RINVOQ 45mg prolonged tablets medication leaflet

RINVOQ 45 mg prolonged-release tablets

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15 mg of upadacitinib.

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg of upadacitinib.

RINVOQ 45 mg prolonged-release tablets

Each prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 45 mg of upadacitinib.

For the full list of excipients, see section 6.1.

Prolonged-release tablet

Purple 14 x 8 mm, oblong biconvex prolonged-release tablets imprinted on one side with ‘a15’.

Red 14 x 8 mm, oblong biconvex prolonged-release tablets imprinted on one side with ‘a30’.

RINVOQ 45 mg prolonged-release tablets

Yellow to mottled yellow 14 x 8 mm, oblong biconvex prolonged-release tablets imprinted on one sidewith ‘a45’.

RINVOQ is indicated for the treatment of moderate to severe active rheumatoid arthritis in adultpatients who have responded inadequately to, or who are intolerant to one or more disease-modifyinganti-rheumatic drugs (DMARDs). RINVOQ may be used as monotherapy or in combination withmethotrexate.

RINVOQ is indicated for the treatment of active psoriatic arthritis in adult patients who haveresponded inadequately to, or who are intolerant to one or more DMARDs. RINVOQ may be used asmonotherapy or in combination with methotrexate.

Non-radiographic axial spondyloarthritis (nr-axSpA)

RINVOQ is indicated for the treatment of active non-radiographic axial spondyloarthritis in adultpatients with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/ormagnetic resonance imaging (MRI), who have responded inadequately to nonsteroidal anti-inflammatory drugs (NSAIDs).

Ankylosing spondylitis (AS, radiographic axial spondyloarthritis)

RINVOQ is indicated for the treatment of active ankylosing spondylitis in adult patients who haveresponded inadequately to conventional therapy.

Giant cell arteritis

RINVOQ is indicated for the treatment of giant cell arteritis in adult patients.

RINVOQ is indicated for the treatment of moderate to severe atopic dermatitis in adults andadolescents 12 years and older who are candidates for systemic therapy.

RINVOQ is indicated for the treatment of adult patients with moderately to severely active ulcerativecolitis who have had an inadequate response, lost response or were intolerant to either conventionaltherapy or a biologic agent.

RINVOQ is indicated for the treatment of adult patients with moderately to severely active Crohn’sdisease who have had an inadequate response, lost response or were intolerant to either conventionaltherapy or a biologic agent.

Treatment with upadacitinib should be initiated and supervised by physicians experienced in thediagnosis and treatment of conditions for which upadacitinib is indicated.

Rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis

The recommended dose of upadacitinib is 15 mg once daily.

Consideration should be given to discontinuing treatment in patients with axial spondyloarthritis whohave shown no clinical response after 16 weeks of treatment. Some patients with initial partialresponse may subsequently improve with continued treatment beyond 16 weeks.

Giant cell arteritis

The recommended dose of upadacitinib is 15 mg once daily in combination with a tapering course ofcorticosteroids. Upadacitinib monotherapy should not be used for the treatment of acute relapses (seesection 4.4).

Based upon the chronic nature of giant cell arteritis, upadacitinib 15 mg once daily can be continued asmonotherapy following discontinuation of corticosteroids. Treatment beyond 52 weeks should beguided by disease activity, physician discretion, and patient choice.

The recommended dose of upadacitinib is 15 mg or 30 mg once daily based on individual patientpresentation.

* A dose of 15 mg is recommended for patients at higher risk of venous thromboembolism(VTE), major adverse cardiovascular events (MACE) and malignancy (see section 4.4).

* A dose of 30 mg once daily may be appropriate for patients with high disease burden who arenot at higher risk of VTE, MACE and malignancy (see section 4.4) or patients with aninadequate response to 15 mg once daily.

* In adolescents (12 to 17 years of age) weighing at least 30 kg, a dose of 15 mg is recommended.

If the patient does not respond adequately to 15 mg once daily, the dose can be increased to30 mg once daily.

* The lowest effective dose to maintain response should be used.

For patients 65 years of age and older, the recommended dose is 15 mg once daily (see section 4.4).

Upadacitinib can be used with or without topical corticosteroids. Topical calcineurin inhibitors may beused for sensitive areas such as the face, neck, and intertriginous and genital areas.

Consideration should be given to discontinuing upadacitinib treatment in any patient who shows noevidence of therapeutic benefit after 12 weeks of treatment.

Induction

The recommended induction dose of upadacitinib is 45 mg once daily for 8 weeks. For patients whodo not achieve adequate therapeutic benefit by week 8, upadacitinib 45 mg once daily may becontinued for an additional 8-week period (see section 5.1). Upadacitinib should be discontinued inany patient who shows no evidence of therapeutic benefit by week 16.

Maintenance

The recommended maintenance dose of upadacitinib is 15 mg or 30 mg once daily based on individualpatient presentation:

* A dose of 15 mg is recommended for patients at higher risk of VTE, MACE andmalignancy (see section 4.4).

* A dose of 30 mg once daily may be appropriate for some patients, such as those with highdisease burden or requiring 16-week induction treatment who are not at higher risk of VTE,

MACE and malignancy (see section 4.4) or who do not show adequate therapeutic benefit to15 mg once daily.

* The lowest effective dose to maintain response should be used.

For patients 65 years of age and older, the recommended dose is 15 mg once daily (see section 4.4).

In patients who have responded to treatment with upadacitinib, corticosteroids may be reduced and/ordiscontinued in accordance with standard of care.

Induction

The recommended induction dose of upadacitinib is 45 mg once daily for 12 weeks. For patients whohave not achieved adequate therapeutic benefit after the initial 12-week induction, prolonged inductionfor an additional 12 weeks with a dose of 30 mg once daily may be considered. For these patients,upadacitinib should be discontinued if there is no evidence of therapeutic benefit after 24 weeks oftreatment.

Maintenance

The recommended maintenance dose of upadacitinib is 15 mg or 30 mg once daily based on individualpatient presentation:

* A dose of 15 mg is recommended for patients at higher risk of VTE, MACE and malignancy(see section 4.4).

* A dose of 30 mg once daily may be appropriate for patients with high disease burden who arenot at higher risk of VTE, MACE and malignancy (see section 4.4) or who do not showadequate therapeutic benefit to 15 mg once daily.

* The lowest effective dose to maintain response should be used.

For patients 65 years of age and older, the recommended maintenance dose is 15 mg once daily (seesection 4.4).

In patients who have responded to treatment with upadacitinib, corticosteroids may be reduced and/ordiscontinued in accordance with standard of care.

For patients with ulcerative colitis and Crohn’s disease receiving strong inhibitors of cytochrome P450(CYP) 3A4 (e.g., ketoconazole, clarithromycin), the recommended induction dose is 30 mg once dailyand the recommended maintenance dose is 15 mg once daily (see section 4.5).

Treatment should not be initiated in patients with an absolute lymphocyte count (ALC) that is < 0.5 x109 cells/L, an absolute neutrophil count (ANC) that is < 1 x 109 cells/L or who have haemoglobin(Hb) levels that are < 8 g/dL (see sections 4.4 and 4.8).

Treatment should be interrupted if a patient develops a serious infection until the infection iscontrolled.

Interruption of dosing may be needed for management of laboratory abnormalities as described in

Table 1.

Table 1 Laboratory measures and monitoring guidance

Laboratory Action Monitoring guidancemeasure

Treatment should be Evaluate at baseline and then no later than 12 weeksinterrupted if ANC is after initiation of treatment. Thereafter evaluate

Absolute< 1 x 109 cells/L and according to individual patient management.

Neutrophil Countmay be restarted once(ANC)

ANC returns abovethis value

Treatment should beinterrupted if ALC is

Absolute<0.5 x 109 cells/L

Lymphocyteand may be restarted

Count (ALC)once ALC returnsabove this value

Treatment should beinterrupted if Hb is< 8 g/dL and may be

Haemoglobin (Hb)restarted once Hbreturns above thisvalue

Treatment should be Evaluate at baseline and thereafter according totemporarily routine patient management.

Hepaticinterrupted if drug-transaminasesinduced liver injuryis suspected

Patients should be Evaluate 12 weeks after initiation of treatment andmanaged according thereafter according to international clinical

Lipids to international guidelines for hyperlipidaemiaclinical guidelines forhyperlipidaemia

Rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis

There are limited data in patients 75 years of age and older (see section 4.4).

For atopic dermatitis, doses higher than 15 mg once daily are not recommended in patients 65 years ofage and older (see sections 4.4 and 4.8).

Ulcerative colitis and Crohn’s disease

For ulcerative colitis and Crohn’s disease, doses higher than 15 mg once daily for maintenance therapyare not recommended in patients 65 years of age and older (see sections 4.4 and 4.8). The safety andefficacy of upadacitinib in patients 75 years of age and older have not yet been established.

No dose adjustment is required in patients with mild or moderate renal impairment. There are limiteddata on the use of upadacitinib in subjects with severe renal impairment (see section 5.2). Upadacitinibshould be used with caution in patients with severe renal impairment as described in Table 2. The useof upadacitinib has not been studied in subjects with end stage renal disease and is therefore notrecommended for use in these patients.

a

Table 2 Recommended dose for severe renal impairment

Therapeutic indication Recommended once daily dose

Rheumatoid arthritis, psoriatic arthritis, 15 mgaxial spondyloarthritis, giant cell arteritis,atopic dermatitis

Ulcerative colitis, Crohn’s disease Induction: 30 mg

Maintenance: 15 mgaestimated glomerular filtration rate (eGFR) 15 to < 30 ml/min/1.73m2

No dose adjustment is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B)hepatic impairment (see section 5.2). Upadacitinib should not be used in patients with severe (Child-

Pugh C) hepatic impairment (see section 4.3).

The safety and efficacy of RINVOQ in children with atopic dermatitis below the age of 12 years havenot been established. No data are available.

The safety and efficacy of RINVOQ in children and adolescents with rheumatoid arthritis, psoriaticarthritis, axial spondyloarthritis, ulcerative colitis, and Crohn’s disease, aged 0 to less than 18 yearshave not yet been established. No data are available.

There is no relevant use of RINVOQ in the paediatric population in the indication giant cell arteritis.

RINVOQ is to be taken orally once daily with or without food and may be taken at any time of theday. Tablets should be swallowed whole and should not be split, crushed, or chewed in order to ensurethe entire dose is delivered correctly.

* Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

* Active tuberculosis (TB) or active serious infections (see section 4.4).

* Severe hepatic impairment (see section 4.2).

* Pregnancy (see section 4.6).

Upadacitinib should only be used if no suitable treatment alternatives are available in patients:

- 65 years of age and older;

- patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors(such as current or past long-time smokers);

- patients with malignancy risk factors (e.g. current malignancy or history of malignancy)

Use in patients 65 years of age and older

Considering the increased risk of MACE, malignancies, serious infections, and all-cause mortality inpatients 65 years of age and older, as observed in a large randomised study of tofacitinib (another

Janus Kinase (JAK) inhibitor), upadacitinib should only be used in these patients if no suitabletreatment alternatives are available.

In patients 65 years of age and older, there is an increased risk of adverse reactions with upadacitinib30 mg once daily. Consequently, the recommended dose for long-term use in this patient population is15 mg once daily (see sections 4.2 and 4.8).

Combination with other potent immunosuppressants such as azathioprine, 6-mercaptopurine,ciclosporin, tacrolimus, and biologic DMARDs or other JAK inhibitors has not been evaluated inclinical studies and is not recommended as a risk of additive immunosuppression cannot be excluded.

Serious and sometimes fatal infections have been reported in patients receiving upadacitinib. The mostfrequent serious infections reported with upadacitinib included pneumonia (see section 4.8) andcellulitis. Cases of bacterial meningitis and sepsis have been reported in patients receivingupadacitinib. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster,oral/oesophageal candidiasis, and cryptococcosis were reported with upadacitinib.

Upadacitinib should not be initiated in patients with an active, serious infection, including localisedinfections (see section 4.3).

Consider the risks and benefits of treatment prior to initiating upadacitinib in patients:

* with chronic or recurrent infection

* who have been exposed to tuberculosis

* with a history of a serious or an opportunistic infection

* who have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or

* with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection duringand after treatment with upadacitinib. Upadacitinib therapy should be interrupted if a patient developsa serious or opportunistic infection. A patient who develops a new infection during treatment withupadacitinib should undergo prompt and complete diagnostic testing appropriate for animmunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient shouldbe closely monitored, and upadacitinib therapy should be interrupted if the patient is not responding toantimicrobial therapy. Upadacitinib therapy may be resumed once the infection is controlled.

A higher rate of serious infections was observed with upadacitinib 30 mg compared to upadacitinib15 mg.

As there is a higher incidence of infections in the elderly and in the diabetic populations in general,caution should be used when treating the elderly and patients with diabetes. In patients 65 years of ageand older, upadacitinib should only be used if no suitable treatment alternatives are available (seesection 4.2).

Patients should be screened for tuberculosis (TB) before starting upadacitinib therapy. Upadacitinibshould not be given to patients with active TB (see section 4.3). Anti-TB therapy should be consideredprior to initiation of upadacitinib in patients with previously untreated latent TB or in patients with riskfactors for TB infection.

Consultation with a physician with expertise in the treatment of TB is recommended to aid in thedecision about whether initiating anti-TB therapy is appropriate for an individual patient.

Patients should be monitored for the development of signs and symptoms of TB, including patientswho tested negative for latent TB infection prior to initiating therapy.

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), was reported inclinical studies (see section 4.8). The risk of herpes zoster appears to be higher in Japanese patientstreated with upadacitinib. If a patient develops herpes zoster, interruption of upadacitinib therapyshould be considered until the episode resolves.

Screening for viral hepatitis and monitoring for reactivation should be performed before starting andduring therapy with upadacitinib. Patients who were positive for hepatitis C antibody and hepatitis Cvirus RNA were excluded from clinical studies. Patients who were positive for hepatitis B surfaceantigen or hepatitis B virus DNA were excluded from clinical studies. If hepatitis B virus DNA isdetected while receiving upadacitinib, a liver specialist should be consulted.

No data are available on the response to vaccination with live vaccines in patients receivingupadacitinib. Use of live, attenuated vaccines during or immediately prior to upadacitinib therapy isnot recommended. Prior to initiating upadacitinib treatment, it is recommended that patients bebrought up to date with all immunisations, including prophylactic zoster vaccinations, in agreementwith current immunisation guidelines (see section 5.1).

Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, includingupadacitinib.

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoidarthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rateof malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer (NMSC) wasobserved with tofacitinib compared to tumour necrosis factor (TNF) inhibitors.

A higher rate of malignancies was observed with upadacitinib 30 mg compared to upadacitinib 15 mg.

In patients 65 years of age and older, patients who are current or past long-time smokers, or with othermalignancy risk factors (e.g., current malignancy or history of malignancy), upadacitinib should onlybe used if no suitable treatment alternatives are available.

Non-melanoma skin cancer (NMSC)

NMSCs have been reported in patients treated with upadacitinib (see section 4.8). A higher rate of

NMSC was observed with upadacitinib 30 mg compared to upadacitinib 15 mg. Periodic skinexamination is recommended for all patients, particularly those with risk factors for skin cancer.

Absolute Neutrophil Count (ANC) < 1 x 109 cells/L, Absolute Lymphocyte Count (ALC) < 0.5 x 109cells/L and haemoglobin < 8 g/dL were reported in ≤1 % of patients in clinical trials (see section 4.8).

Treatment should not be initiated, or should be temporarily interrupted, in patients with an ANC < 1x 109 cells/L, ALC < 0.5 x 109 cells/L or haemoglobin < 8 g/dL observed during routine patientmanagement (see section 4.2).

Events of diverticulitis and gastrointestinal perforations have been reported in clinical trials and frompost-marketing sources (see section 4.8).

Upadacitinib should be used with caution in patients who may be at risk for gastrointestinalperforation (e.g., patients with diverticular disease, a history of diverticulitis, or who are takingnonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, or opioids). Patients with active

Crohn’s disease are at increased risk for developing intestinal perforation. Patients presenting withnew onset abdominal signs and symptoms should be evaluated promptly for early identification ofdiverticulitis or gastrointestinal perforation.

Major adverse cardiovascular events

Events of MACE were observed in clinical studies of upadacitinib.

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoidarthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rateof MACE, defined as cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke,was observed with tofacitinib compared to TNF inhibitors.

Therefore, in patients 65 years of age and older, patients who are current or past long-time smokers,and patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors,upadacitinib should only be used if no suitable treatment alternatives are available.

Treatment with upadacitinib was associated with dose-dependent increases in lipid parameters,including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein(HDL) cholesterol (see section 4.8). Elevations in LDL cholesterol decreased to pre-treatment levels inresponse to statin therapy, although evidence is limited. The effect of these lipid parameter elevationson cardiovascular morbidity and mortality has not been determined (see section 4.2 for monitoringguidance).

Hepatic transaminase elevations

Treatment with upadacitinib was associated with an increased incidence of liver enzyme elevationcompared to placebo (see section 4.8).

Hepatic transaminases must be evaluated at baseline and thereafter according to routine patientmanagement. Prompt investigation of the cause of liver enzyme elevation is recommended to identifypotential cases of drug-induced liver injury.

If increases in ALT or AST are observed during routine patient management and drug-induced liverinjury is suspected, upadacitinib therapy should be interrupted until this diagnosis is excluded.

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) were observed in clinicaltrials for upadacitinib.

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoidarthritis patients 50 years and older with at least one additional cardiovascular risk factor, adose-dependent higher rate of VTE including DVT and PE was observed with tofacitinib compared to

TNF inhibitors.

