevation [on 2 consecutive visits] to ≥ 1 mg/dL) over a period of time; and • Adherence to the 26-week CS taper regimen in Table 1 below. Table 1. Corticosteroid Tapering Schedule -6- ^{WBD (US) 4862-1739-3843v3} [0051] The terms "treating", "treatment", and "therapy" and the like, as used herein, are meant to include therapeutic measures for a disease or disorder leading to a clinically desirable or beneficial effect, including but not limited to clinically significant improvement in the signs and symptoms of GCA over a period of time. -7- ^{WBD (US) 4862-1739-3843v3} II. JAK1 Inhibition [0052] Upadacitinib (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N- (2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide), or a pharmaceutically acceptable salt or solid state form thereof, is an oral Janus kinase (JAK) inhibitor that displays unique selectivity for the JAK1 receptor. Upadacitinib has the structure shown below: [0053] The dosage strength of upadacitinib recited in the present application is based on the weight of anhydrous freebase upadacitinib present in the active ingredient delivered to the patient. For example, a dose of "15 mg of upadacitinib" or "UPA 15 MG" refers to the 15 mg amount of the neutral upadacitinib freebase present in the active ingredient, not including any coformer (e.g., solvent or water molecule(s)) of a solvate or hydrate (including hemihydrate) or counteranions of a pharmaceutically acceptable salt), that may also be present in the active ingredient. So, for example, the administration of "15 mg of upadacitinib" includes the administration of 15.4 mg of crystalline upadacitinib freebase hemihydrate (which includes 1/2 of a water conformer molecule per upadacitinib freebase molecule) which delivers 15 mg of anhydrous freebase upadacitinib to a patient. III. Treatment of Giant Cell Arteritis (GCA) [0054] Provided herein is a method of treating GCA with the selective JAK1 inhibitor, upadacitinib. The method generally comprises orally administering the upadacitinib to the patient daily for a period of time. [0055] The presence of GCA in a patient may be determined by various clinical observations or imaging techniques. These include the presence of symptoms, indicative lab results, biopsy, angiography, or imaging via MRI or the like. In some embodiments, a patient with GCA exhibits a history of erythrocyte sedimentation rate (ESR) >= 50 mm/hour. In some embodiments, a patient with GCA exhibits a history of high sensitivity C-reactive protein (hsCRP)/CRP >=1.0 mg/dL. In some embodiments, a patient with GCA exhibits unequivocal cranial symptoms of GCA such as pain and tenderness affecting both temples, headaches, scalp tenderness, jaw pain, and visual disturbances. In some embodiments, a patient with GCA has polymyalgia rheumatica (PMR). In -8- ^{WBD (US) 4862-1739-3843v3} some embodiments, a patient with GCA has undergone a temporal artery biopsy which revealed features of GCA. In some embodiments, the patient with GCA has evidence of large vessel vasculitis by angiography or cross-sectional imaging. [0056] In some embodiments, the patient has active GCA. In some embodiments, the patient has relapsing GCA. [0057] In some embodiments, the patient has not received any interleukin-6 (IL-6) inhibitor within 4 weeks prior to initiating the treatment or has not had a disease flare during prior treatment with an IL-6 inhibitor. In some embodiments, the patient has not received the IL-6 inhibitor Tocilizumab (Actemra®) within 4 weeks prior to initiating the treatment or has not had a disease flare during prior treatment with Tocilizumab. In some embodiments, the patient has not received a Janus Kinase (JAK) inhibitor prior to initiating the treatment. In some embodiments, the patient has not received the interleukin-1 receptor antagonist (IL-1Ra) anakinra (KINERET®) within 1 week prior to initiating the treatment. In some embodiments, the patient has not received methotrexate, hydroxychloroquine, cyclosporine, azathioprine, or mycophenolate within 4 weeks prior to initiating the treatment. In some embodiments, the patient has not received leflunomide within 8 weeks prior to initiating the treatment if no elimination procedure was followed. In some embodiments, the patient has not received cell-depleting agents or alkylating agents, including but not limited to cyclophosphamide, within 6 months prior to initiating the treatment. [0058] In