JYSELECA 100mg tablets medication leaflet

Each film-coated tablet contains filgotinib maleate equivalent to 100 mg of filgotinib.

Each 100 mg film-coated tablet contains 76 mg of lactose (as monohydrate).

Each film-coated tablet contains filgotinib maleate equivalent to 200 mg of filgotinib.

Each 200 mg film-coated tablet contains 152 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet

Beige 12 × 7 mm, capsule-shaped, film-coated tablet debossed with “G” on one side and “100” on theother side.

Beige 17 × 8 mm, capsule-shaped, film-coated tablet debossed with “G” on one side and “200” on theother side.

Jyseleca 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). Jyseleca may be used as monotherapy or in combination withmethotrexate (MTX).

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

Treatment with filgotinib should be initiated by a physician experienced in the treatment ofrheumatoid arthritis or ulcerative colitis.

The recommended dose of filgotinib for adult patients is 200 mg once daily.

In adults at increased risk of VTE, MACE and malignancy (see section 4.4), the recommended dose is100 mg once daily and may be escalated to 200 mg once daily in case of insufficient disease control.

For long term treatment, the lowest effective dose should be used.

Induction treatment

The recommended dose for induction treatment is 200 mg once daily.

For patients with ulcerative colitis who do not show an adequate therapeutic benefit during the initial10 weeks of treatment, 12 additional weeks of induction treatment with filgotinib 200 mg once dailymay provide additional relief of symptoms (see section 5.1). Patients who have not shown anytherapeutic benefit after 22 weeks of treatment should discontinue filgotinib.

The recommended dose for maintenance treatment is 200 mg once daily.

In adults at higher risk of VTE, MACE and malignancy (see section 4.4), the recommended dose formaintenance treatment is 100 mg once daily. In case of flare of the disease, the dose may be escalatedto 200 mg once daily. For long term treatment, the lowest effective dose should be used.

Guidance for laboratory monitoring, and dose initiation or interruption is provided in Table 1.

Treatment should be interrupted if a patient develops a serious infection until the infection iscontrolled (see section 4.4).

Table 1: Laboratory measures and monitoring guidance

Laboratory measure Action Monitoring guidance

Treatment should not be Before treatment initiation andinitiated, or should be thereafter according to routine

Absolute neutrophil count interrupted, if ANC is patient management(ANC) < 1 × 109 cells/L. Treatmentmay be restarted once ANCreturns above this value

Treatment should not beinitiated, or should be

Absolute lymphocyte count interrupted, if ALC is(ALC) < 0.5 × 109 cells/L. Treatmentmay be restarted once ALCreturns above this value

Treatment should not beinitiated, or should be

Haemoglobin (Hb) interrupted, if Hb is < 8 g/dL.

Treatment may be restartedonce Hb returns above thisvalue

Patients should be managed 12 weeks after initiation of

Lipid parameters according to international treatment and thereafterclinical guidelines for according to internationalhyperlipidaemia clinical guidelines forhyperlipidaemia

In patients with rheumatoid arthritis aged 65 years of age and older, the recommended dose is 100 mgonce daily and may be escalated to 200 mg once daily in case of insufficient disease control (seesection 4.4). For long term treatment, the lowest effective dose should be used.

In patients with ulcerative colitis aged 65 years of age and older, the recommended dose is 200 mgonce daily for the induction treatment and 100 mg once daily for maintenance treatment (seesection 4.4). In case of flare of the disease, the dose may be escalated to 200 mg once daily. For longterm treatment, the lowest effective dose should be used. Filgotinib is not recommended in patientsaged 75 years and older as there is no data in this population.

No dose adjustment is required in patients with mild renal impairment (creatinine clearance[CrCl] ≥ 60 mL/min). A dose of 100 mg of filgotinib once daily is recommended for patients withmoderate or severe renal impairment (CrCl 15 to < 60 mL/min). Filgotinib has not been studied inpatients with end-stage renal disease (CrCl < 15 mL/min) and is therefore not recommended for use inthese patients (see section 5.2).

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh Aor B). Filgotinib has not been studied in patients with severe hepatic impairment (Child-Pugh C) and istherefore not recommended for use in these patients (see section 5.2).

The safety and efficacy of filgotinib in children under the age of 18 years have not yet beenestablished. No data are available.

Oral use.

Jyseleca can be taken with or without food (see section 5.2). It has not been studied if tablets can besplit, crushed, or chewed, and it is recommended that tablets are swallowed whole.

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).

Pregnancy (see section 4.6).

Filgotinib 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)

Combination of filgotinib with other potent immunosuppressants such as ciclosporin, tacrolimus,biologics or other Janus kinase (JAK) inhibitors is not recommended as a risk of additiveimmunosuppression cannot be excluded.

Infections, including serious infections, have been reported in patients receiving filgotinib. The mostfrequent serious infection reported with filgotinib was pneumonia (see section 4.8). Amongopportunistic infections, TB, oesophageal candidiasis, and cryptococcosis were reported withfilgotinib.

The risks and benefits of treatment should be considered prior to initiating filgotinib in patients:

* with chronic or recurrent infection

* who have been exposed to TB

* with a history of a serious or an opportunistic infection

* who have resided or travelled in areas of endemic TB 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 infections duringand after filgotinib treatment. If an infection develops during treatment with filgotinib, the patientshould be carefully monitored and filgotinib treatment should be temporarily interrupted if the patientis not responding to standard antimicrobial therapy. Filgotinib treatment may be resumed once theinfection is controlled.

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, filgotinib should only be used if no suitable treatment alternatives are available (see section4.2).

Patients should be screened for TB before initiating filgotinib. Filgotinib should not be administered topatients with active TB (see section 4.3). In patients with latent TB, standard antimycobacterialtherapy should be initiated before administering filgotinib.

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

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported inclinical studies (see section 4.8). In rheumatoid arthritis clinical studies, the risk of herpes zosterappeared to be higher in female patients, Asian patients, patients ≥ 50 years of age, patients with amedical history of herpes zoster, patients with a medical history of chronic lung disease and patientstreated with filgotinib 200 mg once daily. If a patient develops herpes zoster, filgotinib treatmentshould be temporarily interrupted until the episode resolves.

Screening for viral hepatitis and monitoring for reactivation should be performed in accordance withclinical guidelines before starting and during treatment with filgotinib. Patients who were positive forboth hepatitis C antibody and hepatitis C virus RNA were excluded from clinical studies. Patients whowere positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinicalstudies.

Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, includingfilgotinib. In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) inrheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor,a higher rate of malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer(NMSC) was observed with tofacitinib compared to TNF inhibitors.

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), filgotinib should only beused if no suitable treatment alternatives are available.

NMSCs have been reported in patients treated with filgotinib. Periodic skin examination isrecommended for all patients, particularly those who are at increased risk for skin cancer.