In patients with cardiovascular or malignancy risk factors (see also section 4.4 “Major adversecardiovascular events” and “Malignancy”) upadacitinib should only be used if no suitable treatmentalternatives are available.

In patients with known VTE risk factors other than cardiovascular or malignancy risk factors,upadacitinib should be used with caution. VTE risk factors other than cardiovascular or malignancyrisk factors include previous VTE, patients undergoing major surgery, immobilisation, use ofcombined hormonal contraceptives or hormone replacement therapy, and inherited coagulationdisorder. Patients should be re-evaluated periodically during upadacitinib treatment to assess forchanges in VTE risk. Patients with signs and symptoms of VTE should be promptly evaluated andtreatment should be discontinued in patients with suspected VTE, regardless of dose.

Retinal vein occlusion

Retinal vein occlusion has been reported in patients treated with JAK inhibitors, including upadacitinib.

Patients should be advised to promptly seek medical care in case they experience symptoms suggestiveof retinal vein occlusion.

Serious hypersensitivity reactions such as anaphylaxis and angioedema have been reported in patientsreceiving upadacitinib. If a clinically significant hypersensitivity reaction occurs, treatment withupadacitinib must be discontinued and appropriate therapy must be instituted (see sections 4.3 and4.8).

Hypoglycaemia in patients treated for diabetes

There have been reports of hypoglycaemia following initiation of JAK inhibitors, includingupadacitinib, in patients receiving treatment for diabetes. Dose adjustment of anti-diabetic medicinalproducts may be necessary in the event that hypoglycaemia occurs.

Medication Residue in Stool

Reports of medication residue in stool or ostomy output have occurred in patients taking upadacitinib.

Most reports described anatomic (e.g., ileostomy, colostomy, intestinal resection) or functionalgastrointestinal conditions with shortened gastrointestinal transit times. Patients should be instructed tocontact their healthcare professional if medication residue is observed repeatedly. Patients should beclinically monitored, and alternative treatment should be considered if there is an inadequatetherapeutic response.

Giant Cell Arteritis

Upadacitinib monotherapy should not be used for the treatment of acute relapses as efficacy in thissetting has not been established. Corticosteroids should be given according to medical judgement andpractice guidelines.

Potential for other medicinal products to affect the pharmacokinetics of upadacitinib

Upadacitinib is metabolised mainly by CYP3A4. Therefore, upadacitinib plasma exposures can beaffected by medicinal products that strongly inhibit or induce CYP3A4.

Co-administration with CYP3A4 inhibitors

Upadacitinib exposure is increased when co-administered with strong CYP3A4 inhibitors (such asketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, and grapefruit). In a clinicalstudy, co-administration of upadacitinib with ketoconazole resulted in 70% and 75% increases inupadacitinib Cmax and AUC, respectively. Upadacitinib 15 mg once daily should be used with cautionin patients receiving chronic treatment with strong CYP3A4 inhibitors. Upadacitinib 30 mg once dailydose is not recommended for patients with atopic dermatitis receiving chronic treatment with strong

CYP3A4 inhibitors. For patients with ulcerative colitis or Crohn’s disease using strong CYP3A4inhibitors, the recommended induction dose is 30 mg once daily and the recommended maintenancedose is 15 mg once daily (see section 4.2). Alternatives to strong CYP3A4 inhibitors should beconsidered when used in the long-term. Food or drink containing grapefruit should be avoided duringtreatment with upadacitinib.

Co-administration with CYP3A4 inducers

Upadacitinib exposure is decreased when co-administered with strong CYP3A4 inducers (such asrifampin and phenytoin), which may lead to reduced therapeutic effect of upadacitinib. In a clinicalstudy, co-administration of upadacitinib after multiple doses of rifampicin (strong CYP3A inducer)resulted in approximately 50% and 60% decreases in upadacitinib Cmax and AUC, respectively.

Patients should be monitored for changes in disease activity if upadacitinib is co-administered withstrong CYP3A4 inducers.

Methotrexate and pH modifying medicinal products (e.g., antacids or proton pump inhibitors) have noeffect on upadacitinib plasma exposures.

Potential for upadacitinib to affect the pharmacokinetics of other medicinal products

Administration of multiple 30 mg or 45 mg once daily doses of upadacitinib to healthy subjects had alimited effect on midazolam (sensitive substrate for CYP3A) plasma exposures (24-26% decrease inmidazolam AUC and Cmax), indicating that upadacitinib 30 mg or 45 mg once daily may have a weakinduction effect on CYP3A. In a clinical study, rosuvastatin and atorvastatin AUC were decreased by33% and 23%, respectively, and rosuvastatin Cmax was decreased by 23% following the administrationof multiple 30 mg once daily doses of upadacitinib to healthy subjects. Upadacitinib had no relevanteffect on atorvastatin Cmax or on plasma exposures of ortho-hydroxyatorvastatin (major activemetabolite for atorvastatin). Administration of multiple 45 mg once daily doses of upadacitinib tohealthy subjects led to a limited increase in AUC and Cmax of dextromethorphan (sensitive CYP2D6substrate) by 30% and 35%, respectively, indicating that upadacitinib 45 mg once daily has a weakinhibitory effect on CYP2D6. No dose adjustment is recommended for CYP3A substrates, CYP2D6substrates, rosuvastatin or atorvastatin when co-administered with upadacitinib.

Upadacitinib has no relevant effects on plasma exposures of ethinylestradiol, levonorgestrel,methotrexate, or medicinal products that are substrates for metabolism by CYP1A2, CYP2B6,

CYP2C9, or CYP2C19.

Women of childbearing potential have to use effective contraception during treatment and for 4 weeksfollowing the final dose of upadacitinib. Female paediatric patients and/or their parents/caregiversshould be informed about the need to contact the treating physician once the patient experiencesmenarche while taking upadacitinib.

There are no or limited data on the use of upadacitinib in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). Upadacitinib was teratogenic in rats and rabbits witheffects in bones in rat foetuses and in the heart in rabbit foetuses when exposed in utero.

Upadacitinib is contraindicated during pregnancy (see section 4.3).

If a patient becomes pregnant while taking upadacitinib the parents should be informed of the potentialrisk to the foetus.

It is unknown whether upadacitinib/metabolites are excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in milk (seesection 5.3).

A risk to newborns/infants cannot be excluded.

Upadacitinib should not be used during breast-feeding. A decision must be made whether todiscontinue breast-feeding or to discontinue upadacitinib therapy taking into account the benefit ofbreast-feeding for the child and the benefit of therapy for the woman.

The effect of upadacitinib on human fertility has not been evaluated. Animal studies do not indicateeffects with respect to fertility (see section 5.3).

Upadacitinib may have a minor influence on the ability to drive and use machines because dizzinessand vertigo may occur during treatment with RINVOQ (see section 4.8).

In the placebo-controlled clinical trials for rheumatoid arthritis, psoriatic arthritis, and axialspondyloarthritis, the most commonly reported adverse reactions (≥2% of patients in at least one of theindications with the highest rate among indications presented) with upadacitinib 15 mg were upperrespiratory tract infections (19.5%), blood creatine phosphokinase (CPK) increased (8.6%), alaninetransaminase increased (4.3%), bronchitis (3.9%), nausea (3.5%), neutropenia (2.8%), cough (2.2%),aspartate transaminase increased (2.2%), and hypercholesterolaemia (2.2%).

In the placebo-controlled atopic dermatitis clinical trials, the most commonly reported adversereactions (≥2% of patients) with upadacitinib 15 mg or 30 mg were upper respiratory tract infection(25.4%), acne (15.1%), herpes simplex (8.4%), headache (6.3%), blood CPK increased (5.5%), cough(3.2%), folliculitis (3.2%), abdominal pain (2.9%), nausea (2.7%), neutropenia (2.3%), pyrexia(2.1%), and influenza (2.1%).

In the placebo-controlled ulcerative colitis and Crohn’s disease induction and maintenance clinicaltrials, the most commonly reported adverse reactions (≥3% of patients) with upadacitinib 45 mg,30 mg or 15 mg were upper respiratory tract infection (19.9%), pyrexia (8.7%), blood CPK increased(7.6%), anaemia (7.4%), headache (6.6%), acne (6.3%), herpes zoster (6.1%), neutropenia (6.0%),rash (5.2%), pneumonia (4.1%), hypercholesterolemia (4.0%), bronchitis (3.9%), aspartatetransaminase increased (3.9%), fatigue (3.9%), folliculitis (3.6%), alanine transaminase increased(3.5%), herpes simplex (3.2%), and influenza (3.2%).

The most common serious adverse reactions were serious infections (see section 4.4).

The safety profile of upadacitinib with long-term treatment was generally similar to the safety profileduring the placebo-controlled period across indications.

The following list of adverse reactions is based on experience from clinical studies and post-marketingexperience. The frequency of adverse reactions listed below is defined using the following convention:

very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100). Thefrequencies in Table 3 are based on the higher of the rates for adverse reactions reported with

RINVOQ in clinical trials of rheumatologic disease (15 mg), atopic dermatitis (15 mg and 30 mg),ulcerative colitis (15 mg, 30 mg and 45 mg), or Crohn’s disease (15 mg, 30 mg, and 45 mg). Whennotable differences in frequency were observed between indications, these are presented in thefootnotes below the table.

Table 3 Adverse reactions

System Organ Class Very common Common Uncommon

Infections and Upper respiratory Bronchitisa,b Oral candidiasisinfestations tract infections Herpes zostera Diverticulitis(URTI)a Herpes simplexa Sepsis

Folliculitis

Influenza

Pneumoniaa,h

Neoplasms benign, Non-melanoma skinmalignant and cancerfunspecified (includingcysts and polyps)

Blood and lymphatic Anaemiaasystem disorders Neutropeniaa

Lymphopenia

Immune system Urticariac,g Serious hypersensitivitydisorders reactionsa,e

Metabolism and Hypercholesterolaemiaa,b Hypertriglyceridaemianutrition disorders Hyperlipidaemiaa,b

Nervous system Headachea,jdisorders Dizziness

Ear and labyrinth Vertigoadisorders

Respiratory, thoracic Coughand mediastinaldisorders

Gastrointestinal Abdominal paina Gastrointestinaldisorders Nausea perforationi

Skin and subcutaneous Acnea,c,d,g Rashatissue disorders

General disorders and Fatigueadministration site Pyrexiaconditions Peripheral oedemaa,k

Investigations Blood CPK increased

ALT increasedb

AST increasedb

Weight increasedga Presented as grouped termb In atopic dermatitis trials, the frequency of bronchitis, hypercholesterolaemia, hyperlipidaemia, ALTincreased, and AST increased was uncommon.c In rheumatologic disease trials, the frequency was common for acne and uncommon for urticaria.d In ulcerative colitis trials, the frequency was common for acne.e Serious hypersensitivity reactions including anaphylactic reaction and angioedemaf Most events reported as basal cell carcinoma and squamous cell carcinoma of sking In Crohn’s disease, the frequency was common for acne, and uncommon for urticaria and weightincreased.h Pneumonia was common in Crohn’s disease and uncommon across other indications.i Frequency is based on Crohn’s disease clinical trials.j Headache was very common in the giant cell arteritis trial.k Frequency is based on the giant cell arteritis trial.

In placebo-controlled clinical studies with background DMARDs, the frequency of infection over12/14 weeks in the upadacitinib 15 mg group was 27.4% compared to 20.9% in the placebo group. Inmethotrexate (MTX)-controlled studies, the frequency of infection over 12/14 weeks in theupadacitinib 15 mg monotherapy group was 19.5% compared to 24.0% in the MTX group. The overalllong-term rate of infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies(2 630 patients) was 93.7 events per 100 patient-years.

In placebo-controlled clinical studies with background DMARDs, the frequency of serious infectionover 12/14 weeks in the upadacitinib 15 mg group was 1.2% compared to 0.6% in the placebo group.

In MTX-controlled studies, the frequency of serious infection over 12/14 weeks in the upadacitinib15 mg monotherapy group was 0.6% compared to 0.4% in the MTX group. The overall long-term rateof serious infections for the upadacitinib 15 mg group across all five Phase 3 clinical studies was 3.8events per 100 patient-years. The most common serious infection was pneumonia. The rate of seriousinfections remained stable with long-term exposure.

Opportunistic infections (excluding tuberculosis)

In placebo-controlled clinical studies with background DMARDs, the frequency of opportunisticinfections over 12/14 weeks in the upadacitinib 15 mg group was 0.5% compared to 0.3% in theplacebo group. In MTX-controlled studies, there were no cases of opportunistic infection over 12/14weeks in the upadacitinib 15 mg monotherapy group and 0.2% in the MTX group. The overall long-term rate of opportunistic infections for the upadacitinib 15 mg group across all five Phase 3 clinicalstudies was 0.6 events per 100 patient-years.

The long-term rate of herpes zoster for the upadacitinib 15 mg group across all five Phase 3 clinicalstudies was 3.7 events per 100 patient-years. Most of the herpes zoster events involved a singledermatome and were non-serious.

Hepatic transaminase elevations

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, alanine transaminase(ALT) and aspartate transaminase (AST) elevations ≥ 3 x upper limit of normal (ULN) in at least onemeasurement were observed in 2.1% and 1.5% of patients treated with upadacitinib 15 mg, comparedto 1.5% and 0.7%, respectively, of patients treated with placebo. Of the 22 cases of hepatictransaminase elevations, most were asymptomatic and transient.

In MTX-controlled studies, for up to 12/14 weeks, ALT and AST elevations ≥ 3 x ULN in at least onemeasurement were observed in 0.8% and 0.4% of patients treated with upadacitinib 15 mg, comparedto 1.9% and 0.9%, respectively, of patients treated with MTX.

The pattern and incidence of elevation in ALT/AST remained stable over time including in long-termextension studies.

Lipid elevations

Upadacitinib 15 mg treatment was associated with increases in lipid parameters including totalcholesterol, triglycerides, LDL cholesterol and HDL cholesterol. There was no change in the

LDL/HDL ratio. Elevations were observed at 2 to 4 weeks of treatment and remained stable withlonger-term treatment. Among patients in the controlled studies with baseline values below thespecified limits, the following frequencies of patients were observed to shift to above the specifiedlimits on at least one occasion during 12/14 weeks (including patients who had an isolated elevatedvalue):

* Total cholesterol ≥ 5.17 mmol/L (200 mg/dL): 62% vs. 31%, in the upadacitinib 15 mg andplacebo groups, respectively

* LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 42% vs. 19%, in the upadacitinib 15 mg andplacebo groups, respectively

* HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 89% vs. 61%, in the upadacitinib 15 mg andplacebo groups, respectively

* Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 25% vs. 15%, in the upadacitinib 15 mg and placebogroups, respectively

Creatine phosphokinase

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, increases in CPKvalues were observed. CPK elevations > 5 x upper limit of normal (ULN) were reported in 1.0% and0.3% of patients over 12/14 weeks in the upadacitinib 15 mg and placebo groups, respectively. Mostelevations > 5 x ULN were transient and did not require treatment discontinuation. Mean CPK valuesincreased by 4 weeks with a mean increase of 60 U/L at 12 weeks and then remained stable at anincreased value thereafter including with extended therapy.

In placebo-controlled studies with background DMARDs, for up to 12/14 weeks, decreases inneutrophil counts below 1 x 109 cells/L in at least one measurement occurred in 1.1% and <0.1% ofpatients in the upadacitinib 15 mg and placebo groups, respectively. In clinical studies, treatment wasinterrupted in response to ANC < 1 x 109 cells/L (see section 4.2). Mean neutrophil counts decreasedover 4 to 8 weeks. The decreases in neutrophil counts remained stable at a lower value than baselineover time including with extended therapy.

Overall, the safety profile observed in patients with active psoriatic arthritis treated with upadacitinib15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. A higherrate of serious infections (2.6 events per 100 patient-years and 1.3 events per 100 patient-years,respectively) and hepatic transaminase elevations (ALT elevations Grade 3 and higher rates 1.4% and0.4%, respectively) was observed in patients treated with upadacitinib in combination with MTXtherapy compared to patients treated with monotherapy.

Overall, the safety profile observed in patients with active axial spondyloarthritis treated withupadacitinib 15 mg was consistent with the safety profile observed in patients with rheumatoidarthritis. No new safety findings were identified.

Giant cell arteritis

Overall, the safety profile observed in patients with giant cell arteritis treated with upadacitinib 15 mgwas generally consistent with the known safety profile for upadacitinib.

Serious Infections

In the placebo-controlled clinical study, the frequency of serious infections over 52 weeks was 5.7% inthe upadacitinib 15 mg group and 10.7% in the placebo group. The long-term rate of serious infectionsfor the upadacitinib 15 mg group was 2.9 events per 100 patient-years.

Opportunistic infections (excluding tuberculosis)

In the placebo-controlled clinical study, the frequency of opportunistic infection (excludingtuberculosis and herpes zoster) over 52 weeks was 1.9% in the upadacitinib 15 mg group and 0.9% inthe placebo group. The long-term rate of opportunistic infections (excluding tuberculosis and herpeszoster) for the upadacitinib 15 mg group was 0.6 events per 100 patient-years.

In the placebo-controlled clinical study, the frequency of herpes zoster over 52 weeks was 5.3% in theupadacitinib 15 mg group and 2.7% in the placebo group. The long-term rate of herpes zoster for theupadacitinib 15 mg group was 4.1 events per 100 patient-years.