some embodiments, the patient does not have and has not previously had herpes zoster, herpes simplex, or human immunodeficiency virus (HIV). In some embodiments, the patient does not have active tuberculosis, an active or chronic recurring infection, or active hepatitis B or C. [0059] GCA affects adults only, and generally those 50 years of age or older. Typically, patients develop signs and symptoms between the ages of 70 and 80. Accordingly, in some embodiments, the patient is 50 years old or older, such as about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, or about 90. [0060] In some embodiments, the dose is orally administered once daily in an amount of 7.5 mg. In some embodiments, the dose is orally administered once daily in an amount of 15 mg. In some embodiments, the administration is continued at the same dose and dosing frequency over a treatment period. [0061] In some embodiments, the patient with GCA is receiving, at the time of initiating the treatment, an oral corticosteroid such as prednisone. In some embodiments, the patient is receiving at least 20 mg of oral corticosteroid as a once daily dose. In some embodiments, the patient is receiving 20 mg, 30 mg, 40 mg, 50 mg, or 60 mg as a once daily oral dose. In some embodiments, the method further comprises tapering down the dose of corticosteroid during the period the patient -9- ^{WBD (US) 4862-1739-3843v3} is treated with upadacitinib. In some embodiments, the oral corticosteroid is tapered down according to the 26-week CS taper regimen in Table 1. In some embodiments, the oral corticosteroid is tapered down according to the 52-week CS taper regimen in Table 1. In some embodiments, the dose of the oral corticosteroid is tapered down to 0 mg over 26 weeks. [0062] The duration of the treatment period may vary. For example, the treatment period may be at least one month, such as 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 5 years, 10 years, 20 years, 50 years, or more. In some embodiments, the treatment period is 12 weeks. In some embodiments, the treatment period is 26 weeks. In some embodiments, the treatment period is 52 weeks. In some embodiments, the treatment period is at least 12 weeks, at least 26 weeks, or at least 52 weeks. [0063] In some embodiments, the complete remission is sustained through week 52 after the first daily administration. [0064] In some embodiments, the patient achieves a reduction in cumulative exposure to corticosteroids through week 52 after the first daily administration, relative to a patient that has not been treated with upadacitinib. [0065] In some embodiments, the patient achieves an increase in time to disease flare through week 52 after the first daily administration, relative to a patient that has not been treated with upadacitinib. As used herein, the term "disease flare" means recurrence of GCA signs or symptoms or an erythrocyte sedimentation rate (ESR) measurement > 30 mm/hr (attributable to GCA); and which requires an increase in corticosteroid dose. In some embodiments, the patient achieves a reduction in a number of disease flares through week 52 after the first daily administration, relative to a patient that has not been treated with upadacitinib. [0066] In some embodiments, the patient achieves, relative to a patient that has not been treated with upadacitinib, a positive change from baseline in a 36-item Short Form Quality of Life Questionnaire (SF-36) Physical Component Score (PCS). The SF-36 is a generic health-related quality-of-life instrument that can be used across age, disease and treatment groups and includes 8 domains: physical functioning, role limitations due to physical health problems, role limitations due to emotional health problems, social functioning, pain, energy/fatigue, emotional well-being, and general health problems. [0067] In some embodiments, the patient achieves, relative to a patient that has not been treated with upadacitinib, a positive change from baseline in a Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue). The FACIT-Fatigue is a 13-item electronic-patient reported outcome (ePRO) measure of fatigue, which has been validated in the general population and in other chronic diseases. The FACIT-Fatigue content and measurement validity and related -10- ^{WBD (US) 4862-1739-3843v3} reliability has been extensively tested in the psoriatic arthritis (PsA) population, with evidence of