ANC < 1 × 109 cells/L (see section 4.8) and ALC < 0.5 × 109 cells/L were reported in ≤ 1% of patientsin the rheumatoid arthritis clinical studies and in < 3% of patients in the ulcerative colitis clinicalstudies. Treatment should not be initiated, or should be temporarily interrupted, in patients with an

ANC < 1 × 109 cells/L, ALC < 0.5 × 109 cells/L or haemoglobin < 8 g/dL observed during routinepatient management (see section 4.2).

Use of live vaccines during, or immediately prior to, filgotinib treatment is not recommended. It isrecommended that immunisations, including prophylactic zoster vaccinations, be updated inagreement with current immunisation guidelines prior to initiating filgotinib treatment.

Treatment with filgotinib was associated with dose-dependent increases in lipid parameters, includingtotal cholesterol, and high-density lipoprotein (HDL) levels, while low-density lipoprotein (LDL)levels were slightly increased (see section 4.8). LDL cholesterol returned to pre-treatment levels in themajority of patients who started statin therapy while taking filgotinib. The effect of these lipidparameter elevations on cardiovascular morbidity and mortality has not been determined (seesection 4.2 for monitoring guidance).

Major adverse cardiovascular events (MACE)

Events of MACE have been observed in patients taking filgotinib.

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 major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatalmyocardial infarction (MI) and non-fatal stroke, was observed with tofacitinib compared to TNFinhibitors.

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,filgotinib should only be used if no suitable treatment alternatives are available.

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported inpatients receiving JAK inhibitors including filgotinib.

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 dosedependent higher rate of VTE including deep venous thrombosis (DVT) and pulmonary embolism(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 (MACE)” and “Malignancy”) filgotinib should only be used if no suitabletreatment alternatives are available.

In patients with known VTE risk factors other than cardiovascular or malignancy risk factors,filgotinib should be used with caution. VTE risk factors other than cardiovascular or malignancy riskfactors include previous VTE, patients undergoing major surgery, immobilisation, use of combinedhormonal contraceptives or hormone replacement therapy, inherited coagulation disorder.

Patients should be re-evaluated periodically during filgotinib treatment to assess for changes in VTErisk.

Promptly evaluate patients with signs and symptoms of VTE and discontinue filgotinib in patientswith suspected VTE, regardless of dose.

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 JAKinhibitor), filgotinib should only be used in these patients if no suitable treatment alternatives areavailable.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicinal product.

Effect of other medicinal products on filgotinib

Filgotinib is primarily metabolised by carboxylesterase 2 (CES2), which can be inhibited in vitro bymedicinal products such as fenofibrate, carvedilol, diltiazem or simvastatin. The clinical relevance ofthis interaction is unknown.

Effect of filgotinib on other medicinal products

Filgotinib is not a clinically relevant inhibitor or inducer of most enzymes or transporters commonlyinvolved in interactions such as cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases(UGT).

In vitro studies are inconclusive regarding the potential of filgotinib to induce CYP2B6. In vivoinduction cannot be excluded.

In vitro studies are inconclusive regarding the potential of filgotinib to induce or inhibit CYP1A2. Noclinical studies have been performed to investigate interactions with CYP1A2 substrates and thereforethe potential in vivo effect of concomitant induction and inhibition of CYP1A2 by filgotinib isunknown. Caution is recommended when filgotinib is co-administered with CYP1A2 substrates with anarrow therapeutic index.

In a clinical pharmacology study, there was no effect on the pharmacokinetics of the combinedcontraceptive ethinyl estradiol and levonorgestrel when co-administered with filgotinib; thus no doseadjustment of oral contraceptives is required.

Women of childbearing potential have to use effective contraception during and for at least 1 weekafter cessation of filgotinib treatment.

There are no or limited amount of data from the use of filgotinib in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3).

Based on findings in animals, filgotinib may cause foetal harm and is therefore contraindicated duringpregnancy (see section 4.3).

It is unknown whether filgotinib is excreted in human milk. A risk to breastfed newborns/infantscannot be excluded. Therefore, Jyseleca should not be used during breast-feeding.

In animal studies, decreased fertility, impaired spermatogenesis, and histopathological effects on malereproductive organs were observed (see section 5.3). The data from two dedicated Phase 2 clinicalstudies (MANTA and MANTA RAy, n=240) to evaluate the human testicular safety in men withinflammatory arthritis diseases and inflammatory bowel diseases did not reveal a difference betweentreatment groups in the proportion of patients who had a 50% or more decrease from baseline in semenparameters at week 13 (pooled primary endpoint: filgotinib 6.7%, placebo 8.3%) and at week 26.

Further, the data did not show any relevant changes in sex hormone levels or change from baseline insemen parameters across treatment groups. Overall, these clinical data were not suggestive offilgotinib-related effects on testicular function.

Animal studies did not indicate effects with respect to fertility in females.

Filgotinib has minor influence on the ability to drive and use machines. Patients should be advised thatdizziness and vertigo has been reported during treatment with Jyseleca (see section 4.8).

The most frequently reported adverse reactions are nausea (3.5%), upper respiratory tract infection(URTI, 3.3%), urinary tract infection (UTI, 1.7%), dizziness (1.2%) and lymphopenia (1.0%).

In general, the overall safety profile observed in filgotinib-treated patients with ulcerative colitis wasgenerally consistent with the safety profile observed in patients with rheumatoid arthritis.

The following adverse reactions are based on clinical studies (Table 2). The adverse reactions arelisted below by system organ class and frequency. Frequencies are defined as follows: common(≥ 1/100 to < 1/10) and uncommon (≥ 1/1 000 to < 1/100).

Table 2: Adverse reactions

Frequency a Adverse reaction

Common Urinary tract infection (UTI)

Upper respiratory tract infection (URTI)

Uncommon Herpes zoster

Common Lymphopenia

Uncommon Neutropenia

Uncommon Hypercholesterolaemia

Common Dizziness

Ear and labyrinth disorders

Uncommon Vertigo

Common Nausea

Frequency a Adverse reaction

Common Blood phosphorus decreased

Uncommon Blood creatine phosphokinase increaseda Frequency based on placebo-controlled pre-rescue period (week 12) pooled across FINCH 1 and 2,and DARWIN 1 and 2, for patients with rheumatoid arthritis who received filgotinib 200 mg.

Frequencies reported in the SELECTION study in patients with ulcerative colitis who receivedfilgotinib 200 mg were generally consistent with those reported in the rheumatoid arthritis studies.

Laboratory changes

Creatinine

An increase in serum creatinine occurred with filgotinib treatment. At week 24 in the Phase 3 studies(FINCH 1, 2, and 3), the mean (SD) increase from baseline in serum creatinine was 0.07 (0.12) and0.04 (0.11) mg/dL for filgotinib 200 mg and 100 mg, respectively. Mean creatinine values remainedwithin the normal range.

Treatment with filgotinib was associated with dose-dependent increases in total cholesterol and HDLlevels, while LDL levels were slightly increased. LDL/HDL ratios were generally unchanged. Lipidchanges were observed within the first 12 weeks of filgotinib treatment and remained stable thereafter.