In the placebo-controlled period of the clinical studies, the frequency of infection over 16 weeks in theupadacitinib 15 mg and 30 mg groups was 39% and 43% compared to 30% in the placebo group,respectively. The long-term rate of infections for the upadacitinib 15 mg and 30 mg groups was 98.5and 109.6 events per 100 patient-years, respectively.

In placebo-controlled clinical studies, the frequency of serious infection over 16 weeks in theupadacitinib 15 mg and 30 mg groups was 0.8% and 0.4% compared to 0.6% in the placebo group,respectively. The long-term rate of serious infections for the upadacitinib 15 mg and 30 mg groupswas 2.3 and 2.8 events per 100 patient-years, respectively.

Opportunistic infections (excluding tuberculosis)

In the placebo-controlled period of the clinical studies, all opportunistic infections (excluding TB andherpes zoster) reported were eczema herpeticum. The frequency of eczema herpeticum over 16 weeksin the upadacitinib 15 mg and 30 mg groups was 0.7% and 0.8% compared to 0.4% in the placebogroup, respectively. The long-term rate of eczema herpeticum for the upadacitinib 15 mg and 30 mggroups was 1.6 and 1.8 events per 100 patient-years, respectively. One case of esophageal candidiasiswas reported with upadacitinib 30 mg.

The long-term rate of herpes zoster for the upadacitinib 15 mg and 30 mg groups was 3.5 and 5.2events per 100 patient-years, respectively. Most of the herpes zoster events involved a singledermatome and were non-serious.

Dose-dependent changes in ALT increased and/or AST increased (≥ 3 x ULN), lipid parameters, CPKvalues (> 5 x ULN), and neutropenia (ANC < 1 x 109 cells/L) associated with upadacitinib treatmentwere similar to what was observed in the rheumatologic disease clinical studies.

Small increases in LDL cholesterol were observed after week 16 in atopic dermatitis studies. At week52, the mean increase in LDL cholesterol from baseline was 0.41 mmol/L for upadacitinib 15 mg and0.56 mmol/L for upadacitinib 30 mg.

The overall safety profile observed in patients with ulcerative colitis was generally consistent with thatobserved in patients with rheumatoid arthritis.

A higher rate of herpes zoster was observed with an induction treatment period of 16 weeks vs8 weeks.

In the placebo-controlled induction studies, the frequency of infection over 8 weeks in the upadacitinib45 mg group compared to the placebo group was 20.7% and 17.5%, respectively. In theplacebo-controlled maintenance study, the frequency of infection over 52 weeks in the upadacitinib15 mg and 30 mg groups was 40.4% and 44.2%, respectively, compared to 38.8% in the placebogroup. The long-term rate of infections for upadacitinib 15 mg and 30 mg was 64.5 and 77.8 eventsper 100 patient-years, respectively.

In the placebo-controlled induction studies, the frequency of serious infection over 8 weeks in both theupadacitinib 45 mg group and the placebo group was 1.3%. No additional serious infections wereobserved over 8-week extended treatment with upadacitinib 45 mg. In the placebo-controlledmaintenance study, the frequency of serious infection over 52 weeks in the upadacitinib 15 mg and30 mg groups was 3.6% and 3.2%, respectively, compared to 3.3% in the placebo group. The long-term rate of serious infections for the upadacitinib 15 mg and 30 mg groups was 3.0 and 4.6 events per100 patient-years, respectively. The most frequently reported serious infection in the induction andmaintenance phases was COVID-19 pneumonia.

Opportunistic infections (excluding tuberculosis)

In the placebo-controlled induction studies over 8 weeks, the frequency of opportunistic infection(excluding tuberculosis and herpes zoster) in the upadacitinib 45 mg group was 0.4% and 0.3% in theplacebo group. No additional opportunistic infections (excluding tuberculosis and herpes zoster) wereobserved over 8-week extended treatment with upadacitinib 45 mg. In the placebo-controlledmaintenance study over 52 weeks, the frequency of opportunistic infection (excluding tuberculosis andherpes zoster) in the upadacitinib 15 mg and 30 mg groups was 0.8% and 0.8%, respectively,compared to 0.8% in the placebo group. The long-term rate of opportunistic infections (excludingtuberculosis and herpes zoster) for the upadacitinib 15 mg and 30 mg groups was 0.3 and 0.6 eventsper 100 patient-years, respectively.

In the placebo-controlled induction studies over 8 weeks, the frequency of herpes zoster in theupadacitinib 45 mg group was 0.6% and 0% in the placebo group. The frequency of herpes zoster was3.9% over 16-week treatment with upadacitinib 45 mg. In the placebo-controlled maintenance studyover 52 weeks, the frequency of herpes zoster in the upadacitinib 15 mg and 30 mg groups was 4.8%and 5.6%, respectively, compared to 0% in the placebo group. The long-term rate of herpes zoster forthe upadacitinib 15 mg and 30 mg groups was 4.5 and 7.2 events per 100 patient-years, respectively.

In the placebo-controlled maintenance period, gastrointestinal perforation was reported in 1 patienttreated with placebo (1.5 per 100 patient-years) and no patients treated with upadacitinib 15 mg or30 mg. In the long-term extension study, 1 patient treated with upadacitinib 15 mg (0.1 per 100patient-years) and 1 patient treated with upadacitinib 30 mg (<0.1 per 100 patient-years) reportedevents.

In the induction and maintenance clinical studies, the laboratory changes in ALT increased and/or

AST increased (≥ 3 x ULN), CPK values (> 5 x ULN), and neutropenia (ANC < 1 x 109 cells/L)associated with upadacitinib treatment were generally similar to what was observed in therheumatologic disease and atopic dermatitis clinical studies. Dose-dependent changes for theselaboratory parameters associated with 15 mg and 30 mg upadacitinib treatment were observed.

In the placebo-controlled induction studies for up to 8 weeks, decreases in lymphocyte counts below0.5 x 109 cells/L in at least one measurement occurred in 2.0% and 0.8% of patients in the upadacitinib45 mg and placebo groups, respectively. In the placebo-controlled maintenance study, for up to 52weeks, decreases in lymphocyte counts below 0.5 x 109 cells/L in at least one measurement occurredin 1.6%, 1.2% and 0.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups,respectively. In clinical studies, treatment was interrupted in response to ALC < 0.5 x 109 cells/L (seesection 4.2). No notable mean changes of lymphocyte counts were observed during upadacitinibtreatment over time.

Elevations in lipid parameters were observed at 8 weeks of treatment with upadacitinib 45 mg andremained generally stable with longer-term treatment with upadacitinib 15 mg and 30 mg. Amongpatients in the placebo-controlled induction studies with baseline values below the specified limits, thefollowing frequencies of patients were observed to shift to above the specified limits on at least oneoccasion during 8 weeks (including patients who had an isolated elevated value):

* Total cholesterol ≥ 5.17 mmol/L (200 mg/dL): 49% vs. 11%, in the upadacitinib 45 mg andplacebo groups, respectively

* LDL cholesterol ≥ 3.36 mmol/L (130 mg/dL): 27% vs. 9%, in the upadacitinib 45 mg andplacebo groups, respectively

* HDL cholesterol ≥ 1.03 mmol/L (40 mg/dL): 79% vs. 36%, in the upadacitinib 45 mg andplacebo groups, respectively

* Triglycerides ≥ 2.26 mmol/L (200 mg/dL): 6% vs 4% in the upadacitinib 45 mg and placebogroups, respectively

Overall, the safety profile observed in patients with Crohn’s disease treated with upadacitinib wasconsistent with the known safety profile for upadacitinib.

In the placebo-controlled induction studies, the frequency of serious infection over 12 weeks in theupadacitinib 45 mg group and the placebo group was 1.9% and 1.7%, respectively. In theplacebo-controlled maintenance study, the frequency of serious infection over 52 weeks in theupadacitinib 15 mg and 30 mg groups was 3.2% and 5.7%, respectively, compared to 4.5% in theplacebo group. The long-term rate of serious infections for the upadacitinib 15 mg and 30 mg groupsin patients who responded to upadacitinib 45 mg as induction treatment was 5.1 and 7.3 events per 100patient-years, respectively. The most frequently reported serious infection in the induction andmaintenance studies was gastrointestinal infections.

During the placebo-controlled period in the Phase 3 induction clinical studies, gastrointestinalperforation was reported in 1 patient (0.1%) treated with upadacitinib 45 mg and no patients onplacebo through 12 weeks. In all patients treated with upadacitinib 45 mg (n=938) during the inductionstudies, gastrointestinal perforation was reported in 4 patients (0.4%).

In the long-term placebo-controlled period, gastrointestinal perforation was reported in 1 patient eachtreated with placebo (0.7 per 100 patient-years), upadacitinib 15 mg (0.4 per 100 patient-years), andupadacitinib 30 mg (0.4 per 100 patient-years). In all patients treated with rescue upadacitinib 30 mg(n=336), gastrointestinal perforation was reported in 3 patients (0.8 per 100 patient-years) throughlong-term treatment.

In the induction and maintenance clinical studies, the laboratory changes in ALT increased and/or

AST increased (≥ 3 x ULN), CPK values (> 5 x ULN), neutropenia (ANC < 1 x 109 cells/L), and lipidparameters associated with upadacitinib treatment were generally similar to what was observed in therheumatologic disease, atopic dermatitis and ulcerative colitis clinical studies. Dose-dependentchanges for these laboratory parameters associated with 15 mg and 30 mg upadacitinib treatment wereobserved.

In the placebo-controlled induction studies for up to 12 weeks, decreases in lymphocyte counts below0.5 x 109 cells/L in at least one measurement occurred in 2.2% and 2.0% of patients in the upadacitinib45 mg and placebo groups, respectively. In the placebo-controlled maintenance study, for up to 52weeks, decreases in lymphocyte counts below 0.5 x 109 cells/L in at least one measurement occurredin 4.6%, pct. 5.2% and 1.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups,respectively. In clinical studies, treatment was interrupted in response to ALC < 0.5 x 109 cells/L (seesection 4.2). No notable mean changes of lymphocyte counts were observed during upadacitinibtreatment over time.

In the placebo-controlled induction studies for up to 12 weeks, decreases in haemoglobinconcentration to below 8 g/dL in at least one measurement occurred in 2.7% and 1.4% of patients inthe upadacitinib 45 mg and placebo groups, respectively. In the placebo-controlled maintenance study,for up to 52 weeks, decreases in haemoglobin concentration below 8 g/dL in at least one measurementoccurred in 1.4%, pct. 4.4% and 2.8% of patients in the upadacitinib 15 mg, 30 mg and placebo groups,respectively. In clinical studies, treatment was interrupted in response to Hb < 8 g/dL (see section 4.2).

No notable mean changes of haemoglobin concentration were observed during upadacitinib treatmentover time.

Based on the limited data from patients 65 years and older with atopic dermatitis, ulcerative colitis and

Crohn’s disease, there was a higher rate of overall adverse reactions with the upadacitinib 30 mg dosecompared to the 15 mg dose (see section 4.4).

A total of 541 adolescents aged 12 to 17 years with atopic dermatitis were treated in the global Phase 3studies (n=343) and the supplemental adolescent substudies (n=198), of whom 264 were exposed to15 mg and 265 were exposed to 30 mg. The safety profile for upadacitinib 15 mg and 30 mg inadolescents was similar to that in adults. With long-term exposure, the adverse drug reaction of skinpapilloma was reported in 3.4% and 6.8% of adolescent patients with atopic dermatitis in theupadacitinib 15 mg and 30 mg groups, respectively.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Upadacitinib was administered in clinical studies up to doses equivalent in daily AUC to 60 mgprolonged-release once daily. Adverse reactions were comparable to those seen at lower doses and nospecific toxicities were identified. Approximately 90% of upadacitinib in the systemic circulation iseliminated within 24 hours of dosing (within the range of doses evaluated in clinical studies). In caseof an overdose, it is recommended that the patient be monitored for signs and symptoms of adversereactions. Patients who develop adverse reactions should receive appropriate treatment.

Pharmacotherapeutic group: Immunosuppressants, Janus-associated kinase (JAK) inhibitors ATCcode: L04AF03

Upadacitinib is a selective and reversible Janus kinase (JAK) inhibitor. JAKs are intracellular enzymesthat transmit cytokine or growth factor signals involved in a broad range of cellular processesincluding inflammatory responses, hematopoiesis, and immune surveillance. The JAK family ofenzymes contains four members, JAK1, JAK2, JAK3 and TYK2 which work in pairs to phosphorylateand activate signal transducers and activators of transcription (STATs). This phosphorylation, in turn,modulates gene expression and cellular function. JAK1 is important in inflammatory cytokine signalswhile JAK2 is important for red blood cell maturation and JAK3 signals play a role in immunesurveillance and lymphocyte function.

In human cellular assays, upadacitinib preferentially inhibits signalling by JAK1 or JAK1/3 withfunctional selectivity over cytokine receptors that signal via pairs of JAK2. Atopic dermatitis is drivenby pro-inflammatory cytokines (including IL-4, IL-13, IL-22, TSLP, IL-31 and IFN-γ) that transducesignals via the JAK1 pathway. Inhibiting JAK1 with upadacitinib reduces the signaling of manymediators which drive the signs and symptoms of atopic dermatitis such as eczematous skin lesionsand pruritus. Pro-inflammatory cytokines (primarily IL-6, IL-7, IL-15 and IFNγ) transduce signals viathe JAK1 pathway and are involved in the pathology of inflammatory bowel diseases. JAK1 inhibitionwith upadacitinib modulates the signalling of the JAK-dependent cytokines underlying theinflammatory burden and signs and symptoms of inflammatory bowel diseases.

Inhibition of IL-6 induced STAT3 and IL-7 induced STAT5 phosphorylation

In healthy volunteers, the administration of upadacitinib (immediate-release formulation) resulted in adose- and concentration-dependent inhibition of IL-6 (JAK1/JAK2) - induced STAT3 and IL-7(JAK1/JAK3)-induced STAT5 phosphorylation in whole blood. The maximal inhibition was observed1 hour after dosing which returned to near baseline by the end of dosing interval.

In patients with rheumatoid arthritis, treatment with upadacitinib was associated with a small, transientincrease in mean ALC from baseline up to week 36 which gradually returned to at or near baselinelevels with continued treatment.

hsCRP

In patients with rheumatoid arthritis, treatment with upadacitinib was associated with decreases frombaseline in mean hsCRP levels as early as week 1 which were maintained with continued treatment.

The influence of upadacitinib on the humoral response following administration of adjuvantedrecombinant glycoprotein E herpes zoster vaccine was evaluated in 93 patients with rheumatoidarthritis under stable treatment with upadacitinib 15 mg. 98% of patients were on concomitantmethotrexate. 49% of patients were on oral corticosteroids at baseline. The primary endpoint was theproportion of patients with a satisfactory humoral response defined as ≥ 4-fold increase in pre-vaccination concentration of anti-glycoprotein E titer levels at week 16 (4 weeks post-dose 2vaccination). Vaccination of patients treated with upadacitinib 15 mg resulted in a satisfactoryhumoral response in 79/90 (88% [95% CI: 81.0, 94.5]) of patients at week 16.

The influence of upadacitinib on the humoral response following the administration of inactivatedpneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) was evaluated in 111 patientswith rheumatoid arthritis under stable treatment with upadacitinib 15 mg (n=87) or 30 mg (n=24). 97%of patients (n=108) were on concomitant methotrexate. The primary endpoint was the proportion ofpatients with satisfactory humoral response defined as ≥ 2-fold increase in antibody concentrationfrom baseline to week 4 in at least 6 out of the 12 pneumococcal antigens (1, 3, 4, 5, 6B, 7F, 9V, 14,18C, 19A, 19F, and 23F). Results at week 4 demonstrated a satisfactory humoral response in 67.5%(95% CI: 57.4, 77.5) and 56.5% (95% CI: 36.3, 76.8) of patients treated with upadacitinib 15 mg and30 mg, respectively.

The efficacy and safety of upadacitinib 15 mg once daily was assessed in five Phase 3 randomised,double-blind, multicentre studies in patients with moderately to severely active rheumatoid arthritisand fulfilling the ACR/EULAR 2010 classification criteria (see Table 4). Patients 18 years of age andolder were eligible to participate. The presence of at least 6 tender and 6 swollen joints and evidenceof systemic inflammation based on elevation of hsCRP was required at baseline. Four studies includedlong-term extensions for up to 5 years, and one study (SELECT-COMPARE) included a long-termextension for up to 10 years.

The primary analysis for each of these studies included all randomised subjects who received at least 1dose of upadacitinib or placebo, and non-responder imputation was used for categorical endpoints.

Across the Phase 3 studies, the efficacy seen with upadacitinib 15 mg QD was generally similar to thatobserved with upadacitinib 30 mg QD.