reliability, construct validity, and responsiveness. [0068] In some embodiments, the patient achieves, relative to a patient that has not been treated with upadacitinib, a positive change from baseline in an Assessment of Treatment Satisfaction Questionnaire for Medication (TSQM) Patient Global Satisfaction Subscale. The Treatment Satisfaction Questionnaire for Medications (TSQM) is a generic ePRO measure of treatment satisfaction, developed to compare treatment satisfaction between medication types and conditions. TSQM comprises of 14 items to assess 4 domains (effectiveness, side effects, convenience, and global satisfaction). The TSQM items are rated on a Likert scale (1 = extremely dissatisfied to 7 = extremely satisfied). Scores for each of the 4 domains range from 0 to 100, with higher scores corresponding to higher satisfaction. IV. Pharmaceutical Composition [0069] Upadacitinib can be administered to a human patient by itself or in pharmaceutical composition where it is mixed with pharmaceutically acceptable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. [0070] In some embodiments, the pharmaceutical composition is a tablet dosage form. In some embodiments, the tablet is a controlled-release formulation, such as an extended-release tablet dosage form (also referred to herein as a modified release or sustained release formulation). Examples of solid dosage forms comprising upadacitinib may be found in International Patent Application Publication No. WO2017/066775, which is hereby incorporated by reference in its entirety. EXEMPLIFICATION Example 1: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Upadacitinib in Subjects with Giant Cell Arteritis [0071] This was a Phase 3, three-arm, two-period study to evaluate the efficacy, safety, and tolerability of upadacitinib in subjects with Giant Cell Arteritis (GCA) who were 50 years of age or older. The study included a 35-day maximum screening period, a 52-week randomized, double- blind, PBO-controlled treatment period (Period 1), a 52-week blinded extension period in which subjects were either re-randomized or continued their original treatment assignment (Period 2), and a 30-day follow-up period. The objective of the first period was to evaluate the efficacy of -11- ^{WBD (US) 4862-1739-3843v3} upadacitinib in combination with a 26-week corticosteroid (CS) taper regimen compared to placebo in combination with a 52-week CS taper regimen, as measured by the proportion of participants in sustained remission at Week 52, and to assess the safety and tolerability of upadacitinib in participants with giant cell arteritis (GCA). The objective of the second period was to evaluate the safety and efficacy of continuing versus withdrawing upadacitinib in maintaining remission in participants who achieved sustained remission in Period 1. A schematic of the study is shown in FIG.1. Each arm of the study is described below in Table 2. Table 2. Treatment Groups [0072] In Period 1, a total of 428 subjects were randomized in a 2:1:1 ratio at Baseline to upadacitinib 15 mg once daily (QD), upadacitinib 7.5 mg QD, and placebo (PBO) QD treatment groups, and dosed, where the upadacitinib 15 mg and 7.5 mg treatment groups were required to complete a mandatory 26-week corticosteroid (CS) taper, and the PBO group were required to complete a mandatory 52-week CS taper. At the end of Period 1 (Week 52 visit), subjects who achieved sustained remission for at least 24 consecutive weeks prior to Week 52 visit were re- randomized in 2:1 ratio to either continue on the same upadacitinib treatment group or switch to PBO if subject was on a upadacitinib treatment group in Period 1; or continued to receive PBO if subject was on PBO group in Period 1. Subjects who had absence of GCA signs and symptoms AND were CS-free at Week 52 visit but did not meet the sustained remission criteria for at least -12- ^{WBD (US) 4862-1739-3843v3} 24 consecutive weeks prior to Week 52 visit continued in Period 2 on their originally randomized treatment assignment in Period 1. All other subjects were discontinued from study drug and study at the end of Period 1. Inclusion Criteria [0073] Inclusion criteria were as follows: ^• Diagnosis of giant cell arteritis (GCA) according to the following criteria: o History of erythrocyte sedimentation rate (ESR) >= 50 mm/hour or high sensitivity C-reactive protein (hsCRP)/CRP >=1.0 mg/dL o Presence of at least one of