Serum phosphate

Generally mild, transient or intermittent, and dose-dependent decreases in serum phosphate levelsoccurred during treatment with filgotinib and resolved without discontinuation of treatment. Atweek 24 in the Phase 3 studies (FINCH 1, 2, and 3), serum phosphate values of less than 2.2 mg/dL(the lower limit of normal) were reported in 5.3% and 3.8% of subjects receiving filgotinib 200 mgand 100 mg, respectively; no values below 1.0 mg/dL were reported.

In placebo-controlled Phase 3 studies with background DMARDs (FINCH 1 and FINCH 2) through12 weeks, serum phosphate levels of less than 2.2 mg/dL were reported in 1.6%, 3.1%, and 2.4% inthe placebo, filgotinib 200 mg, and filgotinib 100 mg groups, respectively.

In placebo-controlled studies with background DMARDs (FINCH 1, FINCH 2, DARWIN 1, and

DARWIN 2), the frequency of infection over 12 weeks in the filgotinib 200 mg group was 18.1%compared to 13.3% in the placebo group. In the MTX-controlled study FINCH 3, the frequency ofinfection over 24 weeks in the filgotinib 200 mg monotherapy and filgotinib 200 mg plus MTX groupswas 25.2% and 23.1%, respectively, compared to 24.5% in the MTX group. The overallexposure-adjusted incidence rate (EAIR) of infections for the filgotinib 200 mg group across all seven

Phase 2 and 3 clinical studies (2,267 patients) was 26.5 per 100 patient-years of exposure (PYE).

In placebo-controlled studies with background DMARDs, the frequency of serious infection over12 weeks in the filgotinib 200 mg group was 1.0% compared to 0.6% in the placebo group. In the

MTX-controlled study FINCH 3, the frequency of serious infection over 24 weeks in the filgotinib200 mg monotherapy and filgotinib 200 mg plus MTX groups was 1.4% and 1.0%, respectively,compared to 1.0% in the MTX group. The overall EAIR of serious infections for the filgotinib 200 mggroup across all seven Phase 2 and 3 clinical studies (2,267 patients) was 1.7 per 100 PYE. The mostcommon serious infection was pneumonia. The EAIR of serious infections remained stable withlong-term exposure.

In rheumatoid arthritis clinical studies, there was a higher incidence of serious infections in patientsaged 65 years and older.

In placebo-controlled studies with background DMARDs, the frequencies of infectious ADRs over12 weeks for filgotinib 200 mg compared to placebo were: URTI (3.3% versus 1.8%), UTI (1.7%versus 0.9%), pneumonia (0.6% versus 0.4%), and herpes zoster (0.1% versus 0.3%). Most of theherpes zoster events involved a single dermatome and were non-serious. The overall EAIR of herpeszoster across all seven Phase 2 and 3 clinical studies (2 267 and 1 647 total patients for 200 mg and100 mg, respectively) was 1.6 and 1.1 per 100 PYE in the 200 mg group and 100 mg group,respectively.

The types of serious infections in the ulcerative colitis clinical studies were generally similar to thosereported in the rheumatoid arthritis clinical studies with filgotinib monotherapy treatment groups.

Across the two placebo-controlled induction studies, the frequency of serious infections was 0.6% inthe filgotinib 200 mg group, 1.1% in the filgotinib 100 mg group, and 1.1% in the placebo group. Inthe placebo-controlled maintenance study, the frequency of serious infections in the filgotinib 200 mggroup was 1%, compared to 0% in the respective placebo group. In the maintenance study filgotinib100 mg group, the frequency of serious infections was 1.7%, compared with 2.2% in the respectiveplacebo group.

Opportunistic infections (excluding TB)

In rheumatoid arthritis placebo-controlled studies with background DMARDs, there were noopportunistic infections over 12 weeks in the filgotinib 200 mg group or the placebo group. In the

MTX-controlled study FINCH 3, the frequency of opportunistic infections over 24 weeks was 0, 0.2%,and 0 in the filgotinib 200 mg monotherapy, filgotinib 200 mg plus MTX, and MTX groups,respectively. The overall EAIR of opportunistic infections for the filgotinib 200 mg group across allseven Phase 2 and 3 rheumatoid arthritis clinical studies (2 267 patients) was 0.1 per 100 PYE.

Nausea

Nausea was generally transient and reported during the first 24 weeks of filgotinib treatment.

Creatine phosphokinase

Dose-dependent increases in creatine phosphokinase (CPK) occurred within the first 12 weeks offilgotinib treatment and remained stable thereafter. At week 24 in the Phase 3 studies (FINCH 1, 2,and 3), the mean (SD) increase from baseline in CPK was -16 (449), 61 (260), and 33 (80) U/L forplacebo, filgotinib 200 mg and 100 mg, respectively.

In placebo-controlled Phase 3 studies with background DMARDs (FINCH 1 and FINCH 2) through12 weeks, CPK elevations > 5 × upper limit of normal (ULN) were reported in 0.5%, 0.3%, and 0.3%of patients in the placebo, filgotinib 200 mg, and filgotinib 100 mg groups, respectively. Mostelevations > 5 × ULN did not require treatment discontinuation.

Experience from long-term extension studies

In the long-term extension study DARWIN 3, patients enrolled from DARWIN 1 (N = 497) receivedfilgotinib once a day for a median duration of 5.3 years and patients enrolled from DARWIN 2(N = 242) received filgotinib once a day for a median duration of 5.6 years. In the long-term extensionstudy FINCH 4, 1 530 patients received filgotinib 200 mg once daily and 1 199 patients receivedfilgotinib 100 mg once daily for a median duration of 1.5 years. The safety profile of filgotinib wassimilar to that in the Phase 2 and Phase 3 studies.

In the long-term extension study (SELECTION LTE) in patients who participated in the SELECTIONstudy, patients received filgotinib 200 mg (N = 871), filgotinib 100 mg (N = 157), or placebo(N = 133) for median durations of 55, 36, and 32 weeks, respectively. The safety profile of filgotinibwas similar to that in the SELECTION induction and maintenance studies.

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.

Filgotinib has been administered in clinical studies following single and once daily administration upto 450 mg without dose-limiting toxicity. Adverse reactions were comparable to those seen at lowerdoses and no specific toxicities were identified. Pharmacokinetic data following a single dose of100 mg filgotinib in healthy subjects indicate that approximately 50% of the administered dose iseliminated within 24 hours of dosing and 90% of the dose is eliminated within 72 hours. In case of anoverdose, it is recommended that a patient be monitored for signs and symptoms of adverse reactions.

Treatment of overdose with filgotinib consists of general supportive measures including monitoring ofvital signs as well as observation of the clinical status of the patient. It is unknown whether filgotinibcan be removed by dialysis.

Pharmacotherapeutic group: Immunosuppressants, Janus-associated kinase (JAK) inhibitors, ATCcode: L04AF04

Filgotinib is an adenosine triphosphate (ATP)-competitive and reversible inhibitor of the JAK family.

JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor -receptorinteractions on the cellular membrane. JAK1 is important in mediating inflammatory cytokine signals,

JAK2 in mediating myelopoiesis and erythropoiesis and JAK3 plays critical roles in immunehomeostasis and lymphopoiesis. Within the signalling pathway, JAKs phosphorylate and activatesignal transducers and activators of transcription (STATs) which modulate intracellular activityincluding gene expression. Filgotinib modulates these signalling pathways by preventing thephosphorylation and activation of STATs. In biochemical assays, filgotinib preferentially inhibited theactivity of JAK1 and showed > 5-fold higher potency of filgotinib for JAK1 over JAK2, JAK3 and

TYK2. In human cellular assays, filgotinib preferentially inhibited JAK1/JAK3-mediated signallingdownstream of the heterodimeric cytokine receptors for interleukin (IL)-2, IL-4 and IL-15,

JAK1/2-mediated IL-6, and JAK1/TYK2-mediated type I interferons, with functional selectivity overcytokine receptors that signal via pairs of JAK2 or JAK2/TYK2. GS-829845, the primary metaboliteof filgotinib, was approximately 10-fold less active than filgotinib in in vitro assays, while exhibiting asimilar JAK1 preferential inhibitory activity. In an in vivo rat model, the overall pharmacodynamiceffect was predominantly driven by the metabolite.

Inhibition of IL-6 induced STAT1 phosphorylation

Filgotinib administration resulted in a dose-dependent inhibition of IL-6 induced STAT1phosphorylation in whole blood from healthy subjects. Filgotinib administration did not affect

JAK2-associated GM-CSF induced STAT5 phosphorylation.

Immunoglobulins

In FINCH 1, 2, and 3, the median and interquartile ranges for serum IgG, IgM, and IgA valuesremained largely within the normal reference ranges through 24 weeks of treatment with filgotinib inpatients with rheumatoid arthritis and through 58 weeks of treatment in patients with ulcerative colitis.

Haematologic effects

In FINCH 1, 2, and 3 in patients with rheumatoid arthritis, treatment with filgotinib was associatedwith a small, transient increase in mean ALC that remained within normal reference ranges andgradually returned to at or near baseline levels with continued treatment by week 12. In FINCH 1, 2,and 3, median haemoglobin values remained stable within the normal range through 24 weeks offilgotinib treatment. A slight decrease in median platelet counts occurred within the first 4 weeks offilgotinib treatment and remained stable thereafter through 24 weeks. Median platelet counts remainedwithin the normal range.

In SELECTION, in patients with ulcerative colitis, median haemoglobin values remained stablethrough 58 weeks of filgotinib treatment.

C-reactive protein

Decreases in serum C-reactive protein (CRP) were observed as early as 2 weeks after startingtreatment with filgotinib and were maintained through 24 weeks of treatment in patients withrheumatoid arthritis and through 58 weeks of treatment in patients with ulcerative colitis.

The efficacy and safety of filgotinib once daily were assessed in three Phase 3 studies (FINCH 1, 2,and 3). These were randomised, double-blind, multicentre studies in patients with moderate to severeactive rheumatoid arthritis diagnosed according to American College of Rheumatology(ACR)/European League Against Rheumatism (EULAR) 2010 criteria.

FINCH 1 was a 52-week study in 1 755 patients with rheumatoid arthritis who had an inadequateresponse to MTX. Patients received filgotinib 200 mg once daily, filgotinib 100 mg once daily,adalimumab every 2 weeks, or placebo, all added to stable background MTX. At week 24, patientsreceiving placebo were re-randomised to filgotinib 100 mg or 200 mg once daily through week 52.

The primary endpoint was the proportion of patients who achieved an ACR20 response at week 12.

FINCH 2 was a 24-week study in 448 patients with rheumatoid arthritis who had an inadequateresponse to bDMARDs. Patients received filgotinib 200 mg once daily, filgotinib 100 mg once daily,or placebo, all with a continued stable background dose of conventional synthetic DMARD(s)(csDMARD[s]: MTX, hydroxychloroquine, sulfasalazine, or leflunomide). The primary endpoint wasthe proportion of patients who achieved an ACR20 response at week 12.

FINCH 3 was a 52-week study in 1 249 patients with rheumatoid arthritis who were naïve to MTXtherapy. Patients received filgotinib 200 mg once daily plus MTX once weekly, filgotinib 100 mg oncedaily plus MTX once weekly, filgotinib 200 mg (monotherapy) once daily, or MTX (monotherapy)once weekly. The primary endpoint was the proportion of patients who achieved an ACR20 responseat week 24.

Higher response rates versus placebo or MTX were seen at week 2 for ACR20, and responses weremaintained through week 52.

Treatment with filgotinib 200 mg resulted in improvements in all individual ACR components,including tender and swollen joint counts, patient and physician global assessments, Health

Assessment Questionnaire Disability Index (HAQ-DI), pain assessment and high sensitivity CRP,compared to placebo or MTX. In two of the Phase 3 studies (FINCH 1 and FINCH 2), the comparison(versus placebo) was carried out on top of MTX or csDMARD(s) (see above).

Low disease activity and remission

Across the Phase 3 studies, a significantly higher proportion of patients treated with filgotinib 200 mgplus MTX or other csDMARD achieved low disease activity and/or remission (DAS28-CRP ≤ 3.2 and

DAS28-CRP < 2.6) at weeks 12 and 24 as compared to placebo or MTX. Filgotinib 200 mg wasnon-inferior to adalimumab at week 12 for DAS28-CRP ≤ 3.2 in FINCH 1 (Table 3).

Table 3: Clinical response at weeks 12, 24 and 52 in FINCH 1, 2, and 3

FINCH 1 FINCH 2 FINCH 3

MTX-IR bDMARD-IR MTX-naïve

FIL FIL FIL FIL FIL FIL FIL

Treatment 200 mg 100 mg ADA PBO 200 mg 100 mg PBO 200 mg 100 mg 200 mg MTX+ MTX + csDMARD + MTX + MTX mono

N 475 480 325 475 147 153 148 416 207 210 416

Week

ACR20 (percent of patients)12 77***¶ 70*** 71 50 66*** 58*** 31 77††† 72†† 71†† 5924 78††† 78††† 74 59 69††† 55††† 34 81*** 80* 78 7152 78 76 74 - - - - 75††† 73†† 75††† 62

ACR50 (percent of patients)12 47†††¶¶¶ 36††† 35 20 43††† 32††† 15 53††† 44††† 46††† 2824 58††† 53††† 52 33 46††† 35†† 19 62††† 57†† 58†† 4652 62 59 59 - - - - 62††† 59†† 61††† 48

ACR70 (percent of patients)12 26†††¶¶¶ 19††† 14 7 22††† 14† 7 33††† 27††† 29††† 1324 36†††¶ 30††† 30 15 32††† 20†† 8 44††† 40††† 40††† 2652 44 38 39 - - - - 48††† 40†† 45††† 30