Table 4 Clinical trials summary

Study name Population (n) Treatment arms Key outcome measures

SELECT-EARLY MTX-naïvea * Upadacitinib 15 mg * Primary endpoint: clinical remission(947) * Upadacitinib 30 mg (DAS28-CRP) at week 24

* MTX * Low disease activity (DAS28-CRP)

* ACR50

Monotherapy * Radiographic progression (mTSS)

* Physical function (HAQ-DI)

* SF-36 PCS

SELECT- MTX-IRb * Upadacitinib 15 mg * Primary endpoint: low disease activity

MONOTHERAPY (648) * Upadacitinib 30 mg (DAS28-CRP) at week 14

* MTX * Clinical remission (DAS28-CRP)

* ACR20

Monotherapy * Physical function (HAQ-DI)

* SF-36 PCS

* Morning stiffness

SELECT-NEXT csDMARD-IRc * Upadacitinib 15 mg * Primary endpoint: low disease activity(661) * Upadacitinib 30 mg (DAS28-CRP) at week 12

* Placebo * Clinical remission (DAS28-CRP)

* ACR20

On background * Physical function (HAQ-DI)csDMARDs * SF-36 PCS

* Low disease activity (CDAI)

* Morning stiffness

* FACIT-F

SELECT- MTX-IRd * Upadacitinib 15 mg * Primary endpoint: clinical remission

COMPARE (1,629) * Placebo (DAS28-CRP) at week 12

* Adalimumab 40 mg * Low disease activity (DAS28-CRP)

* ACR20

On background MTX * Low disease activity (DAS28-CRP) vsadalimumab

* Radiographic progression (mTSS)

* Physical function (HAQ-DI)

* SF-36 PCS

* Low disease activity (CDAI)

* Morning stiffness

* FACIT-F

SELECT- bDMARD-IRe * Upadacitinib 15 mg * Primary endpoint: low disease activity

BEYOND (499) * Upadacitinib 30 mg (DAS28-CRP) at week 12

* Placebo * ACR20

* Physical function (HAQ-DI)

On background * SF-36 PCScsDMARDs

Abbreviations: ACR20 (or 50) = American College of Rheumatology ≥20% (or ≥50%) improvement; bDMARD =biologic disease-modifying anti-rheumatic drug, CRP = C-Reactive Protein, DAS28 = Disease Activity Score 28 joints,mTSS = modified Total Sharp Score, csDMARD = conventional synthetic disease-modifying anti-rheumatic drug,

HAQ-DI = Health Assessment Questionnaire-Disability Index, SF-36 PCS = Short Form (36) Health Survey (SF-36)

Physical Component Summary, CDAI = Clinical Disease Activity Index, FACIT-F = Functional Assessment of

Chronic Illness Therapy-Fatigue score, IR = inadequate responder, MTX = methotrexate, n = number randomised

a. Patients were naïve to MTX or received no more than 3 weekly MTX dosesb Patients had inadequate response to MTXc Patients who had an inadequate response to csDMARDs; patients with prior exposure to at most one bDMARD wereeligible (up to 20% of total number of patients) if they had either limited exposure (<3 months) or had to discontinuethe bDMARD due to intolerabilityd Patients who had an inadequate response to MTX; patients with prior exposure to at most one bDMARD (exceptadalimumab) were eligible (up to 20% of total study number of patients) if they had either limited exposure (<3months) or had to discontinue the bDMARD due to intolerabilitye Patients who had an inadequate response or intolerance to at least one bDMARD

Remission and low disease activity

In the studies, a significantly higher proportion of patients treated with upadacitinib 15 mg achievedlow disease activity (DAS28-CRP ≤3.2) and clinical remission (DAS28-CRP <2.6) compared toplacebo, MTX, or adalimumab (Table 5). Compared to adalimumab, significantly higher rates of lowdisease activity were achieved at week 12 in SELECT-COMPARE. Overall, both low disease activityand clinical remission rates were consistent across patient populations, with or without MTX. At3 years, 297/651 (45.6%) and 111/327 (33.9%) patients remained on originally randomised treatmentof upadacitinib 15 mg or adalimumab, respectively, in SELECT-COMPARE, and 216/317 (68.1%)and 149/315 (47.3%) patients remained on originally randomised treatment of upadacitinib 15 mg or

MTX monotherapy, respectively, in SELECT-EARLY. Among the patients who remained on theiroriginally allocated treatment, low disease activity and clinical remission were maintained through3 years.

In all studies, more patients treated with upadacitinib 15 mg achieved ACR20, ACR50, and ACR70responses at 12 weeks compared to placebo, MTX, or adalimumab (Table 5). Time to onset of efficacywas rapid across measures with greater responses seen as early as week 1 for ACR20. Durableresponse rates were observed (with or without MTX), with ACR20/50/70 responses maintainedthrough 3 years among the patients who remained on their originally allocated treatment.

Treatment with upadacitinib 15 mg, alone or in combination with csDMARDs, resulted inimprovements in individual ACR components, including tender and swollen joint counts, patient andphysician global assessments, HAQ-DI, pain assessment and hsCRP.

Table 5 Response and remission

SELECT SELECT SELECT SELECT SELECT

EARLY MONO NEXT COMPARE BEYOND

Study MTX-Naїve MTX-IR csDMARD-IR MTX-IR bDMARD-IR

UPA UPA UPA UPA ADA UPA

MTX 15mg MTX 15mg PBO 15mg PBO 15mg 40mg PBO 15mg

N 314 317 216 217 221 221 651 651 327 169 164

Week

LDA DAS28-CRP ≤3.2 (% of patients)12a/14b 28 53g 19 45e 17 48e 14 45e,h 29 14 43e24c/26d 32 60f 18 55g,h 3948 39 59g 50h 35

CR DAS28-CRP <2.6 (% of patients)12a/14b 14 36g 8 28e 10 31e 6 29e,h 18 9 29g24c/26d 18 48e 9 41g,h 2748 29 49g 38i 28

ACR20 (% of patients)12a/14b 54 76g 41 68e 36 64e 36 71e,j 63 28 65e24c/26d 59 79g 36 67g,i 5748 57 74g 65i 54

ACR50 (% of patients)12a/14b 28 52g 15 42g 15 38g 15 45g,h 29 12 34g24c/26d 33 60e 21 54g,h 4248 43 63g 49i 40

ACR70 (% of patients)12a/14b 14 32g 3 23g 6 21g 5 25g,h 13 7 1224c/26d 18 44g 10 35g,h 2348 29 51g 36h 23

CDAI ≤10 (% of patients)12a/14b 30 46g 25 35l 19 40e 16 40e,h 30 14 32g24c/26d 38 56g 22 53g,h 3848 43 60g 47h 34

Abbreviations: ACR20 (or 50 or 70) = American College of Rheumatology ≥20% (or ≥50% or ≥70%)improvement; ADA = adalimumab; CDAI = Clinical Disease Activity Index; CR = Clinical Remission;

CRP = C-Reactive Protein, DAS28 = Disease Activity Score 28 joints; IR = inadequate responder; LDA =

Low Disease Activity; MTX = methotrexate; PBO = placebo; UPA= upadacitiniba SELECT-NEXT, SELECT-EARLY, SELECT-COMPARE, SELECT-BEYONDb SELECT-MONOTHERAPYc SELECT-EARLYd SELECT-COMPAREe multiplicity-controlled p≤0.001upadacitinib vs placebo or MTX comparisonf multiplicity-controlled p≤0.01 upadacitinib vs placebo or MTX comparisong nominal p≤0.001 upadacitinib vs placebo or MTX comparisonh nominal p≤0.001upadacitinib vs adalimumab comparisoni nominal p≤0.01 upadacitinib vs adalimumab comparisonj nominal p<0.05 upadacitinib vs adalimumab comparisonk nominal p≤0.01 upadacitinib vs placebo or MTX comparisonl nominal p<0.05 upadacitinib vs MTX comparison

Note: Week 48-data derived from analysis on Full Analysis set (FAS) by randomised group using Non-

Responder Imputation

Inhibition of progression of structural joint damage was assessed using the modified Total Sharp Score(mTSS) and its components, the erosion score and joint space narrowing score, at weeks 24/26 andweek 48 in SELECT-EARLY and SELECT-COMPARE.

Treatment with upadacitinib 15 mg resulted in significantly greater inhibition of the progression ofstructural joint damage compared to placebo in combination with MTX in SELECT-COMPARE andas monotherapy compared to MTX in SELECT-EARLY (Table 6). Analyses of erosion and jointspace narrowing scores were consistent with the overall scores. The proportion of patients with noradiographic progression (mTSS change ≤ 0) was significantly higher with upadacitinib 15 mg in bothstudies. Inhibition of progression of structural joint damage was maintained through week 96 in bothstudies for patients who remained on their originally allocated treatment with upadacitinib 15 mg(based on available results from 327 patients in SELECT-COMPARE and 238 patients in SELECT-

EARLY).

Table 6 Radiographic changes

SELECT SELECT

EARLY COMPARE

Study MTX-Naїve MTX-IR

UPA UPA ADA

Treatment Group MTX 15 mg PBOa 15 mg 40 mg

Modified Total Sharp Score, mean change from baseline

Week 24b/26c 0.7 0.1f 0.9 0.2g 0.1

Week 48 1.0 0.03e 1.7 0.3e 0.4d

Proportion of patients with no radiographic progression

Week 24b/26c 77.7 87.5f 76.0 83.5f 86.8

Week 48 74.3 89.9e 74.1 86.4e 87.9

Abbreviations: ADA = adalimumab; IR = inadequate responder; MTX = methotrexate; PBO = placebo;

UPA= upadacitiniba All placebo data at week 48 derived using linear extrapolationb SELECT-EARLYc SELECT-COMPAREd No progression defined as mTSS change ≤ 0e nominal p≤0.001 upadacitinib vs placebo or MTX comparisonf multiplicity-controlled p≤0.01 upadacitinib vs placebo or MTX comparisong multiplicity-controlled p≤0.001 upadacitinib vs placebo or MTX comparison

Physical function response and health-related outcomes

Treatment with upadacitinib 15 mg, alone or in combination with csDMARDs, resulted in asignificantly greater improvement in physical function compared to all comparators as measured by

HAQ-DI (see Table 7). Improvement in HAQ-DI was maintained through 3 years for patients whoremained on their originally allocated treatment with upadacitinib 15 mg based on available resultsfrom SELECT-COMPARE and SELECT-EARLY.

a,b

Table 7 Mean change from baseline in HAQ-DI

SELECT SELECT SELECT SELECT SELECT

EARLY MONO NEXT COMPARE BEYOND

Study MTX-Naїve MTX-IR csDMARD-IR MTX-IR BIO-IR

Treatment UPA UPA UPA UPA ADA UPAgroup MTX 15mg MTX 15mg PBO 15mg PBO 15mg 40mg PBO 15mg

N 313 317 216 216 220 216 648 644 324 165 163

Baselinescore, 1.6 1.6 1.5 1.5 1.4 1.5 1.6 1.6 1.6 1.6 1.7mean

Week

- 0.5 -0.8h -0.3 -0.7gc d -0.3 -0.6g -0.3 -0.6g,i -0.5 -0.2 -0.4g12 /14

Week

- 0.6 -0.9g -0.3 -0.7h,ie f -0.624 /26

Abbreviations: ADA = adalimumab; HAQ-DI = Health Assessment Questionnaire-Disability Index; IR =inadequate responder; MTX = methotrexate; PBO = placebo; UPA = upadacitiniba Data shown are meanb Health Assessment Questionnaire-Disability Index: 0=best, 3=worst; 20 questions; 8 categories:

dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.c SELECT-EARLY, SELECT-NEXT, SELECT-COMPARE, SELECT-BEYONDd SELECT-MONOTHERAPYe SELECT-EARLYf SELECT-COMPAREg multiplicity-controlled p≤0.001 upadacitinib vs placebo or MTX comparisonh nominal p≤0.001 upadacitinib vs placebo or MTX comparisoni nominal p≤0.01 upadacitinib vs adalimumab comparison

In the studies SELECT-MONOTHERAPY, SELECT-NEXT, and SELECT-COMPARE, treatmentwith upadacitinib 15 mg resulted in a significantly greater improvement in the mean duration ofmorning joint stiffness compared to placebo or MTX.

In the clinical studies, upadacitinib-treated patients reported significant improvements in patient-reported quality of life, as measured by the Short Form (36) Health Survey (SF-36) Physical

Component Summary compared to placebo and MTX. Moreover, upadacitinib-treated patientsreported significant improvements in fatigue, as measured by the Functional Assessment of Chronic

Illness Therapy-Fatigue score (FACIT-F) compared to placebo.

The efficacy and safety of upadacitinib 15 mg once daily were assessed in two Phase 3 randomised,double-blind, multicentre, placebo-controlled studies in patients 18 years of age or older withmoderately to severely active psoriatic arthritis. All patients had active psoriatic arthritis for at least 6months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender jointsand at least 3 swollen joints, and active plaque psoriasis or history of plaque psoriasis. For bothstudies, the primary endpoint was the proportion of patients who achieved an ACR20 response at week12.

SELECT-PsA 1 was a 24-week trial in 1705 patients who had an inadequate response or intolerance toat least one non-biologic DMARD. At baseline, 1393 (82%) of patients were on at least oneconcomitant non-biologic DMARD; 1084 (64%) of patients received concomitant MTX only; and 311(18%) of patients were on monotherapy. Patients received upadacitinib 15 mg or 30 mg once daily,adalimumab, or placebo. At week 24, all patients randomised to placebo were switched to upadacitinib15 mg or 30 mg once daily in a blinded manner. SELECT-PsA 1 included a long-term extension forup to 5 years.

SELECT-PsA 2 was a 24-week trial in 642 patients who had an inadequate response or intolerance toat least one biologic DMARD. At baseline, 296 (46%) of patients were on at least one concomitantnon-biologic DMARD; 222 (35%) of patients received concomitant MTX only; and 345 (54%) ofpatients were on monotherapy. Patients received upadacitinib 15 mg or 30 mg once daily or placebo.

At week 24, all patients randomised to placebo were switched to upadacitinib 15 mg or 30 mg oncedaily in a blinded manner. SELECT-PsA 2 included a long-term extension for up to 3 years.

In both studies, a statistically significant greater proportion of patients treated with upadacitinib 15 mgachieved ACR20 response compared to placebo at week 12 (Table 8). Time to onset of efficacy wasrapid across measures with greater responses seen as early as week 2 for ACR20.

Treatment with upadacitinib 15 mg resulted in improvements in individual ACR components,including tender/painful and swollen joint counts, patient and physician global assessments, HAQ-DI,pain assessment, and hsCRP compared to placebo.

In SELECT-PsA 1, upadacitinib 15 mg achieved non-inferiority compared to adalimumab in theproportion of patients achieving ACR20 response at week 12; however, superiority to adalimumabcould not be demonstrated.

In both studies, consistent responses were observed alone or in combination with methotrexate forprimary and key secondary endpoints.

The efficacy of upadacitinib 15 mg was demonstrated regardless of subgroups evaluated includingbaseline BMI, baseline hsCRP, and number of prior non-biologic DMARDs (≤ 1 or >1).

Table 8 Clinical response in SELECT-PsA 1 and SELECT-PsA 2

Study SELECT-PsA 1 SELECT-PsA 2non-biologic DMARD-IR bDMARD-IR

Treatment Group PBO UPA ADA PBO UPA15 mg 40 mg 15 mg

N 423 429 429 212 211

ACR20, % of patients (95% CI)

Week 12 36 (32, 41) 71 (66, 75)f 65 (61, 70) 24 (18, 30) 57 (50, 64)

Difference from35 (28, 41)d,e -33 (24, 42)d,eplacebo (95% CI)

Week 24 45 (40, 50) 73 (69, 78) 67 (63, 72) 20 (15, 26) 59 (53, 66)

Week 56 74 (70, 79) 69 (64, 73) 60 (53, 66)

ACR50, % of patients (95% CI)

Week 12 13 (10, 17) 38 (33, 42) 38 (33, 42) 5 (2, 8) 32 (26, 38)

Week 24 19 (15, 23) 52 (48, 57) 44 (40, 49) 9 (6, 13) 38 (32, 45)

Week 56 60 (55, 64) 51 (47, 56) 41 (34, 47)

ACR70, % of patients (95% CI)

Week 12 2 (1, 4) 16 (12, 19) 14 (11, 17) 1 (0, 1) 9 (5, 12)

Week 24 5 (3, 7) 29 (24, 33) 23 (19, 27) 1 (0, 2) 19 (14, 25)

Week 56 41 (36, 45) 31 (27, 36) 24 (18, 30)

MDA, % of patients (95% CI)

Week 12 6 (4, 9) 25 (21, 29) 25 (21, 29) 4 (2, 7) 17 (12, 22)

Week 24 12 (9, 15) 37 (32, 41)e 33 (29, 38) 3 (1, 5) 25 (19, 31)e

Week 56 45 (40, 50) 40 (35, 44) 29 (23, 36)a

Resolution of enthesitis (LEI=0), % of patients (95% CI)

Week 12 33 (27, 39) 47 (42, 53) 47 (41, 53) 20 (14, 27) 39 (31, 47)

Week 24 32 (27, 39) 54 (48, 60)e 47 (42, 53) 15 (9, 21) 43 (34, 51)

Week 56 59 (53, 65) 54 (48, 60) 43 (34, 51)b

Resolution of dactylitis (LDI=0), % of patients (95% CI)

Week 12 42 (33, 51) 74 (66, 81) 72 (64, 80) 36 (24, 48) 64 (51, 76)

Week 24 40 (31, 48) 77 (69, 84) 74 (66, 82) 28 (17, 39) 58 (45, 71)

Week 56 75 (68, 82) 74 (66, 82) 51 (38, 64)c

PASI75, % of patients (95% CI)

Week 16 21 (16, 27) 63 (56, 69)e 53 (46, 60) 16 (10, 22) 52 (44, 61)e

Week 24 27 (21, 33) 64 (58, 70) 59 (52, 65) 19 (12, 26) 54 (45, 62)

Week 56 65 (59, 72) 61 (55, 68) 52 (44, 61)c

PASI90, % of patients (95% CI)

Week 16 12 (8, 17) 38 (32, 45) 39 (32, 45) 8 (4, 13) 35 (26, 43)

Week 24 17 (12, 22) 42 (35, 48) 45 (38, 52) 7 (3, 11) 36 (28, 44)

Week 56 49 (42, 56) 47 (40, 54) 41 (32, 49)

Abbreviations: ACR20 (or 50 or 70) = American College of Rheumatology ≥20% (or ≥50% or≥70%) improvement, ADA = adalimumab; bDMARD = biologic disease-modifying anti-rheumatic drug; IR = inadequate responder; MDA = minimal disease activity; PASI75 (or 90) =≥75% (or ≥90%) improvement in Psoriasis Area and Severity Index; PBO = placebo; UPA=upadacitinib

Patients who discontinued randomised treatment or were missing data at week of evaluation wereimputed as non-responders in the analyses. For MDA, resolution of enthesitis, and resolution ofdactylitis at week 24/56, the subjects rescued at week 16 were imputed as non-responders in theanalyses.

a In patients with enthesitis at baseline (n=241, 270, and 265, respectively, for SELECT-PsA 1 andn=144 and 133, respectively, for SELECT-PsA 2)b In patients with dactylitis at baseline (n=126, 136, and 127, respectively, for SELECT-PsA 1 andn=64 and 55, respectively, for SELECT-PsA 2)c In patients with ≥ 3% BSA psoriasis at baseline (n=211, 214, and 211, respectively, for

SELECT-PsA 1 and n=131 and 130, respectively, for SELECT-PsA 2)d primary endpointe multiplicity-controlled p≤0.001 upadacitinib vs placebo comparisonf multiplicity-controlled p≤0.001 upadacitinib vs adalimumab comparison (non-inferiority test)

In SELECT-PsA 1, inhibition of progression of structural damage was assessed radiographically andexpressed as the change from baseline in modified Total Sharp Score (mTSS) and its components, theerosion score and the joint space narrowing score, at week 24.