the following: Unequivocal cranial symptoms of GCA or Unequivocal symptoms of polymyalgia rheumatica (PMR) o Presence of at least one of the following: temporal artery biopsy revealing features of GCA or evidence of large vessel vasculitis by angiography or cross-sectional imaging such as ultrasound, magnetic resonance imaging (MRI), computed tomography (CT) or positron emission tomography (PET). • Active GCA, either new onset or relapsing, within 8 weeks of Baseline. ^• Clinically stable CGA to allow the participant to safely initiate the corticosteroid (CS) taper regimen in Table 1. • Participants must have received treatment with >=40 mg prednisone (or equivalent) at any time prior to Baseline and be receiving prednisone (or equivalent) >= 20 mg once daily (QD) at Baseline. Exclusion Criteria [0074] Exclusion criteria were as follows: ^• Prior exposure to any Janus Kinase (JAK) inhibitor. • Treatment with an interleukin-6 (IL-6) inhibitor within 4 weeks of study start, or prior treatment with an IL-6 inhibitor and experienced a disease flare during treatment. ^• Use of any of the following systemic immunosuppressant treatments within the specified timeframe prior to study start: o Anakinra within 1 week of study start; o Methotrexate, hydroxychloroquine, cyclosporine, azathioprine, or mycophenolate within 4 weeks of study start; o Oral corticosteroid (CS) for conditions other than GCA within 4 weeks of study start, or intravenous CS within 4 weeks of study start; -13- ^{WBD (US) 4862-1739-3843v3} o Greater than or equal to 8 weeks for leflunomide if no elimination procedure was followed, or adhere to an elimination procedure; o Cell-depleting agents or alkylating agents including cyclophosphamide within 6 months of study start; • Current or past history of infection including herpes zoster or herpes simplex, human immunodeficiency virus (HIV), active Tuberculosis, active or chronic recurring infection, active hepatitis B or C. Primary Outcome Measure [0075] The primary outcome measure was the percentage of participants achieving sustained remission from Week 12 through Week 52. Sustained remission was defined as having achieved absence of GCA signs and symptoms and adherence to the corticosteroid (CS) taper regimen in Table 1. Secondary and Other Outcome Measures [0076] The secondary outcome measure was the percentage of participants achieving sustained complete remission. Sustained complete remission was defined as having absence of GCA signs and symptoms; normalization of erythrocyte sedimentation rate (ESR); Normalization of high sensitivity C-reactive protein (hs-CRP), and adherence to the CS taper regimen in Table 1. Other outcome measures included: • Cumulative Corticosteroid (CS) exposure. The cumulative exposure to corticosteroid(s) was assessed. • Time to First Disease Flare. Disease flare was defined as an event determined by the investigator to represent recurrence of GCA signs or symptoms or an ESR measurement > 30 mm/hr (attributable to GCA) AND requiring an increase in CS dose. • Number of Disease Flares per Participant. The number of disease flares per participant during Period 1 was assessed. • Percentage of Participants Who Experience at Least 1 Disease Flare. The percentage of participants who experienced at least 1 disease flare was assessed. • Percentage of Participants in Complete Remission. Complete remission was defined as having achieved absence of GCA signs and symptoms; normalization of ESR; normalization of hs-CRP and adherence to the CS taper regimen in Table 1. • Change from Baseline in the 36-item Short Form Quality of Life Questionnaire (SF-36) Physical Component Score (PCS). -14- ^{WBD (US) 4862-1739-3843v3} • Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue). • Assessment of Treatment Satisfaction Questionnaire for Medication (TSQM) Patient Global Satisfaction Subscale. • Rate of CS-related Adverse Events. The rate of CS-related adverse events was assessed. Results Demographic, Baseline Characteristics, and Subject Disposition [0077] A total of 428 subjects were randomized and dosed (112 in PBO, 107 in upadacitinib 7.5 mg and 209 in upadacitinib 15 mg). In Period 1, 299 (69.9%) subjects completed study drug (Table 3). The rate of premature discontinuation from study drug was higher in the PBO group (36.6%) than in the upadacitinib 7.5 mg (31.8%) and upadacitinib 15 mg (25.8%) groups. The most common reason for study