DAS28-CRP ≤ 3.2 (percent of patients)12 50***### 39*** 43 23 41*** 37*** 16 56††† 50††† 48††† 2924 61†††§§§¶¶ 53†††§§§ 50 34 48††† 38††† 21 69††† 63††† 60††† 4652 66¶ 59 59 - - - - 69††† 60†† 66††† 48

DAS28-CRP < 2.6 (percent of patients)12 34†††§§§¶¶¶ 24†††§§ 24 9 22††† 25††† 8 40††† 32††† 30††† 1724 48***§§§¶¶¶ 35***§§§ 36 16 31††† 26†† 12 54*** 43*** 42††† 2952 54¶ 43 46 - - - - 53††† 43†† 46††† 31

FINCH 1 FINCH 2 FINCH 3

MTX-IR bDMARD-IR MTX-naïve

FIL FIL FIL FIL FIL FIL FIL

Treatment 200 mg 100 mg ADA PBO 200 mg 100 mg PBO 200 mg 100 mg 200 mg MTX+ MTX + csDMARD + MTX + MTX mono

N 475 480 325 475 147 153 148 416 207 210 416

CDAI, change from baseline (mean)12 -26.0††† -23.3††† -23.5 -20.3 -26.2††† -23.8††† -17.3 -27.8††† -26.1††† -27.5††† -22.724 -30.6††† -28.6††† -28.4 -26.3 -30.9††† -27.8†† -25.4 -31.3††† -30.0††† -31.3††† -28.252 -32.9 -30.9 -31.6 - - - - -33.8††† -31.9† -33.6††† -31.2

ADA: adalimumab; bDMARD: biologic DMARD; csDMARD: conventional synthetic DMARD; DMARD:disease-modifying anti-rheumatic drug; FIL: filgotinib; IR: inadequate responder; mono: monotherapy; MTX:methotrexate; PBO: placebo.

* p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001 versus placebo (versus MTX for FINCH 3) (statistically significantdifference with multiplicity adjustment).† p ≤ 0.05; †† p ≤ 0.01; ††† p ≤ 0.001 versus placebo (versus MTX for FINCH 3) (nominal p-value).# p ≤ 0.05; ## p ≤ 0.01; ### p ≤ 0.001 versus adalimumab for FINCH 1 (non-inferiority test, statisticallysignificant difference with multiplicity adjustment) (analysed for DAS28-CRP ≤ 3.2 and < 2.6 pairwisecomparisons only).

§ p ≤ 0.05; §§ p ≤ 0.01; §§§ p ≤ 0.001 versus adalimumab for FINCH 1 (non-inferiority test, nominal p-value)(analysed for DAS28-CRP ≤ 3.2 and < 2.6 pairwise comparisons only).

¶ p ≤ 0.05; ¶¶ p ≤ 0.01; ¶¶¶ p ≤ 0.001 versus adalimumab for FINCH 1 (superiority test, nominal p-value)(analysed for ACR20/50/70, and DAS28-CRP ≤ 3.2 and < 2.6 pairwise comparisons only).

Note: Comparisons were carried out on top of a stable background of MTX (FINCH 1) or csDMARD(s)(FINCH 2).

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 and 52 in

FINCH 1 and FINCH 3.

In patients who had an inadequate response to MTX, treatment with filgotinib plus MTX resulted instatistically significant inhibition of progression of structural joint damage compared to placebo plus

MTX at week 24 (Table 4). Analyses of erosion and joint space narrowing scores were consistent withthe overall scores.

Table 4: Radiographic response at weeks 24 and 52 in FINCH 1 and 3

FINCH 1 FINCH 3

MTX-IR MTX-naïve

FIL FIL ADA PBO FIL FIL FIL

Treatment 200 mg 100 mg 200 mg 100 mg 200 mg MTX+ MTX + MTX + MTX mono

N 475 480 325 475 416 207 210 416

Week

Modified Total Sharp Score (mTSS), mean (SD) change from baseline24 0.13 0.17 0.16 0.37 0.21 0.22 -0.04 0.51(0.94)*** (0.91)*** (0.95) (1.42) (1.68) (1.53) (1.71)†† (2.89)52 0.21 0.50 0.58 0.31 0.23 0.33 0.81(1.43) (2.10) (3.62) - (1.81)††† (1.11)†† (1.90)†† (3.09)

FINCH 1 FINCH 3

MTX-IR MTX-naïve

FIL FIL FIL FIL FIL

Treatment 200 mg 100 mg ADA PBO 200 mg 100 mg 200 mg MTX+ MTX + MTX + MTX mono

Proportion of patients with no radiographic progression a24 88%** 86% 86% 81% 81%† 77% 83%† 72%52 88% 81% 82% - 81%†† 76% 77% 71%

ADA: adalimumab; FIL: filgotinib; IR: inadequate responder; mono: monotherapy; MTX:methotrexate; PBO: placebo.a No progression defined as mTSS change ≤ 0.

* p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001 versus placebo (statistically significant difference withmultiplicity adjustment).† p ≤ 0.05; †† p ≤ 0.01; ††† p ≤ 0.001 versus placebo (versus MTX for FINCH 3) (nominal p-value).

Physical function response and health related outcomes

Treatment with filgotinib 200 mg resulted in a significant improvement in physical function, asmeasured by change from baseline in HAQ-DI (Table 5).

Table 5: Mean change from baseline in HAQ-DI at weeks 12, 24 and 52 in FINCH 1, 2, and 3

Mean change from baseline

FINCH 1 FINCH 2 FINCH 3

MTX-IR bDMARD-IR MTX-naïve

FIL FIL FIL FIL FIL FIL FIL

Treatment 200 mg 100 mg ADA PBO 200 mg 100 mg PBO 200 mg 100 mg 200 mg MTX+ MTX + MTX mono+ MTX + csDMARD

N 475 480 325 475 147 153 148 416 207 210 416

Week

Health Assessment Questionnaire Disability Index (HAQ-DI)

Baselinescore 1.59 1.55 1.59 1.63 1.70 1.64 1.65 1.52 1.56 1.56 1.6012 -0.69*** -0.56*** -0.61 -0.42 -0.55*** -0.48*** -0.23 -0.85††† -0.77††† -0.76††† -0.6124 -0.82††† -0.75††† -0.78 -0.62 -0.75††† -0.60†† -0.42 -0.94*** -0.90** -0.89† -0.7952 -0.93 -0.85 -0.85 - - - - -1.00††† -0.97 -0.95† -0.88

ADA: adalimumab; bDMARD: biologic DMARD; csDMARD: conventional synthetic DMARD;

DMARD: disease-modifying antirheumatic drug; FIL: filgotinib; IR: inadequate responder; mono:monotherapy; MTX: methotrexate; PBO: placebo.

* p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001 versus placebo (statistically significant difference withmultiplicity adjustment).† p ≤ 0.05; †† p ≤ 0.01; ††† p ≤ 0.001 versus placebo (versus MTX for FINCH 3) (nominal p-value).