Treatment with upadacitinib 15 mg resulted in statistically significant greater inhibition of theprogression of structural joint damage compared to placebo at week 24 (Table 9). Erosion and jointspace narrowing scores were consistent with the overall scores. The proportion of patients with noradiographic progression (mTSS change ≤ 0.5) was higher with upadacitinib 15 mg compared toplacebo at week 24.

Table 9 Radiographic changes in SELECT-PsA 1

Treatment Group PBO UPA ADA15 mg 40 mg

Modified Total Sharp Score, mean change from baseline (95% CI)

Week 24 0.25 (0.13, 0.36) -0.04 (-0.16, 0.07)c 0.01 (-0.11, 0.13)

Week 56a 0.44 (0.29, 0.59) -0.05 (-0.20, 0.09) -0.06 (-0.20, 0.09)b

Proportion of patients with no radiographic progression , % (95% CI)

Week 24 92 (89, 95) 96 (94, 98) 95 (93, 97)

Week 56a 89 (86, 92) 97 (96, 99) 94 (92, 97)

Abbreviations: ADA = adalimumab; PBO = placebo; UPA= upadacitiniba All placebo data at week 56 derived using linear extrapolationb No progression defined as mTSS change ≤0.5c multiplicity-controlled p≤0.001 upadacitinib vs placebo comparison

Physical function response and health-related outcomes

In SELECT-PsA 1, patients treated with upadacitinib 15 mg showed statistically significantimprovement from baseline in physical function as assessed by HAQ-DI at week 12 (-0.42 [95% CI: -0.47, -0.37]) compared to placebo (-0.14 [95% CI: -0.18, -0.09]); improvement in patients treated withadalimumab was -0.34 (95% CI: -0.38, -0.29). In SELECT-PsA 2, patients treated with upadacitinib15 mg showed statistically significant improvement from baseline in HAQ-DI at week 12 (-0.30 [95%

CI: -0.37, -0.24]) compared to placebo (-0.10 [95% CI: -0.16, -0.03]). Improvement in physicalfunction was maintained through week 56 in both studies.

Health-related quality of life was assessed by SF-36v2. In both studies, patients receiving upadacitinib15 mg experienced statistically significant greater improvement from baseline in the Physical

Component Summary score compared to placebo at week 12. Improvements from baseline weremaintained through week 56 in both studies.

Patients receiving upadacitinib 15 mg experienced statistically significant improvement from baselinein fatigue, as measured by FACIT-F score, at week 12 compared to placebo in both studies.

Improvements from baseline were maintained through week 56 in both studies.

At baseline, psoriatic spondylitis was reported in 31% and 34% of patients in SELECT-PsA 1 and

SELECT-PsA 2, respectively. Patients with psoriatic spondylitis treated with upadacitinib 15 mgshowed improvements from baseline in Bath Ankylosing Spondylitis Disease Activity Index(BASDAI) scores compared to placebo at week 24. Improvements from baseline were maintainedthrough week 56 in both studies.

Non-radiographic axial spondyloarthritis

The efficacy and safety of upadacitinib 15 mg once daily were assessed in a randomised, double-blind,multicentre, placebo-controlled study in patients 18 years of age or older with active non-radiographicaxial spondyloarthritis. Study SELECT-AXIS 2 (nr-axSpA) was a 52-week placebo-controlled trial in314 patients with active non-radiographic axial spondyloarthritis with an inadequate response to atleast two NSAIDs or intolerance to or contraindication for NSAIDs. Patients must have had objectivesigns of inflammation indicated by elevated C-reactive protein (CRP) (defined as > upper limit ofnormal), and/or sacroiliitis on magnetic resonance imaging (MRI), and no definitive radiographicevidence of structural damage on sacroiliac joints. Patients had active disease as defined by the Bath

Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4, and a Patient's Assessment of Total

Back Pain score ≥ 4 based on a 0 - 10 numerical rating scale (NRS) at the Screening and Baseline

Visits. At baseline, patients had symptoms of non-radiographic axial spondyloarthritis for an averageof 9.1 years and 29.1% of the patients were on a concomitant csDMARD. 32.9% of the patients had aninadequate response or intolerance to bDMARD therapy. Patients received upadacitinib 15 mg oncedaily or placebo. At week 52, all patients randomised to placebo were switched to upadacitinib 15 mgonce daily. The primary endpoint was the proportion of patients achieving an Assessment of

SpondyloArthritis international Society 40 (ASAS40) response at week 14. The study included a long-term extension for up to 2 years. Of patients who were initially randomised to upadacitinib, 75%(117/156) in SELECT-AXIS 2 (nr-axSpA) continued therapy through 2 years.

In SELECT-AXIS 2 (nr-axSpA), a significantly greater proportion of patients treated withupadacitinib 15 mg achieved an ASAS40 response compared to placebo at week 14 (Table 10).

A numerical difference between treatment groups was observed at all timepoints from week 2 to week14.

Treatment with upadacitinib 15 mg resulted in improvements in individual ASAS components (patientglobal assessment of disease activity, total back pain assessment, inflammation, and function) andother measures of disease activity, including hsCRP, compared to placebo at week 14.

The efficacy of upadacitinib 15 mg was demonstrated across subgroups including gender, baseline

BMI, symptom duration of non-radiographic axial spondyloarthritis, baseline hsCRP, MRI sacroiliitis,and prior use of bDMARDs.

Table 10 Clinical response in SELECT-AXIS 2 (nr-axSpA)

Treatment Group PB O UPA 1 5 mg

N 157 156a

ASAS40, % of patients (95% CI)

Week 14 22.5 (16.0, 29.1) 44.9 (37.1, 52.7)

Difference from placebo (95% CI) 22.2 (12.1, 32.3)b

Week 52 42.7 (34.9, 50.4) 62.8 (55.2, 70.4)da

ASAS20, % of patients (95% CI)

Week 14 43.8 (36.0, 51.5) 66.7 (59.3, 74.1)b

ASAS Partial Remission, % of patients (95% CI)

Week 14 7.6 (3.5, 11.8) 18.6 (12.5, 24.7)c

BASDAI 50, % of patients (95% CI)

Week 14 22.1 (15.5, 28.6) 42.3 (34.6, 50.1)b

Change from baseline in ASDAS-CRP (95% CI)

Week 14 -0.71 (-0.85, -0.56) -1.36 (-1.50, -1.21)b

ASDAS Inactive Disease, % of patients (95% CI)

Week 14 5.2 (1.7, 8.7) 14.1 (8.6, 19.6)c

ASDAS Low Disease Activity, % of patients (95% CI)

Week 14 18.3 (12.2, 24.4) 42.3 (34.6, 50.1)b

Abbreviations: ASAS20 (or ASAS40) = Assessment of SpondyloArthritis international Society ≥20%(or ≥40%) improvement; ASDAS-CRP = Ankylosing Spondylitis Disease Activity Score C-Reactive

Protein; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; PBO = placebo; UPA=upadacitiniba An ASAS20 (ASAS40) response is defined as a ≥20% (≥40%) improvement and an absoluteimprovement from baseline of ≥1 (≥2) unit(s) (range 0 to 10) in ≥3 of 4 domains (Patient Global,

Total Back Pain, Function, and Inflammation), and no worsening in the potential remainingdomain (defined as worsening ≥20% and ≥1 unit for ASAS20 or defined as worsening of > 0 units for

ASAS40).b multiplicity-controlled p≤0.001 upadacitinib vs placebo comparisonc multiplicity-controlled p≤0.01 upadacitinib vs placebo comparisond Nominal p≤0.001 for upadacitinib vs placebo comparison, according to prespecified multiplicity-controlled testing sequence

For binary endpoints, results are based on non-responder imputation in conjunction with multipleimputation. For continuous endpoints, results are based on the least squares mean change frombaseline using mixed-effect models repeated measures analysis.

Efficacy was maintained through 2 years as assessed by the endpoints presented in Table 10.

Physical function response and health-related outcomes

Patients treated with upadacitinib 15 mg showed significant improvement in physical function frombaseline compared to placebo as assessed by the BASFI at week 14.

Patients treated with upadacitinib 15 mg showed significant improvements in total back pain andnocturnal back pain compared to placebo at week 14.

Patients treated with upadacitinib 15 mg showed significant improvements in health-related quality oflife and overall health as measured by ASQoL and ASAS Health Index, respectively, compared toplacebo at week 14.

Improvements in BASFI, total and nocturnal back pain, ASQoL and ASAS Health Index weremaintained through 2 years.

Objective measure of inflammation

Signs of inflammation were assessed by MRI and expressed as change from baseline in the

Spondyloarthritis Research Consortium of Canada (SPARCC) score of the sacroiliac joints. At week14, significant improvement of inflammatory signs in the sacroiliac joints was observed in patientstreated with upadacitinib 15 mg compared to placebo. Improvement in inflammation as assessed by

MRI was maintained through 2 years.

Ankylosing spondylitis (AS, radiographic axial spondyloarthritis)

The efficacy and safety of upadacitinib 15 mg once daily were assessed in two randomised,double-blind, multicentre, placebo-controlled studies in patients 18 years of age or older with activeankylosing spondylitis based upon the Bath Ankylosing Spondylitis Disease Activity Index(BASDAI) ≥4 and Patient’s Assessment of Total Back Pain score ≥4. Both studies included along-term extension for up to 2 years.

SELECT-AXIS 1 was a 14-week placebo-controlled trial in 187 ankylosing spondylitis patients withan inadequate response to at least two NSAIDs or intolerance to or contraindication for NSAIDs andhad no previous exposure to biologic DMARDs. At baseline, patients had symptoms of ankylosingspondylitis for an average of 14.4 years and approximately 16% of the patients were on a concomitantcsDMARD. Patients received upadacitinib 15 mg once daily or placebo. At week 14, all patientsrandomised to placebo were switched to upadacitinib 15 mg once daily. The primary endpoint was theproportion of patients achieving an Assessment of SpondyloArthritis international Society 40(ASAS40) response at week 14.

SELECT-AXIS 2 (AS) was a 14-week placebo-controlled trial in 420 ankylosing spondylitis patientswith prior exposure to bDMARDs (77.4% had lack of efficacy to either a TNF inhibitor or interleukin-17 inhibitor (IL-17i); 30.2% had intolerance; 12.9% had prior exposure but not lack of efficacy to twobDMARDs). At baseline, patients had symptoms of ankylosing spondylitis for an average of 12.8years and approximately 31% of the patients were on a concomitant csDMARD. Patients receivedupadacitinib 15 mg once daily or placebo. At week 14, all patients randomised to placebo wereswitched to upadacitinib 15 mg once daily. The primary endpoint was the proportion of patientsachieving an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week14.

Of patients who were initially randomised to upadacitinib, 72% (67/93) in SELECT-AXIS 1 and 77%(163/211) in SELECT-AXIS 2 (AS) continued therapy through 2 years.

In both studies, a significantly greater proportion of patients treated with upadacitinib 15 mg achievedan ASAS40 response compared to placebo at week 14 (Table 11). A numerical difference betweentreatment groups was observed from week 2 in SELECT-AXIS 1 and week 4 in SELECT-AXIS 2(AS) for ASAS40.

Treatment with upadacitinib 15 mg resulted in improvements in individual ASAS components (patientglobal assessment of disease activity, total back pain assessment, inflammation, and function) andother measures of disease activity, including hsCRP, at week 14 compared to placebo.

The efficacy of upadacitinib 15 mg was demonstrated regardless of subgroups evaluated includinggender, baseline BMI, symptom duration of AS, baseline hsCRP, and prior use of bDMARDs.

Table 11 Clinical response

Study SELECT-AXIS 1 SELECT-AXIS 2 (AS)bDMARD-naïve bDMARD-IR

Treatment PBO UPA 15 mg PBO UPA 15 mg

Group

N 94 93 209 211

ASAS40, % of patients (95% CI)a,b

Week 14 25.5 (16.7, 34.3) 51.6 (41.5, 61.8) 18.2 (13.0, 23.4) 44.5 (37.8, 51.3)

Difference from 26.1 (12.6, 39.5)c 26.4 (17.9, 34.9)cplacebo (95%

CI)

ASAS20, % of patients (95% CI)a

Week 14 40.4 (30.5, 50.3) 64.5 (54.8, 38.3 (31.7, 44.9) 65.4 (59.0, 71.8)c74.2)e

ASAS Partial Remission, % of patients (95% CI)

Week 14 1.1 (0.0, 3.1) 19.4 (11.3, pct. 4.3 (1.6, 7.1) 17.5 (12.4, 22.7)c27.4)c

BASDAI 50, % of patients (95% CI)

Week 14 23.4 (14.8, 32.0) 45.2 (35.0, 16.7 (11.7, 21.8) 43.1 (36.4, 49.8)c55.3)d

Change from baseline in ASDAS-CRP (95% CI)

Week 14 -0.54 (-0.71, - -1.45 (-1.62, - -0.49 (-0.62, - -1.52 (-1.64, -1.39)c0.37) 1.28)c 0.37)

ASDAS Inactive Disease, % of patients (95% CI)

Week 14 0 16.1 (8.7, 23.6)e 1.9 (0.1, 3.8) 12.8 (8.3, 17.3)c

ASDAS Low Disease Activity, % of patients (95% CI)

Week 14 10.6 (4.4, 16.9) 49.5 (39.3, 10.1 (6.0, 14.2) 44.1 (37.4, 50.8)c59.6)f

ASDAS Major Improvement, % of patients (95% CI)

Week 14 5.3 (0.8, 9.9) 32.3 (22.8, pct. 4.8 (1.9, 7.7) 30.3 (24.1, 36.5)e41.8)ea An ASAS20 (ASAS40) response is defined as a ≥20% (≥40%) improvement and an absoluteimprovement from baseline of ≥1 (≥2) unit(s) (range 0 to 10) in ≥3 of 4 domains (Patient Global,

Total Back Pain, Function, and Inflammation), and no worsening in the potential remainingdomain (defined as worsening ≥20% and ≥1 unit for ASAS20 or defined as worsening of > 0 unitsfor ASAS40).b primary endpointc multiplicity-controlled p≤0.001 upadacitinib vs placebo comparisond multiplicity-controlled p≤0.01 upadacitinib vs placebo comparisone comparison not multiplicity-controlledf post-hoc analysis for SELECT-AXIS 1, not multiplicity-controlled

For binary endpoints, week 14 results are based on non-responder imputation (SELECT-AXIS 1)and on non-responder imputation in conjunction with multiple imputation (SELECT-AXIS 2 [AS]).

For continuous endpoints, week 14 results are based on the least squares mean change from baselineusing mixed models for repeated measures analysis.

In both studies, efficacy was maintained through 2 years as assessed by the endpoints presented in

Table 11.

Physical function response and health-related outcomes

In both studies, patients treated with upadacitinib 15 mg showed significant improvement in physicalfunction from baseline compared to placebo as assessed by the Bath Ankylosing Spondylitis

Functional Index (BASFI) change from baseline at week 14. Improvement in BASFI was maintainedthrough 2 years.

In SELECT-AXIS 2 (AS), patients treated with upadacitinib 15 mg showed significant improvementsin total back pain and nocturnal back pain compared to placebo at week 14. Improvements in totalback pain and nocturnal back pain were maintained through 2 years.

In SELECT-AXIS 2 (AS), patients treated with upadacitinib 15 mg showed significant improvementsin health-related quality of life and overall health as measured by ASQoL and ASAS Health Index,respectively, compared to placebo at week 14. Improvements in ASQoL and ASAS Health Index weremaintained through 2 years.

Enthesitis

In SELECT-AXIS 2 (AS), patients with pre-existing enthesitis (n=310) treated with upadacitinib15 mg showed significant improvement in enthesitis compared to placebo as measured by change frombaseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at week 14. Improvement inenthesitis was maintained through 2 years.

Spinal mobility

In SELECT-AXIS 2 (AS), patients treated with upadacitinib 15 mg showed significant improvementin spinal mobility compared to placebo as measured by change from baseline in Bath Ankylosing

Spondylitis Metrology Index (BASMI) at week 14. Improvement in BASMI was maintained through2 years.