drug premature discontinuation was due to adverse event, followed by lack of efficacy. Demographics and baseline characteristics were generally balanced among treatment groups (Table 4). Table 3. Subject Disposition in the Period 1 (Population: Full Analysis Set 1 (FAS1)) Table 4. Demographics and Baseline Disease Characteristics (Population: FAS1) -15- ^{WBD (US) 4862-1739-3843v3} Efficacy Primary and Secondary Efficacy Endpoints [0078] The primary endpoint and secondary endpoints were tested for each upadacitinib treatment group (15 mg or 7.5 mg) vs. placebo. Graphical depictions of efficacy are provided in FIGS.2, 3, 4A, 4B, 5A, 5B, 6, and 7. Based on the alpha-spending approach, upadacitinib 15 mg met the primary endpoint (sustained remission from Week 12 through Week 52; upadacitinib 15 mg: 46.4% vs. PBO: 29.0%, p=0.0019). Upadacitinib 15 mg also achieved 9 of the 11 secondary endpoints (Table 5). Numerically better efficacy was observed in the upadacitinib 7.5 mg treatment group; however, none of the endpoints achieved statistical significance (Table 5). Under type-I error control using the graphical approach for Japan PMDA, upadacitinib 15 mg met the primary endpoint but did not achieve any of the secondary endpoints (Table 6). Upadacitinib 7.5 mg did not meet the primary or any of the secondary endpoints. The efficacy of upadacitinib 15 mg was in general consistent across pre-specified subgroups, with treatment differences in favor of upadacitinib 15 mg. -16- ^{WBD (US) 4862-1739-3843v3} Table 5. Overview of Primary and Secondary Endpoints under type-I error control for global except PMDA (Population: FAS1) -17- ^{WBD (US) 4862-1739-3843v3 &}Diff: stratum-adjusted treatment difference; HR: hazard ratio; OR: odds ratio; RR: rate ratio. * Percentage for categorical endpoints, least squares mean for continuous endpoints (except for cumulative CS exposure), median for cumulative CS exposure and time to first disease flare, and mean number of events per subject per patient-year for number of disease flares and rate of CS- related AEs. ^S/NS: Achieved/not achieved statistical significance according to the pre-specified testing strategy for overall type-I error control. Table 6. Overview of Primary and Secondary Endpoints under Type-I Error Control for PMDA (Population: FAS1) -18- ^{WBD (US) 4862-1739-3843v3} &Diff: stratum-adjusted treatment difference; HR: hazard ratio; OR: odds ratio; RR: rate ratio. Pharmacokinetics and Preliminary Exposure-Response Analyses for Efficacy Pharmacokinetics [0079] The pharmacokinetics of upadacitinib in subjects with GCA were consistent with prior assessments in subjects with rheumatoid arthritis (RA). The median upadacitinib average plasma concentration for the 7.5 mg and 15 mg treatment groups were 7.9 ng/mL and 15.7 ng/mL, respectively. Preliminary Exposure-Response Analyses for Efficacy [0080] There was a clear trend for increase in response for both sustained remission and sustained complete remission from Week 12 through Week 52 with increasing upadacitinib plasma exposures, with the highest response observed in the highest quartile of exposures (FIGS.4A and 5A). A linear model with a clear exposure-response relationship (nominal p < 0.01) was selected as the optimal model to describe both endpoints (FIGS.4B and 5B). Simulations based on the logistic regression models showed that upadacitinib 15 mg is predicted to provide 9% and 10% higher efficacy compared to upadacitinib 7.5 mg for sustained remission and sustained complete remission, respectively. Safety -19- ^{WBD (US) 4862-1739-3843v3} [0081] Both upadacitinib treatment groups were generally safe and well-tolerated in subjects with GCA. No new safety signals were identified with upadacitinib 7.5 mg and 15 mg treatment groups in this GCA population as compared to the safety profile of upadacitinib in previously approved indications. It is notable that no new safety signals were identified with upadacitinib in this trial, which was comprised of an elderly patient population on high dose steroids at Baseline (~50% > 30mg /day) and at higher risk for multiple complications, including but not limited to, major cardiovascular events, malignancy, serious infections, etc. Based upon the overall positive benefit and risk assessment, orally administered upadacitinib 15 mg effectively treated GCA, which is a disease with a high unmet need. -20- ^{WBD (US) 4862-1739-3843v3}