Health status outcomes were assessed by the Short Form health survey (SF-36). Patients treated withfilgotinib 200 mg plus MTX or other csDMARD demonstrated numerically greater improvement frombaseline in the physical component summary score of SF-36 as well as in the Functional Assessmentof Chronic Illness Therapy-Fatigue score (FACIT-Fatigue) at weeks 12 and 24 compared to placeboplus MTX/csDMARD or MTX.

DARWIN 3 was a long-term open-label extension study of patients who participated in one of theoriginator studies DARWIN 1 or DARWIN 2 (filgotinib versus placebo, with or without MTX) andwho would continue to benefit from filgotinib treatment in the opinion of the investigator. A total of739 patients were included. Mean duration of follow-up was 5.4 years with a maximum of 8 years.

Concomitant MTX use at any timepoint during DARWIN 3 was reported for 70% of subjects.

At week 396, ACR20/50/70 responses rates were 87.3%/65.4%/47.8% among patients who remainedon filgotinib with or without MTX (N=228/739). DAS28 (CRP) ≤ 3.2 low disease activity and DAS28(CRP) < 2.6 clinical remission rates were 75.5% and 62.8% at week 396 among patients whoremained on filgotinib with or without MTX (N=196/739).

The efficacy and safety of filgotinib once daily were evaluated in a randomised, double-blind,placebo-controlled combined Phase 2b/3 study (SELECTION) in patients with moderately to severelyactive ulcerative colitis (Mayo Clinic Score 6 to 12; endoscopy subscore ≥ 2; rectal bleedingsubscore ≥ 1; stool frequency subscore ≥ 1; and Physician’s Global Assessment subscore ≥ 2).

SELECTION included two induction studies (UC-1 and UC-2) followed by a maintenance study(UC-3), with a total duration of 58 weeks of therapy. Patients were permitted to use stable doses ofconcomitant therapies for ulcerative colitis, including oral aminosalicylates, oral corticosteroids(prednisone equivalent dose up to 30 mg/day), and immunomodulators (azathioprine, 6-MP, ormethotrexate).

UC-1 was an 11-week induction study in 659 patients with ulcerative colitis who were naïve tobiologic therapy and had an inadequate response, loss of response, or intolerance to corticosteroids orimmunomodulators. Patients received filgotinib 200 mg once daily (N = 245), filgotinib 100 mg oncedaily (N = 277), or placebo (N = 137). At baseline, 56% of patients had an endoscopic subscore of 3;24% were receiving oral corticosteroids only, 23% immunomodulators only, 7% corticosteroids andimmunomodulators, and 47% neither corticosteroids nor immunomodulators.

UC-2 was an 11-week induction study in 689 patients with ulcerative colitis who werebiologic-experienced and had an inadequate response, loss of response, or intolerance to a tumournecrosis factor (TNF) blocker or vedolizumab. Patients received filgotinib 200 mg once daily(N = 262), filgotinib 100 mg once daily (N = 285), or placebo (N = 142). At baseline, 78% of patientshad an endoscopic subscore of 3; 85% had failed at least 1 prior TNF blocker, 52% had failedvedolizumab, and 43% had failed at least 1 TNF blocker and vedolizumab; 36% were receiving oralcorticosteroids only, 13% immunomodulators only, 10% corticosteroids and immunomodulators, and41% neither corticosteroids nor immunomodulators.

The primary endpoint for UC-1 and UC-2 was the proportion of patients who achieved clinicalremission at week 10. Clinical remission was defined as MCS endoscopy subscore of 0 or 1(endoscopy subscore of 0 defined as normal or inactive disease and subscore of 1 defined as presenceof erythema, decreased vascular pattern, and no friability), rectal bleeding subscore of 0 (no rectalbleeding), and at least a one point decrease in stool frequency subscore from baseline to achieve 0 or1. Key secondary efficacy endpoints included MCS remission, endoscopic remission, and histologicremission at week 10.

UC-3 was a 47-week maintenance study in 558 patients with ulcerative colitis who achieved clinicalresponse or remission at week 10 from filgotinib in UC-1 (N = 320) or UC-2 (N = 238). Clinicalresponse was defined as a decrease in MCS of ≥ 3 points and ≥ 30% decrease from baseline, with anaccompanying decrease in rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscoreof 0 or 1. Patients were re-randomised at week 11 to receive their induction dose of filgotinib orplacebo through week 58. As in UC-1 and UC-2, patients were permitted to use stable doses of oralaminosalicylates or immunomodulators; however, corticosteroid tapering was required three weeksafter entering this study. The primary endpoint was the proportion of patients who achieved clinicalremission at week 58. Key secondary efficacy endpoints were MCS remission, sustained clinicalremission, 6-month corticosteroid-free clinical remission, endoscopic remission, and histologicremission at week 58.

Clinical outcomes

Across the UC-1 and UC-2 studies, a significantly greater proportion of patients receiving filgotinib200 mg achieved clinical remission at week 10 as compared to placebo (Table 6). A significantlygreater proportion of biologic-naïve patients (UC-1) receiving filgotinib 200 mg achieved MCSremission, endoscopic remission, and histologic remission at week 10 as compared to placebo(Table 6).

Efficacy in the filgotinib 100 mg group as compared to placebo was not statistically significant atweek 10 in either UC-1 or UC-2.

Table 6: Proportion of patients meeting efficacy endpoints at week 10 in induction studies UC-1and UC-2

UC-1 UC-2

Biologic naïve Biologic experienced a

N = 659 N = 689

FIL Treatment FIL Treatment

Endpoint 200 mg Placebo difference 200 mg Placebo differencen (%) N = 245 N = 137 and 95% CI N = 262 N = 142 and 95% CI

Clinical 64 21 10.8% 30 6 7.2%remission b (26.1%) (15.3%) (2.1%, 19.5%) (11.5%) (4.2%) (1.6%, 12.8%)p = 0.0157 p = 0.0103

Failure to - - - 8/120 1/64 -both TNF and (6.7%) (1.6%)vedolizumab c

MCS 60 17 12.1% 25 6 5.3%remission d (24.5%) (12.4%) (3.8%, 20.4%) (9.5%) (4.2%) (−0.1%,p = 0.0053 10.7%)

Endoscopic 30 5 8.6% 9 3 1.3%remission e (12.2%) (3.6%) (2.9%, 14.3%) (3.4%) (2.1%) (−2.5%,p = 0.0047 5.1%)

Histologic 86 22 19.0% 52 12 11.4%remission f (35.1%) (16.1%) (9.9%, 28.2%) (19.8%) (8.5%) (4.2%, 18.6%)p < 0.0001

CI: Confidence interval; FIL: filgotinib; MCS: Mayo Clinic Score.a Biologic experienced = Patients who previously demonstrated an inadequate response, loss ofresponse to, or intolerance of a TNF blocker or vedolizumab.b Primary endpoint. Clinical remission was defined as MCS endoscopy subscore of 0 or 1(endoscopy subscore of 0 defined as normal or inactive disease and subscore of 1 defined aspresence of erythema, decreased vascular pattern, and no friability), rectal bleeding subscore of 0(no rectal bleeding), and at least a one point decrease in stool frequency subscore from baseline toachieve 0 or 1.

c Subgroup analysis based on patients with prior treatment failure to both a TNF blocker andvedolizumab.

d MCS remission was defined as MCS ≤ 2 with no individual subscore of > 1.e Endoscopic remission was defined as MCS endoscopic subscore of 0.f Histologic remission was assessed using Geboes histologic scores and defined as Grade 0 of ≤ 0.3,

Grade 1 of ≤ 1.1, Grade 2a of ≤ 2A.3, Grade 2b of 2B.0, Grade 3 of 3.0, Grade 4 of 4.0, and

Grade 5 of 5.0.