Objective measure of inflammation

Signs of inflammation were assessed by MRI and expressed as change from baseline in the SPARCCscore for spine. In both studies at week 14, significant improvement of inflammatory signs in the spinewas observed in patients treated with upadacitinib 15 mg compared to placebo. Improvement ininflammation as assessed by MRI was maintained through 2 years.

Giant cell arteritis

The efficacy and safety of upadacitinib 15 mg once daily were assessed in SELECT-GCA, a Phase 3randomised, double-blind, multicentre, placebo-controlled study in patients 50 years of age and olderwith new onset or relapsing giant cell arteritis. SELECT-GCA was a 52-week study in which 428patients were randomised in a 2:1:1 ratio and dosed once daily with upadacitinib 15 mg, upadacitinib7.5 mg, or placebo. All patients received background corticosteroid (prednisone or prednisolone)therapy. The upadacitinib-treated groups followed a pre-specified corticosteroid taper regimen withthe aim to reach 0 mg by 26 weeks; the placebo-treated group followed a pre-specified corticosteroidtaper regimen with the aim to reach 0 mg by 52 weeks. The primary endpoint was the proportion ofpatients achieving sustained remission at week 52 as defined by the absence of giant cell arteritis signsand symptoms from week 12 through week 52 and adherence to the protocol-defined corticosteroidtaper regimen. Patients who prematurely discontinued study treatment (upadacitinib or placebo) or hada missing assessment were classified as non-responders. The study included a 52-week extension for atotal study duration of up to 2 years.

Upadacitinib 15 mg and a 26-week corticosteroid taper showed superiority in achieving corticosteroid-free sustained remission at week 52 compared to placebo and a 52-week corticosteroid taper (Table12). Results for each component of sustained remission and sustained complete remission at week 52were consistent with those of the composite endpoints. For sustained remission at week 52 (theprimary endpoint), a similar percentage of patients in each arm were classified as non-responders dueto premature discontinuation of study treatment (placebo: 19.6%; upadacitinib 15 mg: 20.1%) or dueto a missing assessment (placebo: 0.9%; upadacitinib 15 mg: 0.5%).

Treatment effects in subgroups (gender, age, race, prior use of interleukin-6 inhibitor, new onset orrelapsing giant cell arteritis, baseline corticosteroid dose, and giant cell arteritis with or withoutpolymyalgia rheumatica) were consistent with the results in the overall study population.

A significantly lower proportion of patients treated with upadacitinib 15 mg and a 26-weekcorticosteroid taper experienced at least one giant cell arteritis flare compared to those treated withplacebo and a 52-week corticosteroid taper through week 52. In addition, the risk of flare in theupadacitinib arm was significantly lower compared to the placebo arm as measured by time to firstflare through week 52 (Table 12).

Table 12 Clinical response in SELECT-GCA

Treatment Group PBO + 52-week UPA 15 mg + 26-week Treatmentcorticosteroid taper corticosteroid taper Difference

N=112 N=209 (95% CI)

Sustained 29.0% 46.4% 17.1%eremission at (6.3, 27.8)

Week 52a

Sustained 16.1% 37.1% 20.7%fcomplete (11.3, 30.2)remission at

Week 52b

Complete 19.6% 50.2% 30.3%fremission at (20.4, 40.2)

Week 52c

Complete 36.1% 57.2% 20.8%fremission at (9.7, 31.9)

Week 24c

Time to first 0.57e,g

GCA flare (0.399, 0.826)through Week52d

Patients with one 55.6% 34.3% 0.47e,hor more GCA (0.29, 0.74)flares through

Week 52d

Abbreviations: ESR = erythrocyte sedimentation rate; GCA = giant cell arteritis; hsCRP = highsensitivity C-reactive protein; PBO = placebo; UPA = upadacitiniba Sustained remission is defined as having achieved both the absence of GCA signs and symptomsfrom Week 12 through Week 52 and adherence to the protocol-defined corticosteroid taper regimenb Sustained complete remission is defined as having achieved absence of GCA signs and symptomsfrom Week 12 through Week 52, normalization of ESR (to ≤ 30 mm/hr; if ESR > 30 mm/hr andelevation is not attributable to GCA, this criterion can still be met) from Week 12 through Week 52,normalization of hsCRP to < 1 mg/dL without elevation to ≥ 1 mg/dL (on 2 consecutive visits) from

Week 12 through Week 52, and adherence to the protocol-defined corticosteroid taper regimenc Complete remission is defined as having achieved 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, and adherence to the protocol-defined corticosteroid taper regimend GCA flare is defined as an event representing recurrence of GCA signs or symptoms or an ESRmeasurement > 30 mm/hr (attributable to GCA) and requiring an increase in corticosteroid dose,and is only considered after all of the 3 following criteria are met: absence of recurrence of GCAsigns and symptoms, normalization of ESR, and no corticosteroid dose increase. Subjects who donot have an assessment that meets all 3 criteria are considered as having a GCA flare at baseline.

Time to first GCA flare is calculated from the time when all three criteria above are met. Subjectswho meet all 3 criteria above but never experience GCA flare are censored at the last assessmente p≤0.01f p≤0.001g Hazard ratioh Odds ratio

Cumulative corticosteroid dose

Among patients who completed 52 weeks of follow-up, the cumulative corticosteroid exposure atweek 52 was significantly lower in patients treated with upadacitinib 15 mg and a 26-weekcorticosteroid taper compared to placebo and a 52-week corticosteroid taper (median 1615 mg vs2882 mg, respectively). The comparison of cumulative corticosteroid dose between the upadacitinibarm and the placebo arm is affected by the different pre-specified regimens for steroid tapering in theupadacitinib arm versus the placebo arm.

Health-related outcomes

Fatigue was assessed using FACIT-Fatigue score. Patients treated with upadacitinib 15 mg and a26-week corticosteroid taper experienced significantly greater improvement from baseline comparedto placebo and a 52-week corticosteroid taper in FACIT-Fatigue score at week 52 (4.0, 95% CI: 1.33,6.76).

Health-related quality of life was assessed using SF-36. Patients receiving upadacitinib 15 mg and a26-week corticosteroid taper experienced significantly greater improvement from baseline comparedto placebo and a 52-week corticosteroid taper in the Physical Component Summary score of SF-36 atweek 52 (3.75, 95% CI: 1.39, 6.11).

The efficacy and safety of upadacitinib 15 mg and 30 mg once daily ware assessed in three Phase 3randomised, double-blind, multicentre studies (MEASURE UP 1, MEASURE UP 2 and AD UP) in atotal of 2782 patients (12 years of age and older). Upadacitinib was evaluated in 542 (344 in theprimary analysis) adolescent and 2240 adult patients with moderate to severe atopic dermatitis (AD)not adequately controlled by topical medication(s). At baseline, patients had to have all the following:

an Investigator's Global Assessment (vIGA-AD) score ≥ 3 in the overall assessment of AD (erythema,induration/papulation, and oozing/crusting) on an increasing severity scale of 0 to 4, an Eczema Areaand Severity Index (EASI) score ≥16 (composite score assessing extent and severity of erythema,oedema/papulation, scratches and lichenification across 4 different body sites), a minimum bodysurface area (BSA) involvement of ≥ 10%, and weekly average Worst Pruritus Numerical Rating Scale(NRS) ≥ 4.

In all three studies, patients received upadacitinib once daily doses of 15 mg, 30 mg, or matchingplacebo for 16 weeks. In the AD UP study, patients also received concomitant topical corticosteroids(TCS). Following completion of the double blinded period, patients originally randomised toupadacitinib were to continue receiving the same dose until week 260. Patients in the placebo groupwere re-randomised in a 1:1 ratio to receive upadacitinib 15 mg or 30 mg until week 260.

Baseline characteristics

In the monotherapy studies (MEASURE UP 1 and 2), 50.0% of patients had a baseline vIGA-ADscore of 3 (moderate) and 50.0% of patients had a baseline vIGA-AD of 4 (severe). The mean baseline

EASI score was 29.3 and the mean baseline weekly average Worst Pruritus NRS was 7.3. In theconcomitant TCS study (AD UP), 47.1% of patients had a baseline vIGA-AD score of 3 (moderate)and 52.9% of patients had a baseline vIGA-AD of 4 (severe). The mean baseline EASI score was 29.7and the mean baseline weekly average Worst Pruritus NRS was 7.2.

Monotherapy (MEASURE UP 1 AND MEASURE UP 2) and Concomitant TCS (AD UP) studies

A significantly greater proportion of patients treated with upadacitinib 15 mg or 30 mg achievedvIGA-AD 0 or 1, EASI 75, or a ≥ 4-point improvement on the Worst Pruritus NRS compared toplacebo at week 16. Rapid improvements in skin clearance and itch were also achieved (see Table 13).

Figure 1 shows the proportion of patients achieving an EASI 75 response and mean percent changefrom baseline in Worst Pruritus NRS, respectively up to week 16 for MEASURE UP 1 and 2.

Table 13 Efficacy results of upadacitinib

Study MEASURE UP 1 MEASURE UP 2 AD UP

Treatment PBO UPA UPA PBO UPA UPA PBO + UPA UPA

Group 15 mg 30 mg 15 mg 30 mg TCS 15 mg 30 mg ++ TCS TCS

Number ofsubjects281 281 285 278 276 282 304 300 297randomised

Week 16 endpoints, % responders (95% CI)vIGA-AD 8 48d 62d 5 39d 52d 11 40d 59d,0/1a b (5,12) (42,54) (56,68) (2,7) (33,45) (46,58) (7,14) (34,45) (53,64)(co-primary)

EASI 75a 16 70d 80d 13 60d 73d 26 65d 77d(co-primary) (12,21) (64,75) (75,84) (9,17) (54,66) (68,78) (21,31) (59,70) (72,82)

EASI 90a 8 53d 66d 5 42d 58d 13 43d 63d(5,11) (47,59) (60,71) (3,8) (37,48) (53,64) (9,17) (37,48) (58,69)

EASI 100a 2 17d 27d 1 14d 19d 1 12e 23d(0,3) (12,21) (22,32) (0,2) (10,18) (14,23) (0,3) (8,16) (18,27)

Worst Pruritus 12 52d 60d 9 42d 60d 15 52d 64d

NRSc (8,16) (46,58) (54,66) (6,13) (36,48) (54,65) (11,19) (46,58) (58,69)(≥ 4-pointimprovement)

Early onset endpoints, % responders (95% CI)

EASI 75a 4 38d 47d 4 33d 44d 7 31d 44d(Week 2) (1,6) (32,44) (42,53) (1,6) (27,39) (38,50) (4,10) (26,36) (38,50)

Worst Pruritus 0 15d 20d 1 7d 16d 3 12d 19d

NRS (0,1) (11,19) (15,24) (0,2) (4,11) (11,20) (1,5) (8,16) (15,24)(≥ 4-pointimprovementat week 1)c,f

Abbreviations: UPA= upadacitinib (RINVOQ); PBO = placebo

Subjects with rescue medication or with missing data were counted as non-responders. The number andpercentage of subjects who were imputed as non-responders for EASI 75 and vIGA-AD 0/1 at Week 16 due tothe use of rescue therapy in the placebo, upadacitinib 15 mg, and upadacitinib 30 mg groups, respectively, were132 (47.0%), 31 (11.0%), 16 (5.6%) in MEASURE UP 1, 119 (42.8%), 24 (8.7%), 16 (5.7%) in MEASURE

UP 2, and 78 (25.7%), 15 (5.0%), 14 (4.7%) in AD UP.a Based on number of subjects randomisedb Responder was defined as a patient with vIGA-AD 0 or 1 (“clear” or “almost clear”) with a reduction of≥ 2 points on a 0-4 ordinal scalec Results shown in subset of patients eligible for assessment (patients with Worst Pruritus NRS ≥ 4 at baseline)d Statistically significant vs. placebo with p < 0.001e p < 0.001 vs placebo, without multiplicity controlf Statistically significant improvements vs placebo were seen as early as 1 day after initiating upadacitinib30 mg and 2 days after initiating upadacitinib 15 mg in MEASURE UP 1 and 2

Figure 1 Proportion of patients achieving an EASI 75 response and mean percent change frombaseline in Worst Pruritus NRS in MEASURE UP 1 and MEASURE UP 2

Proportion of patients achieving an Mean percent change from baseline in

EASI 75 response Worst Pruritus NRS100 - 0 - T T T

T90 - -10 - o. YT, 1 T80 - -20 - O,, T T70 - -30 -60 - -40 -

T*50 - -50 - T.

N.1* T * T * T * T. T* T * T * T* T* T40 - T -58**

- 60 1 1 I i 1 1 1

T T T T T T T T T T T30 - -70 1 ....A A 0-.6 701 *1 -1 a -1 a a 120 - -B010 - -ao0 1 2 4 a 16 0 2 fo 12 14 16

Weeks Weeks—O- Placebo -O- Placebo

RINVOQ 15 mg QD -M- RINVOQ 15 mg QD

RINVOQ 30 mg QD -A— RINVOQ 30 mg QD

*: p < 0.001 vs placebo, without multiplicity control

**: statistically significant vs. placebo with p < 0.001

Treatment effects in subgroups (weight, age, gender, race, and prior systemic treatment withimmunosuppressants) were consistent with the results in the overall study population.

Response Rate (%) and 95%

Confidence Interval

Percent Change from Baseline (%)and 95% Confidence Interval

Results at week 16 continued to be maintained through week 52 in patients treated with upadacitinib15 mg or 30 mg.

Quality of life/patient-reported outcomes

Table 14 Patient-reported outcomes results of upadacitinib at week 16

Study MEASURE UP 1 MEASURE UP 2

Treatment group PBO UPA UPA PBO UPA UPA15 mg 30 mg 15 mg 30 mg

Number of subjects 281 281 285 278 276 282randomised% responders (95% CI)

ADerm-SS Skin Pain 15 54 e 63e 13 49e 65e(≥ 4-point improvement)a (10,20) (47,60) (57,69) (9,18) (43,56) (59,71)

ADerm-IS Sleep 13 55e 66e 12 50e 62e(≥ 12-point improvement) a,b (9,18) (48,62) (60,72) (8,17) (44,57) (56,69)

DLQI 0/1c 4 30e 41e 5 24e 38e(2,7) (25,36) (35,47) (2,7) (19,29) (32,44)

HADS Anxiety <8 and 14 46e 49e 11 46e 56e

HADS Depression < 8d (8,20) (37,54) (41,57) (6,17) (38,54) (48,64)

Abbreviations: UPA= upadacitinib (RINVOQ); PBO = placebo; DLQI = Dermatology Life

Quality Index; HADS = Hospital Anxiety and Depression Scale

Subjects with rescue medication or with missing data were counted as non-responders.

The threshold values specified correspond to the minimal clinically important difference(MCID) and was used to determine response.a Results shown in subset of patients eligible for assessment (patients with assessment score >

MCID at baseline).b ADerm-IS Sleep assesses difficulty falling asleep, sleep impact, and waking up at night due to

AD.c Results shown in subset of patients eligible for assessment (patients with DLQI > 1 atbaseline).d Results shown in subset of patients eligible for assessment (patients with HADS Anxiety ≥ 8or HADS Depression ≥ 8 at baseline)e Statistically significant vs. placebo with p < 0.001

The efficacy and safety of upadacitinib was evaluated in three multicentre, double-blind,placebo-controlled Phase 3 clinical studies: two replicate induction studies, UC-1 (U-ACHIEVE

Induction) and UC-2 (U-ACCOMPLISH), and a maintenance study UC-3 (U-ACHIEVE

Maintenance). In addition, safety and efficacy of upadacitinib were assessed in a long-term extensionstudy, UC-4 (U-ACTIVATE).

Disease activity was based on the adapted Mayo score (aMS, Mayo scoring system excluding

Physician's Global Assessment), which ranged from 0 to 9 and has three subscores that were eachscored 0 (normal) to 3 (most severe): stool frequency subscore (SFS), rectal bleeding subscore (RBS)and a centrally-reviewed endoscopy subscore (ES).

Induction studies (UC-1 and UC-2)

In UC-1 and UC-2, 988 patients (473 and 515 patients, respectively) were randomised to upadacitinib45 mg once daily or placebo for 8 weeks with a 2:1 treatment allocation ratio and included in theefficacy analysis. All enrolled patients had moderately to severely active ulcerative colitis defined asan aMS of 5 to 9 with an ES of 2 or 3 and demonstrated prior treatment failure including inadequateresponse, loss of response, or intolerance to prior conventional and/or biologic treatment. Priortreatment failure to at least 1 biologic therapy (prior biologic failure) was seen in 52% (246/473)and 51% (262/515) of patients, respectively. Previous treatment failure to conventional therapy but notbiologics (without prior biologic failure) was seen in 48% (227/473) and 49% (253/515) of patients,respectively.

At baseline in UC-1 and UC-2, 39% and 37% of patients received corticosteroids, 1.1% and 0.6% ofpatients received methotrexate and 68% and 69% of patients received aminosalicylates. Concomitantuse of thiopurine was not allowed during the studies. Patient disease activity was moderate (aMS ≥5,≤7) in 61% and 60% of patients and severe (aMS >7) in 39% and 40% of patients.

The primary endpoint was clinical remission per aMS at week 8. Table 15 shows the primary and keysecondary endpoints including clinical response, mucosal healing, histologic-endoscopic mucosalhealing and deep mucosal healing.