Claims

CLAIMS What is claimed is: 1. A method of treating giant cell arteritis (GCA) in a patient having GCA, the method comprising orally administering once daily to the patient 15 mg of upadacitinib.

2. The method of claim 1, wherein the patient achieves remission of GCA 12 weeks following the first daily administration.

3. The method of claim 2, wherein the patient achieves sustained remission of GCA from 12 weeks following the first daily administration through 52 weeks following the first daily administration.

4. The method of claim 1, wherein the patient achieves complete remission of GCA 12 weeks following the first daily administration.

5. The method of claim 4, wherein the patient achieves sustained complete remission of GCA from 12 weeks following the first daily administration through 52 weeks following the first daily administration.

6. A method of inducing remission of giant cell arteritis (GCA) in a patient having GCA, the method comprising orally administering once daily to the patient 15 mg of upadacitinib.

7. The method of claim 6, wherein the patient achieves remission of GCA 12 weeks following the first daily administration.

8. A method of inducing and sustaining remission of giant cell arteritis (GCA) in a patient having GCA, the method comprising orally administering once daily to the patient 15 mg of upadacitinib.

9. The method of claim 8, wherein the patient achieves remission of GCA 12 weeks following the first daily administration.

10. The method of claim 9, wherein the patient achieves sustained remission of GCA from 12 weeks following the first daily administration through 52 weeks following the first daily administration.

11. A method of inducing complete remission of giant cell arteritis (GCA) in a patient having GCA, the method comprising orally administering once daily to the patient 15 mg of upadacitinib. -21- ^{WBD (US) 4862-1739-3843v3}

12. The method of claim 11, wherein the patient achieves complete remission of GCA 12 weeks following the first daily administration.

13. A method of inducing and sustaining complete remission of giant cell arteritis (GCA) in a patient having GCA, the method comprising orally administering once daily to the patient 15 mg of upadacitinib.

14. The method of claim 13, wherein the patient achieves complete remission of GCA 12 weeks following the first daily administration.

15. The method of claim 14, wherein the patient achieves sustained complete remission of GCA from 12 weeks following the first daily administration through 52 weeks following the first daily administration.

16. The method of any one of claims 1-15, wherein the patient achieves a reduction in cumulative exposure to corticosteroids through week 52 after the first daily administration, relative to a patient that has not been treated with upadacitinib.

17. The method of any one of claims 1-16, wherein the patient achieves an increase in time to disease flare through week 52 after the first daily administration, relative to a patient that has not been treated with upadacitinib.

18. The method of any one of claims 1-17, wherein the patient achieves a reduction in a number of disease flares through week 52 after the first daily administration, relative to a patient that has not been treated with upadacitinib.

19. The method of any one of claims 1-18, wherein the patient achieves, relative to a patient that has not been treated with upadacitinib, one or more of the following: a positive change from baseline in a 36-item Short Form Quality of Life Questionnaire (SF- 36) Physical Component Score (PCS); a positive change from baseline in a Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-Fatigue); a positive change from baseline in an Assessment of Treatment Satisfaction Questionnaire for Medication (TSQM) Patient Global Satisfaction Subscale.

20. The method of any one of claims 1-20, wherein the patient is currently receiving at least 20 mg oral corticosteroid once daily at the time of the first daily administration.

21. The method of any one of claims 1-20, wherein the method further comprises tapering a dose of the oral corticosteroid over a period of 26 weeks. -22- ^{WBD (US) 4862-1739-3843v3}

22. The method of any one of claims 1-21, wherein the patient has: a history of erythrocyte sedimentation rate (ESR) >= 50 mm/hour or high sensitivity C- reactive protein (hsCRP)/CRP >=1.0 mg/dL; unequivocal cranial symptoms of GCA, unequivocal symptoms of polymyalgia rheumatica (PMR), or both; a temporal artery biopsy revealing features of GCA, evidence of large vessel vasculitis by angiography or cross-sectional imaging, or both; active GCA, either new onset or relapsing, within 8 weeks prior to the first administration; and clinically stable GCA.

23. The method of any one of claims 1-22, wherein the patient has not received any Janus Kinase (JAK) inhibitor within 4 weeks prior to initiating the method.

24. The method of any one of claims 1-23, wherein the patient has not received any interleukin- 6 (IL-6) inhibitor within 4 weeks prior to initiating the treatment or has not had a disease flare during prior treatment with an IL-6 inhibitor.

25. The method of any one of claims 1-24, wherein the patient has not received: anakinra within 1 week prior to initiating the treatment; methotrexate, hydroxychloroquine, cyclosporine, azathioprine, or mycophenolate within 4 weeks prior to initiating the treatment; greater than or equal to 8 weeks for leflunomide if no elimination procedure was followed; and cell-depleting agents or alkylating agents including cyclophosphamide within 6 months prior to initiating the treatment.

26. The method of any one of claims 1-25, wherein the patient is 50 years of age or older with new-onset or relapsing GCA.

27. The method of any one of claims 1-26, wherein the patient does not have and has not previously had herpes zoster, herpes simplex, or human immunodeficiency virus (HIV).

28. The method of any one of claims 1-27, wherein the patient does not have active tuberculosis, an active or chronic recurring infection, or active hepatitis B or C. -23- ^{WBD (US) 4862-1739-3843v3}