The proportion of patients in UC-1 and UC-2 achieving a clinical response was 66.5% and 53.1%,respectively, for patients receiving filgotinib 200 mg compared with 46.7% and 17.6%, respectively,for patients receiving placebo at week 10.

In the maintenance study (UC-3), a significantly greater proportion of patients receiving filgotinib200 mg or filgotinib 100 mg achieved clinical remission at week 58 as compared to placebo. Theproportion of patients achieving clinical remission is shown in Table 7. A significantly greaterproportion of patients receiving filgotinib 200 mg achieved MCS remission, sustained clinicalremission, 6-month corticosteroid-free clinical remission, endoscopic remission, and histologicremission at week 58 as compared to placebo.

Key secondary efficacy outcomes for treatment with filgotinib 100 mg as compared to placebo werenot statistically significant at week 58.

Table 7: Proportion of patients meeting efficacy endpoints at week 58 in maintenance study

UC-3

Induction FIL 200 mg

Endpoint FIL 200 mg Placebo difference and 95%n (%) N = 199 N = 98 CI26.0%

Clinical remission a b 74 11(37.2%) (11.2%) (16.0%, 35.9%)p < 0.0001

Biologic naïve 52/107 9/54(48.6%) (16.7%) -

Biologic experienced 22/92 2/44(23.9%) (4.5%) -25.5%

MCS remission c 69 9(34.7%) (9.2%) (16.0%, 35.0%)p < 0.0001

Sustained clinical 36 5 13.0%remission d b (18.1%) (5.1%) (5.3%, 20.6%)p = 0.0024

Biologic naïve 25/107 4/54(23.4%) (7.4%) -

Biologic experienced 11/92 1/44(12.0%) (2.3%) -6-month corticosteroid-free 25/92 3/47 20.8%clinical remission e b (27.2%) (6.4%) (7.7%, 33.9%)p = 0.0055

Biologic naïve 18/43 2/22(41.9%) (9.1%) -

Biologic experienced 7/49 1/25(14.3%) (4.0%) -9.5%

Endoscopic remission f 31 6(15.6%) (6.1%) (1.8%, 17.1%)p = 0.015724.9%

Histologic remission g 76 13(38.2%) (13.3%) (14.6%, 35.2%)p < 0.0001

CI: Confidence interval; FIL: filgotinib; MCS: Mayo Clinic Score.a Primary endpoint. Clinical remission was defined as MCS endoscopy subscore of 0 or 1(endoscopy subscore of 0 defined as normal or inactive disease and subscore of 1 defined aspresence of erythema, decreased vascular pattern, and no friability), rectal bleeding subscore of 0(no rectal bleeding), and at least a one point decrease in stool frequency subscore from inductionbaseline to achieve 0 or 1.

b Subgroup analysis based on patient participation in UC-1 (biologic naïve) or UC-2 (biologicexperienced; TNF blocker and/or vedolizumab).

c MCS remission was defined as MCS ≤ 2 with no individual subscore of > 1.d Sustained clinical remission was defined as clinical remission at both week 10 and week 58.e 6-month corticosteroid-free clinical remission was defined as clinical remission at week 58 inpatients who were on corticosteroid at UC-3 baseline and who were not receiving corticosteroidsfor at least 6 months prior to week 58.

f Endoscopic remission was defined as MCS endoscopic subscore of 0.g Histologic remission was assessed using Geboes histologic scores and defined as Grade 0 of ≤ 0.3,

Grade 1 of ≤ 1.1, Grade 2a of ≤ 2A.3, Grade 2b of 2B.0, Grade 3 of 3.0, Grade 4 of 4.0, and

Grade 5 of 5.0.

Endoscopic response

Endoscopic response was defined as an endoscopic subscore of 0 or 1. The proportion of patients in

UC-1 and UC-2 achieving an endoscopic response was 33.9% and 17.2%, respectively, for patientsreceiving filgotinib 200 mg compared with 20.4% and 7.7%, respectively, for patients receivingplacebo, at week 10. In UC-3, 40.7% of patients receiving filgotinib 200 mg versus 15.3% of patientsreceiving placebo achieved endoscopic response at week 58.

Health-related quality of life (HRQoL) outcomes

Patients receiving filgotinib 200 mg reported increases (improvements) in the total and all four domainscores of the Inflammatory Bowel Disease Questionnaire ([IBDQ] bowel symptoms, systemicfunction, emotional function, and social function) at week 10 in UC-1 and UC-2, and at week 58 in

UC-3.

Long-term extension study

Patients who did not achieve clinical response or remission at week 10 in UC-1 or UC-2 had theoption to receive open-label filgotinib 200 mg in the SELECTION LTE study. After 12 weeks ofadditional treatment with filgotinib 200 mg in the SELECTION LTE study, the proportion of patientsfrom UC-1 and UC-2 achieving partial MCS remission was 17.1% (12/70) and 16.7% (15/90),respectively and partial MCS response was achieved by 65.7% (46/70) and 62.2% (56/90),respectively. Partial MCS remission was defined as partial MCS ≤ 1 and partial MCS response wasdefined as a reduction of ≥ 2 in partial MCS and at least 30% reduction from the induction baselinescore, with an accompanying decrease of ≥ 1 in the rectal bleeding subscore or an absolute rectalbleeding subscore of 0 or 1.

The European Medicines Agency has deferred the obligation to submit the results of studies withfilgotinib in one or more subsets of the paediatric population in the treatment of chronic idiopathicarthritis (including rheumatoid arthritis, ankylosing spondylarthritis, psoriatic arthritis, and juvenileidiopathic arthritis) and in ulcerative colitis (see section 4.2 for information on paediatric use).

Following oral administration, filgotinib was absorbed quickly and its median peak plasmaconcentration was observed 2 to 3 hours postdose after multiple dosing; the median peak plasmaconcentrations of its primary metabolite GS-829845 were observed 5 hours postdose after multipledosing. Filgotinib and GS-829845 exposures (AUC) and Cmax were similar in healthy adult subjectsand patients with rheumatoid arthritis and ulcerative colitis. Filgotinib and GS-829845 exposures(AUC) and Cmax are dose-proportional over the therapeutic dose range. Steady-state concentrations offilgotinib are achieved in 2 3 days with negligible accumulation after once daily administration.