Table 15 Proportion of patients meeting primary and key secondary efficacy endpoints at week 8in the induction studies UC-1 and UC-2

UC-1 UC-2(U-ACHIEVE) (U-ACCOMPLISH)

Endpoint UPA Treatment UPA Treatment

PBO 45 mg Difference PBO 45 mg Difference

N=154 N=319 (95% CI) N=174 N=341 (95% CI)a

Clinical remission 4.8% 26.1% 21.6%* 4.1% 33.5% 29.0%*(15.8, 27.4) (23.2, 34.7)

Prior biologic failure+ 0.4% 17.9% 17.5% 2.4% 29.6% 27.1%

Without prior biologic 9.2% 35.2% 26.0% 5.9% 37.5% 31.6%failure+b

Clinical response 27.3% 72.6% 46.3%* 25.4% 74.5% 49.4%*(38.4, 54.2) (41.7, 57.1)

Prior biologic failure+ 12.8% 64.4% 51.6% 19.3% 69.4% 50.1%

Without prior biologic 42.1% 81.8% 39.7% 31.8% 79.8% 48.0%failure+c

Mucosal healing 7.4% 36.3% 29.3%* 8.3% 44.0% 35.1%*(22.6, 35.9) (28.6, 41.6)

Prior biologic failure+ 1.7% 27.0% 25.3% 4.8% 37.1% 32.3%

Without prior biologic 13.2% 46.8% 33.6% 12.0% 51.2% 39.2%failure+

Histologic-endoscopic 6.6% 30.1% 23.7%* 5.9% 36.7% 30.1%*dmucosal healing(17.5, 30.0) (24.1, 36.2)

Prior biologic failure+ 1.4% 22.7% 21.3% 4.6% 30.7% 26.1%

Without prior biologic 11.8% 38.2% 26.4% 7.2% 42.9% 35.7%failure+e

Deep mucosal healing 1.3% 10.7% 9.7%* 1.7% 13.5% 11.3%*(5.7, 13.7) (7.2, 15.3)

Prior biologic failure+ 0 6.5% 6.5% 1.1% 9.2% 8.1%

Without prior biologic 2.6% 15.4% 12.8% 2.4% 17.9% 15.5%failure+

Abbreviations: PBO = placebo; UPA= upadacitinib; aMS = adapted Mayo Score, based on the Mayo

Scoring system (excluding Physician's Global Assessment), which ranged from 0 to 9 and has threesubscores that were each scored 0 (normal) to 3 (most severe): stool frequency subscore (SFS), rectalbleeding subscore (RBS) and a centrally-reviewed endoscopy subscore (ES).+The number of “Prior biologic failure” patients in UC-1 and UC-2 are 78 and 89 in the placebo group,and 168 and 173 in the upadacitinib 45 mg group, respectively; the number of “Without prior biologicfailure” patients in UC-1 and UC-2 are 76 and 85 in the placebo group, and 151 and 168 in theupadacitinib 45 mg group, respectively.

*p <0.001, adjusted treatment difference (95% CI)a Per aMS: SFS≤ 1 and not greater than baseline, RBS = 0, ES ≤ 1 without friabilityb

Per aMS: decrease ≥ 2 points and ≥ 30% from baseline and a decrease in RBS ≥ 1 from baseline or anabsolute RBS ≤ 1.cES ≤ 1 without friabilityd ES ≤ 1 without friability and Geboes score ≤ 3.1 (indicating neutrophil infiltration in < 5% of crypts,no crypt destruction, and no erosions, ulcerations, or granulation tissue.)e ES = 0, Geboes score < 2 (indicating no neutrophil in crypts or lamina propria and no increase ineosinophil, no crypt destruction, and no erosions, ulcerations, or granulation tissue)

Disease activity and symptoms

The partial adapted Mayo score (paMS) is composed of SFS and RBS. Symptomatic response perpaMS is defined as a decrease of ≥1 point and ≥30% from baseline and a decrease in RBS ≥ 1 or anabsolute RBS ≤1. Statistically significant improvement compared to placebo per paMS was seen asearly as week 2 (UC-1: 60.1% vs 27.3% and UC-2: 63.3% vs 25.9%).

Extended induction

A total of 125 patients in UC-1 and UC-2 who did not achieve clinical response after 8 weeks oftreatment with upadacitinib 45 mg once daily entered an 8-week open-label extended induction period.

After the treatment of an additional 8 weeks (16 weeks total) of upadacitinib 45 mg once daily, 48.3%of patients achieved clinical response per aMS. Among patients who responded to treatment of16-week upadacitinib 45 mg once daily, 35.7% and 66.7% of patients maintained clinical response peraMS and 19.0% and 33.3% of patients achieved clinical remission per aMS at week 52 withmaintenance treatment of upadacitinib 15 mg and 30 mg once daily, respectively.

Maintenance study (UC-3)

The efficacy analysis for UC-3 was evaluated in 451 patients who achieved clinical response per aMSwith 8-week upadacitinib 45 mg once daily induction treatment. Patients were randomised to receiveupadacitinib 15 mg, 30 mg or placebo once daily for up to 52 weeks.

The primary endpoint was clinical remission per aMS at week 52. Table 16 shows the key secondaryendpoints including maintenance of clinical remission, corticosteroid-free clinical remission, mucosalhealing, histologic-endoscopic mucosal healing and deep mucosal healing.

Table 16 Proportion of patients meeting primary and key secondary efficacy endpoints at week52 in the maintenance study UC-3

Treatment Treatment

UPA UPA

PBO Difference Difference15 mg 30 mg

N=149 15 mg vs PBO 30 mg vs PBO

N=1 48 N=1(95% CI) (95% CI)a

Clinical remission 12.1% 42.3% 51.7% 30.7%* 39.0%*(21.7, 39.8) (29.7, 48.2)

Prior biologic failure+ 7.5% 40.5% 49.1% 33.0% 41.6%

Without prior biologic failure+ 17.6% 43.9% 54.0% 26.3% 36.3%

Maintenance of clinical N = 54 N = 47 N = 58 37.4%* 47.0%*bremission 22.2% 59.2% 69.7% (20.3, 54.6) (30.7, 63.3)

N = 22 N = 17 N = 20

Prior biologic failure 62.8% 59.4%13.6% 76.5% 73.0%

N = 32 N = 30 N = 38

Without prior biologic failure 21.3% 39.9%28.1% 49.4% 68.0%

Corticosteroid-free clinical N = 54 N = 47 N = 58 35.4%* 45.1%*cremission 22.2% 57.1% 68.0% (18.2, 52.7) (28.7, 61.6)

Prior biologic failure N = 22 N = 17 N = 20 57.0% 59.4%13.6% 70.6% 73.0%

Without prior biologic failure N = 32 N = 30 N = 38 21.3% 37.2%28.1% 49.4% 65.4%d

Mucosal healing 14.5% 48.7% 61.6% 34.4%* 46.3%*(25.1, 43.7) (36.7, 55.8)

Prior biologic failure+ 7.8% 43.3% 56.1% 35.5% 48.3%

Without prior biologic failure+ 22.5% 53.6% 66.6% 31.1% 44.1%

Histologic-endoscopic 11.9% 35.0% 49.8% 23.8%* 37.3%*emucosal healing (14.8, 32.8) (27.8, 46.8)

Prior biologic failure+ 5.2% 32.9% 47.6% 27.7% 42.4%

Without prior biologic failure+ 20.0% 36.9% 51.8% 16.9% 31.8%f

Deep mucosal healing 4.7% 17.6% 19.0% 13.0%* 13.6%*(6.0, 20.0) (6.6, 20.6)

Prior biologic failure+ 2.5% 17.2% 16.1% 14.7% 13.6%

Without prior biologic failure+ 7.5% 18.0% 21.6% 10.6% 14.2%

Abbreviations: PBO = placebo; UPA= upadacitinib; aMS = adapted Mayo Score, based on the Mayo Scoringsystem (excluding Physician's Global Assessment), which ranged from 0 to 9 and has three subscores thatwere each scored 0 (normal) to 3 (most severe): stool frequency subscore (SFS), rectal bleeding subscore(RBS) and a centrally-reviewed endoscopy subscore (ES).+The number of “Prior biologic failure” patients are 81, 71, and 73 in the placebo, upadacitinib 15 mg, and30 mg group, respectively. The number of “Without prior biologic failure” patients are 68, 77, and 81 in theplacebo, upadacitinib 15 mg, and 30 mg group, respectively.

* p <0.001, adjusted treatment difference (95% CI)a Per aMS: SFS≤ 1 and not greater than baseline, RBS = 0, ES ≤ 1 without friabilityb Clinical remission per aMS at Week 52 among patients who achieved clinical remission at the end ofinduction treatment.c Clinical remission per aMS at Week 52 and corticosteroid-free for ≥90 days immediately preceding Week52 among patients who achieved clinical remission at the end of the induction treatment.d ES ≤1 without friabilitye ES ≤1 without friability and Geboes score ≤ 3.1 (indicating neutrophil infiltration in <5% of crypts, no cryptdestruction and no erosions, ulcerations or granulation tissue).f ES = 0, Geboes score < 2 (indicating no neutrophil in crypts or lamina propria and no increase in eosinophil,no crypt destruction, and no erosions, ulcerations or granulation tissue).

Disease symptoms

Symptomatic remission per paMS, defined as SFS ≤ 1 and RBS = 0, was achieved over time throughweek 52 in more patients treated with both upadacitinib 15 mg and 30 mg once daily compared withplacebo (Figure 2).

Figure 2 Proportion of patients with symptomatic remission per partial adapted Mayo score overtime in maintenance study UC-370 64.560-57.450-40-30 - ...... ................. .................

20 .................. . ................ 117 5.110-4 8 12 20 28 36 44 52

Weekso Placebo (N=149) UPA 15 mg QD (N=148) UPA 30 mg QD (N=154)

Endoscopic assessment

Endoscopic remission (normalisation of the endoscopic appearance of the mucosa) was defined as ESof 0. At week 8, a significantly greater proportion of patients treated with upadacitinib 45 mg oncedaily compared to placebo achieved endoscopic remission (UC-1: 13.7% vs 1.3%, UC-2: 18.2% vs1.7%). In UC-3, a significantly greater proportion of patients treated with upadacitinib 15 mg and30 mg once daily compared to placebo achieved endoscopic remission at week 52 (24.2% and 25.9%vs 5.6%). Maintenance of mucosal healing at week 52 (ES ≤1 without friability) was seen in asignificantly greater proportion of patients treated with upadacitinib 15 mg and 30 mg once dailycompared to placebo (61.6% and 69.5% vs 19.2%) among patients who achieved mucosal healing atthe end of induction.

Patients treated with upadacitinib demonstrated significantly greater and clinically meaningfulimprovement in health-related quality of life measured by the Inflammatory Bowel Disease

Questionnaire (IBDQ) total score compared to placebo. Improvements were seen in all 4 domainscores: systemic symptoms (including fatigue), social function, emotional function and bowelsymptoms (including abdominal pain and bowel urgency). Changes in IBDQ total score at week 8from baseline with upadacitinib 45 mg once daily compared to placebo were 55.3 and 21.7 in UC-1and 52.2 and 21.1 in UC-2, respectively. Changes in IBDQ total score at week 52 from baseline were49.2, 58.9 and 17.9 in patients treated with upadacitinib 15 mg, 30 mg once daily and placebo,respectively.

Percent Responders and 95%

Confidence Interval

Long-term extension study (UC-4)

Patients who achieved clinical remission in UC-3 per aMS at 1 year were eligible to continue with thesame dose in the extension study (UC-4). At the entry of UC-4, there were 96 and 146 patients inclinical remission and 49 and 82 patients in endoscopic remission with upadacitinib 15 mg and 30 mg,respectively. This population is partly, but not fully, overlapping with the population presented in theabove table depicting proportion of patients meeting endpoints at week 52 in the maintenance study

UC-3. Among patients who achieved remission in UC-3 per aMS at 1 year and had available 96 weeksdata, 55/70 (78.6%) and 75/89 (84.3%) maintained clinical remission and 22/34 (64.7%) and 40/54(74.1%) maintained endoscopic remission after 96 weeks of additional treatment with upadacitinib15 mg and 30 mg, respectively.

In patients entering the extension study upon completion of UC-3 (1 year) and had available 96 weeksdata, improvements in IBDQ total scores and in IBDQ domain scores were maintained through week96 of UC-4.

The safety profile of upadacitinib with long-term treatment was consistent with that in theplacebo-controlled period.

The efficacy and safety of upadacitinib was evaluated in three multicenter, double-blind,placebo-controlled Phase 3 studies: two induction studies, CD-1 (U-EXCEED) and CD-2 (U-EXCEL),followed by a 52-week maintenance treatment and long-term extension study, CD-3 (U-ENDURE).

The co-primary endpoints were clinical remission and endoscopic response at week 12 for CD-1 and

CD-2, and at week 52 for CD-3.

Enrolled patients were 18 to 75 years of age with moderately to severely active Crohn’s disease (CD),defined as an average daily very soft or liquid stool frequency (SF) ≥ 4 and/or average daily abdominalpain score (APS) ≥ 2, and a centrally-reviewed Simple Endoscopic Score for CD (SES-CD) of ≥ 6, or≥ 4 for isolated ileal disease, excluding the narrowing component. Patients with symptomatic bowelstrictures were excluded from CD studies.

Induction studies (CD-1 and CD-2)

In CD-1 and CD-2, 1021 patients (495 and 526 patients, respectively) were randomised to upadacitinib45 mg once daily or placebo for 12 weeks with a 2:1 treatment allocation ratio.

In CD-1, all patients had inadequate response or were intolerant to treatment with one or morebiologic therapies (prior biologic failure). Of these patients, 61% (301/495) had inadequate responseor were intolerant to two or more biologic therapies.

In CD-2, 45% (239/526) patients had an inadequate response or were intolerant to treatment with oneor more biologic therapies (prior biologic failure), and 55% (287/526) had an inadequate response orwere intolerant to treatment with conventional therapies but not to biologic therapy (without priorbiologic failure).

At baseline in CD-1 and CD-2, 34% and 36% of patients received corticosteroids, 7% and 3% ofpatients received immunomodulators, and 15% and 25% of patients received aminosalicylates.

In both studies, patients receiving corticosteroids at baseline initiated a corticosteroid taper regimenstarting at week 4.

Both studies included a 12-week extended treatment period with upadacitinib 30 mg once daily forpatients who received upadacitinib 45 mg once daily and did not achieve clinical response per SF/APS(≥ 30% decrease in average daily very soft or liquid SF and/or ≥ 30% decrease in average daily APSand neither greater than baseline) at week 12.

Clinical disease activity and symptoms

In CD-1 and CD-2, a significantly greater proportion of patients treated with upadacitinib 45 mgachieved the co-primary endpoint of clinical remission at week 12 compared to placebo (Table 17).

Onset of efficacy was rapid and achieved as early as week 2 (Table 17).

In both studies, patients receiving upadacitinib 45 mg experienced significantly greater improvementfrom baseline in fatigue, as measured by FACIT-F score at week 12 compared to placebo.

Endoscopic assessment

In CD-1 and CD-2, a significantly greater proportion of patients treated with upadacitinib 45 mgachieved the co-primary endpoint of endoscopic response at week 12 compared to placebo (Table 17).

In CD-1 and CD-2, a greater proportion of patients treated with upadacitinib 45 mg (14% and 19%,respectively) compared to placebo (0% and 5%, respectively) achieved SES-CD 0-2.

Table 17 Proportion of patients meeting primary and additional efficacy endpoints in inductionstudies CD-1 and CD-2

Study CD-1 CD-2(U-EXCEED) (U-EXCEL)

Treatment Group UPA Treatment UPA Treatment

PBO PBO45 mg Difference 45 mg Difference

N=1 71 N=176

N=324 (95% CI) N=3 50 (95% CI)

Co-Primary Endpoints at Week 12a

Clinical remission 14% 40% 26% 22% 51% 29%

*(19, 33) (21, 36)*

Prior biologic N=78 N=161 33%failure 14% 47% (22, 44)

Without prior N=98 N=189 26%biologic failure 29% 54% (14, 37)b

Endoscopic response 4% 35% 31% 13% 46% 33%

*(25, 37) (26, 40)*

Prior biologic N=78 N=161 29%failure 9% 38% (19, 39)

Without prior N=98 N=189 36%biologic failure 16% 52% (25, 46)

Additional Endpoints at Week 12

Clinical remission per 21% 39% 18% 29% 49% 21%c *

CDAI (10, 26) (13, 29)*

Clinical response 27% 51% 23% 37% 57% 20%d *(CR-100) (14, 31) (11, 28)*

Corticosteroid-free N=60 N=108 30% N=64 N=126 33%a,eclinical remission 7% 37% (19, 41)* 13% 44% (22, 44)*f

Endoscopic remission 2% 19% 17% 7% 29% 22%

*(12, 22) (16, 28)*g

Mucosal healing N=171 N= 322 17% N=174 N=349 20%0% 17% (13, 21)*** 5% 25% (14, 25)***

Early Onset Endpoints

Clinical remission at 9% 32% 23% 15% 36% 21%a

Week 4 (17, 30)* (14, 28)*d

CR-100 at Week 2 12% 33% 21% 20% 32% 12%

*(14, 28) (4, 19)**

Abbreviation: PBO = placebo, UPA = upadacitinib

* p < 0.001, adjusted treatment difference (95% CI)

** p < 0.01, adjusted treatment difference (95% CI)

*** nominal p < 0.001 UPA vs PBO comparison, adjusted treatment difference (95% CI)a Average daily SF ≤ 2.8 and APS ≤ 1.0 and neither greater than baselineb Decrease in SES-CD > 50% from baseline of the induction study (or for patients with an SES-CDof 4 at baseline of the induction study, at least a 2-point reduction from baseline of the inductionstudy)c CDAI < 150d Decrease of at least 100 points in CDAI from baselinee Discontinuation of steroid and achievement of clinical remission among patients on steroid atbaselinef SES-CD ≤ 4 and at least a 2-point reduction versus baseline and no subscore > 1 in any individualvariableg SES-CD ulcerated surface subscore of 0 in patients with SES-CD ulcerated surface subscore ≥ 1at baseline

Maintenance study (CD-3)

The efficacy analysis for CD-3 evaluated 502 patients who achieved clinical response per SF/APSwith the 12-week upadacitinib 45 mg once daily induction treatment. Patients were re-randomised toreceive a maintenance regimen of either upadacitinib 15 mg or 30 mg once daily or placebo for 52weeks.

Clinical disease activity and symptoms

A significantly greater proportion of patients treated with upadacitinib 15 mg and 30 mg achieved theco-primary endpoint of clinical remission at week 52 compared to placebo (Figure 3, Table 18).

Figure 3 Proportion of patients achieving clinical remission in maintenance study CD-3100 -90 -80 -70 - .

60 - *...= ..

50 - ' ... 46

I ....

40 - * ...... 3630 - ..I. ......................... .20 -10 - ........I.. 14o0 .`i 12 22 32 42 52

Weekso Placebo (N=165) ---Alk- UPA 15 mg QD (N=169) UPA 30 mg QD (N=168)

Patients receiving upadacitinib 30 mg experienced significantly greater improvement from baseline infatigue, as measured by FACIT-F score at week 52 compared to placebo.

Percent Responders and 95%

Confidence Interval

Table 18 Proportion of patients meeting primary and additional efficacy endpoints at week 52 inmaintenance study CD-3+

Treatment Group PBO UPA UPA Treatment Treatment

N=1 65 15 mg 30 mg Difference Difference

N=1 69 N=1 68 15 mg vs 30 mg vs

PBO PBO(95% CI) (95% CI)

Co-Primary Endpointsa 22% 32%

Clinical remission 14% 36% 46%(14, 30)* (23, 40)*

N=126 N=124 N=127 24% 34%

Prior biologic failure9% 32% 43% (14, 33) (24, 44)

N=39 N=45 N=41 12% 26%

Without prior biologic failure33% 44% 59% (-9, 33) (5, 47)b 21% 34%

Endoscopic response 7% 28% 40%(14, 28)* (26, 41)*

N=126 N=124 N=127 19% 35%

Prior biologic failure4% 23% 39% (11, 27) (26, 44)

N=39 N=45 N=41 22% 26%

Without prior biologic failure18% 40% 44% (3, 41) (7, 45)

Additional Endpointsc 24% 33%

Clinical remission per CDAI 15% 37% 48% * *(15, 32) (24, 42)d 27% 36%

Clinical response (CR-100) 15% 41% 51%(18, 36)* (28, 45)*

Corticosteroid-free clinical 21% 30%a,e 14% 35% 45%remission (13, 30)* (21, 39)*

Maintenance of clinical N=101 N=105 N=105 32% 40%a,fremission 20% 50% 60% (20, 44)* (28, 52)*g 14% 24%

Endoscopic remission 5% 19% 29%(8, 21)* (16, 31)*h N=164 N=167 N=168 10% 21%

Mucosal healing4% 13% 24% (4, 16)*** (14, 27)***a,i 10% 18%

Deep remission 4% 14% 23%(4, 16)** (11, 25)*

Abbreviation: PBO = placebo, UPA = upadacitinib+ The placebo group consisted of patients who achieved clinical response per SF/APS withupadacitinib 45 mg at the end of the induction study and were randomised to receive placebo at thestart of maintenance therapy

* p < 0.001, adjusted treatment difference (95% CI)

** p < 0.01, adjusted treatment difference (95% CI)

*** nominal p < 0.001 UPA vs PBO comparison, adjusted treatment difference (95% CI)a Average daily SF ≤ 2.8 and APS ≤ 1.0 and neither greater than baselineb Decrease in SES-CD > 50% from baseline of the induction study (or for patients with an SES-CDof 4 at baseline of the induction study, at least a 2-point reduction from baseline of the inductionstudy)c CDAI < 150d Reduction of CDAI ≥ 100 points from baselinee Corticosteroid-free for 90 days prior to week 52 and achievement of clinical remission. Among thesubset of patients who were on corticosteroids at induction baseline, 38% (N=63) in upadacitinib15 mg group, 38% (N=63) in upadacitinib 30 mg group, and 5% (N=61) in placebo werecorticosteroid-free for 90 days prior to week 52 and in clinical remissionf Defined as achievement of clinical remission at Week 52 in patients who achieved clinicalremission at the entry of the maintenance studyg SES-CD ≤ 4 and at least a 2-point reduction versus baseline and no subscore >1 in any individualvariableh SES-CD ulcerated surface subscore of 0 in patients with SES-CD ulcerated surface subscore ≥ 1 atbaselinei

Clinical remission and endoscopic remission

Patients who were not in clinical response per SF/APS to upadacitinib induction at week 12 in CD-1and CD-2 (122 patients) received upadacitinib 30 mg once daily for an additional 12 weeks. Of thesepatients, 53% achieved clinical response at week 24. Of the patients who responded to the extendedtreatment period and continued to receive maintenance treatment with upadacitinib 30 mg, 25%achieved clinical remission and 22% achieved endoscopic response at week 52.

Endoscopic assessment

In CD-3, a significantly greater proportion of patients treated with upadacitinib 15 mg and 30 mgachieved the co-primary endpoint of endoscopic response at week 52 compared to placebo (Table 18).

In addition to the endoscopic endpoints described in Table 18, a greater proportion of patients treatedwith upadacitinib 15 mg and 30 mg (11% and 21%, respectively) compared to placebo (3%) achieved

SES-CD 0-2 at week 52. Corticosteroid-free endoscopic remission among patients on steroid atbaseline was achieved in a greater proportion of patients treated with upadacitinib 15 mg and 30 mg(17% and 25%, respectively) compared to placebo (3%) at week 52.

Resolution of extra-intestinal manifestations

Resolution of extra-intestinal manifestations was observed in a greater proportion of patients treatedwith upadacitinib 15 mg (25%) and a significantly greater proportion of patients treated withupadacitinib 30 mg (36%) compared to placebo (15%) at week 52.

Rescue treatment

In CD-3, patients who demonstrated inadequate response or lost response during maintenance wereeligible to receive rescue treatment with upadacitinib 30 mg. Of the patients who were randomised toupadacitinib 15 mg group and received rescue treatment of upadacitinib 30 mg for at least 12 weeks,84% (76/90) achieved clinical response per SF/APS and 48% (43/90) achieved clinical remission 12weeks after initiating rescue.

Health-related quality of life outcomes

Patients treated with upadacitinib achieved greater improvement in health-related quality of life(HRQOL) measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) total score comparedto placebo. Improvements were seen in all 4 domain scores: systemic symptoms (including fatigue)and bowel symptoms (including abdominal pain and bowel urgency), as well as social and emotionalfunctioning. Changes from baseline in IBDQ total score at week 12 with upadacitinib 45 mg oncedaily compared to placebo were 46.0 and 21.6 in CD-1 and 46.3 and 24.4 in CD-2, respectively.

Changes in IBDQ total score at week 52 from baseline were 59.3, 64.5 and 46.4 in patients treatedwith upadacitinib 15 mg, 30 mg once daily and placebo, respectively.

A total of 542 adolescents aged 12 to 17 years with moderate to severe atopic dermatitis wererandomised across the three global Phase 3 studies, of which 344 were evaluated for the primaryanalysis. Adolescents in the primary analysis were randomised to receive either 15 mg (N=114) or30 mg (N=114) upadacitinib or matching placebo (N=116), in monotherapy or combination withtopical corticosteroids. Efficacy was consistent between the adolescents and adults. The safety profilein adolescents was generally similar to that in adults, with dose-dependent increases in the rate ofsome adverse events, including neutropenia and herpes zoster. At both doses, the rate of neutropeniawas slightly increased in adolescents compared to adults. At both doses, the rate of herpes zoster washigher in adults compared to that in adolescents.

Table 19 Efficacy results of upadacitinib for adolescents at week 16

Study MEASURE UP 1 MEASURE UP 2 AD UP

Treatment PBO UPA UPA PBO UPA UPA PBO + UPA UPA

Group 15 mg 30 mg 15 mg 30 mg TCS 15 mg 30 mg ++ TCS TCS

Number ofadolescent 40 42 42 36 33 35 40 39 37subjectsrandomised% responders (95% CI)vIGA-AD 0/1 a,b 8 38 69 3 42 62 8 31 65(0,16) (23,53) (55,83) (0,8) (26,59) (46,79) (0,16) (16,45) (50,80)

EASI 75a 8 71 83 14 67 74 30 56 76(0,17) (58,85) (72,95) (3,25) (51,83) (59,90) (16,44) (41,72) (62,90)

Worst Pruritus 15 45 55 3 33 50 13 42 55

NRSc (4,27) (30,60) (40,70) (0,8) (16,50) (33,67) (2,24) (26,58) (38,72)(≥ 4-pointimprovement)

Abbreviations: UPA= upadacitinib (RINVOQ); PBO = placebo

Subjects with rescue medication or with missing data were counted as non-responders.a Based on number of subjects randomisedb Responder was defined as a patient with vIGA-AD 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2points on a 0-4 ordinal scale.c Results shown in subset of patients eligible for assessment (patients with Worst Pruritus NRS ≥ 4 atbaseline).

The European Medicines Agency has deferred the obligation to submit the results of studies with

RINVOQ in one or more subsets of the paediatric population in chronic idiopathic arthritis (includingrheumatoid arthritis, psoriatic arthritis, spondyloarthritis and juvenile idiopathic arthritis) atopicdermatitis, ulcerative colitis, and Crohn’s disease (see section 4.2 for information on paediatric use).

Upadacitinib plasma exposures are proportional to dose over the therapeutic dose range. Steady-stateplasma concentrations are achieved within 4 days with minimal accumulation after multiple once dailyadministrations.

Following oral administration of upadacitinib prolonged-release formulation, upadacitinib is absorbedwith a median Tmax of 2 to 4 hours. Coadministration of upadacitinib with a high-fat meal had noclinically relevant effect on upadacitinib exposures (increased AUC by 29% and Cmax by 39% to 60%).

In clinical trials, upadacitinib was administered without regard to meals (see section 4.2). In vitro,upadacitinib is a substrate for the efflux transporters P-gp and BCRP.

Upadacitinib is 52% bound to plasma proteins. Upadacitinib partitions similarly between plasma andblood cellular components, as indicated by the blood to plasma ratio of 1.0.

Upadacitinib metabolism is mediated by CYP3A4 with a potential minor contribution from CYP2D6.

The pharmacologic activity of upadacitinib is attributed to the parent molecule. In a humanradiolabeled study, unchanged upadacitinib accounted for 79% of the total radioactivity in plasmawhile the main metabolite (product of monooxidation followed by glucuronidation) accounted for 13%of the total plasma radioactivity. No active metabolites have been identified for upadacitinib.

Following single dose administration of [14C]-upadacitinib immediate-release solution, upadacitinibwas eliminated predominantly as the unchanged parent substance in urine (24%) and faeces (38%).

Approximately 34% of upadacitinib dose was excreted as metabolites. Upadacitinib mean terminalelimination half-life ranged from 9 to 14 hours.

Upadacitinib AUC was 18%, 33%, and 44% higher in subjects with mild (estimated glomerularfiltration rate 60 to 89 ml/min/1.73 m2), moderate (estimated glomerular filtration rate 30 to59 ml/min/1.73 m2), and severe (estimated glomerular filtration rate 15 to 29 ml/min/1.73 m2) renalimpairment, respectively, compared to subjects with normal renal function. Upadacitinib Cmax wassimilar in subjects with normal and impaired renal function. Mild or moderate renal impairment has noclinically relevant effect on upadacitinib exposure (see section 4.2).

Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment has no clinically relevanteffect on upadacitinib exposure. Upadacitinib AUC was 28% and 24% higher in subjects with mildand moderate hepatic impairment, respectively, compared to subjects with normal liver function.

Upadacitinib Cmax was unchanged in subjects with mild hepatic impairment and 43% higher insubjects with moderate hepatic impairment compared to subjects with normal liver function.

Upadacitinib was not studied in patients with severe (Child-Pugh C) hepatic impairment.

The pharmacokinetics of upadacitinib have not yet been evaluated in paediatric patients withrheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, ulcerative colitis, and Crohn’s disease(see section 4.2).

Upadacitinib pharmacokinetics and steady-state concentrations are similar for adults and adolescents12 to 17 years of age with atopic dermatitis. The posology in adolescent patients 30 kg to < 40 kg wasdetermined using population pharmacokinetic modelling and simulation. No clinical exposure data areavailable in adolescents < 40 kg.

The pharmacokinetics of upadacitinib in paediatric patients (< 12 years of age) with atopic dermatitishave not been established.

Intrinsic factors

Age, sex, body weight, race, and ethnicity did not have a clinically meaningful effect on upadacitinibexposure. Upadacitinib pharmacokinetics are consistent between rheumatoid arthritis, psoriaticarthritis, axial spondyloarthritis, giant cell arteritis, atopic dermatitis, ulcerative colitis, and Crohn’sdisease patients.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology.

Upadacitinib, at exposures (based on AUC) approximately 4 and 10 times the clinical dose of 15 mg, 2and 5 times the clinical dose of 30 mg, and 1.7 and 4 times the clinical dose of 45 mg in male andfemale Sprague-Dawley rats, respectively, was not carcinogenic in a 2-year carcinogenicity study in

Sprague-Dawley rats. Upadacitinib was not carcinogenic in a 26-week carcinogenicity study in

CByB6F1-Tg(HRAS)2Jic transgenic mice.

Upadacitinib was not mutagenic or genotoxic based on the results of in vitro and in vivo tests for genemutations and chromosomal aberrations.

Upadacitinib had no effect on fertility in male or female rats at exposures up to approximately 17 and34 times the maximum recommended human dose (MRHD) of 45 mg in males and females,respectively, on an AUC basis in a fertility and early embryonic development study. Dose-relatedincreases in foetal resorptions associated with post-implantation losses in this fertility study in ratswere attributed to the developmental/teratogenic effects of upadacitinib. No adverse effects wereobserved at exposures below clinical exposure (based on AUC). Post-implantation losses wereobserved at exposures 9 times the clinical exposure at the MRHD of 45 mg (based on AUC).

In animal embryo-foetal development studies, upadacitinib was teratogenic in both rats and rabbits.

Upadacitinib resulted in increases in skeletal malformations in rats at 1.6, 0.8, and 0.6 times theclinical exposure (AUC-based) at the 15, 30, and 45 mg (MRHD) doses, respectively. In rabbits anincreased incidence of cardiovascular malformations was observed at 15, 7.6, and 6 times the clinicalexposure at the 15, 30, and 45 mg doses (AUC-based), respectively.

Following administration of upadacitinib to lactating rats, the concentrations of upadacitinib in milkover time generally paralleled those in plasma, with approximately 30-fold higher exposure in milkrelative to maternal plasma. Approximately 97% of upadacitinib-related material in milk was theparent molecule, upadacitinib.

Tablet contents

Microcrystalline cellulose

Hypromellose

Mannitol

Tartaric acid

Silica, colloidal anhydrous

Magnesium stearate

Poly(vinyl alcohol)

Macrogol

Talc

Titanium dioxide (E171)

Iron oxide black (E172) (15 mg strength only)

Iron oxide red (E172)

Iron oxide yellow (E172) (45 mg strength only)

Not applicable.

Prolonged-release tablets in blisters: 2 years

Prolonged-release tablets in bottles: 3 years

Prolonged-release tablets in blisters: 2 years

Prolonged-release tablets in bottles: 3 years

RINVOQ 45 mg prolonged-release tablets2 years

This medicinal product does not require any special temperature storage conditions.

Store in the original blister or bottle in order to protect from moisture. Keep the bottle tightly closed.

Polyvinylchloride/polyethylene/polychlorotrifluoroethylene - aluminium calendar blisters in packscontaining 28 or 98 prolonged-release tablets, or multipacks containing 84 (3 packs of 28) prolonged-release tablets.

HDPE bottles with desiccant and polypropylene cap in carton containing 30 prolonged-release tablets.

Pack size: 1 bottle (30 prolonged-release tablets) or 3 bottles (90 prolonged-release tablets).

Not all pack sizes may be marketed.

Polyvinylchloride/polyethylene/polychlorotrifluoroethylene - aluminium calendar blisters in packscontaining 28 or 98 prolonged-release tablets.

HDPE bottles with desiccant and polypropylene cap in carton containing 30 prolonged-release tablets.

Pack size: 1 bottle (30 prolonged-release tablets) or 3 bottles (90 prolonged-release tablets).

Not all pack sizes may be marketed.

RINVOQ 45 mg prolonged-release tablets

Polyvinylchloride/polyethylene/polychlorotrifluoroethylene - aluminium calendar blisters in packscontaining 28 prolonged-release tablets.

HDPE bottles with desiccant and polypropylene cap in carton containing 28 prolonged-release tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

EU/1/19/1404/001

EU/1/19/1404/002

EU/1/19/1404/003

EU/1/19/1404/004

EU/1/19/1404/005

EU/1/19/1404/006

EU/1/19/1404/007

EU/1/19/1404/008

EU/1/19/1404/009

EU/1/19/1404/010

EU/1/19/1404/011

Date of first authorisation: 16 December 2019

Date of latest renewal: 19 September 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.