Steady-state concentrations of GS-829845 are achieved in 4 days with approximately 2-foldaccumulation after once daily dosing of filgotinib.

There were no clinically relevant differences in exposures when filgotinib was administered with ahigh-fat or low-fat meal as compared to a fasted state. Filgotinib can be administered with or withoutfood.

Steady-state exposures of filgotinib and GS-829845 are provided in Table 8.

Table 8: Multiple dose pharmacokinetic parameters of filgotinib and GS-829845 following oraladministration of filgotinib 200 mg with or without food in patient populations

Rheumatoid arthritis a Ulcerative colitis b

Parameter c

Mean (%CV) Filgotinib GS-829845 d Filgotinib GS-829845

Cmax (µg/mL) 2.15 (48.1) 4.43 (29.3) 2.12 (50.3) e 4.02 (30.5) e

AUCtau 6.77 (43.7) 83.2 (27.3)(µg*h/mL) 6.15 (28.1) f 72.1 (33.9) g

CV: coefficient of variation.a From intensive PK analyses of studies FINCH 1, FINCH 2, and FINCH 3 in rheumatoid arthritispatients receiving 200 mg filgotinib once daily.b From intensive PK analysis of SELECTION study in ulcerative colitis patients receiving 200 mgfilgotinib once daily.c N = 37d N = 33e N = 13f N = 12g N = 11

Filgotinib and GS-829845 binding to human plasma proteins is low (55 - 59% and 39 - 44% bound,respectively). The blood-to-plasma ratio of filgotinib ranged from 0.85 to 1.1 indicating no preferentialdistribution of filgotinib and GS-829845 into blood cells. Filgotinib and GS-829845 are substrates ofthe P-gp transporter.

Filgotinib is extensively metabolised with approximately 9.4% and 4.5% of an orally administereddose recovered as unchanged filgotinib in urine and faeces, respectively. Filgotinib is primarilymetabolised by CES2, and to a lesser extent by CES1. Both CES2 and CES1 form GS-829845, anactive circulating metabolite that is approximately 10-fold less potent than the parent compound. In aclinical pharmacology study, filgotinib and GS-829845 accounted for the majority of radioactivitycirculating in plasma (2.9% and 92%, respectively). No other major metabolites were identified.

As both filgotinib and GS-829845 contribute to efficacy, their exposures were combined into a singleparameter, AUCeff. AUCeff is the sum of the AUC of filgotinib and GS-829845, corrected for theirrespective molecular weights and potencies.

Approximately 87% of the administered dose was eliminated in the urine as filgotinib and itsmetabolites, while about 15% of the dose was eliminated in the faeces. GS-829845 accounted forapproximately 54% and 8.9% of dose recovered in urine and faeces, respectively. The mean terminalhalf-lives of filgotinib and GS-829845 were approximately 7 and 19 hours, respectively.

Weight, gender, race, and age

Bodyweight, gender, race, and age did not have a clinically relevant effect on the pharmacokinetics(AUC) of filgotinib or GS-829845.

There were no clinically relevant differences in mean filgotinib and GS-829845 exposures (AUC and

Cmax) between older patients aged ≥ 65 years relative to adult patients aged < 65 years.

The pharmacokinetics of filgotinib and GS-829845 were unaffected in subjects with mild renalimpairment (CrCl 60 to < 90 mL/min). Increases in exposures (AUC) of filgotinib, GS-829845, andcombined AUCeff (≤ 2-fold), were observed in subjects with moderate renal impairment (CrCl 30 to< 60 mL/min). In subjects with severe renal impairment (CrCl 15 to < 30 mL/min), filgotinib exposure(AUC) increased by 2.2-fold and GS-829845 exposure significantly increased by 3.5-fold leading to a3-fold increase in AUCeff. The pharmacokinetics of filgotinib has not been studied in subjects withend-stage renal disease (CrCl < 15 mL/min).

No clinically relevant changes in the exposures (AUC) of filgotinib and GS-829845 individually, ortheir combined exposure (AUCeff), were observed in subjects with moderate hepatic impairment(Child-Pugh B). The pharmacokinetics of filgotinib has not been studied in subjects with severehepatic impairment (Child-Pugh C).

Effect of filgotinib on other medicinal products

Potential interactions between filgotinib and co-administered medicinal products are listed in Table 9below (increase is indicated as “↑”, decrease as “↓”, and no change as “↔”; no effect boundaries are70 - 143% unless otherwise indicated).

Table 9: Interaction studies with filgotinib 1

Medicinal product by Effects on medicinal product Recommendationtherapeutic areas/Possible levels. concerningmechanism of interaction Mean percent change in AUC, co-administration with

Cmax filgotinib

ANTI-INFECTIVES

Antimycobacterials

Rifampicin (600 mg once Filgotinib: No dose adjustment isdaily) 2 AUC: ↓ 27% required upon

Cmax: ↓ 26% co-administration.(P-gp induction)

GS-829845:

AUC: ↓ 38%

Cmax: ↓ 19%

AUCeff 6: ↓ 33%

Medicinal product by Effects on medicinal product Recommendationtherapeutic areas/Possible levels. concerningmechanism of interaction Mean percent change in AUC, co-administration with

Cmax filgotinib

Antifungals

Itraconazole (200 mg single Filgotinib: No dose adjustment isdose) 3 AUC: ↑ 45% required upon

Cmax: ↑ 64% co-administration.(P-gp inhibition)

GS-829845:

AUC: ↔

Cmax: ↔

AUCeff: ↑ 21%

GASTRIC ACID REDUCING AGENTS

Famotidine (40 mg twice Filgotinib: No dose adjustment isdaily) 2 AUC: ↔ required upon

Cmax: ↔ co-administration.(Increases gastric pH)

GS-829845:

AUC: ↔

Cmax: ↔

Omeprazole (40 mg once Filgotinib: No dose adjustment isdaily) 2 AUC: ↔ required upon

Cmax: ↓ 27% co-administration.(Increases gastric pH)

GS-829845:

AUC: ↔

Cmax: ↔

HMG-CoA REDUCTASE INHIBITORS

Atorvastatin (40 mg single Atorvastatin: No dose adjustment isdose) 4 AUC: ↔ required upon

Cmax: ↓ 18% co-administration.

(Inhibition of CYP3A4/ 2-hydroxy-atorvastatin:

OATP/BCRP) AUC: ↔

Cmax: ↔

Pravastatin (40 mg single dose) Pravastatin: No dose adjustment is4 AUC: ↔ required upon

Cmax: ↑ 25% co-administration.(Inhibition of OATP)

Rosuvastatin (10 mg single Rosuvastatin: No dose adjustment isdose) 4 AUC: ↑ 42% required upon

Cmax: ↑ 68% co-administration.(Inhibition of OATP and

BCRP)

ORAL ANTI-DIABETICS

Metformin (850 mg single Metformin: No dose adjustment isdose) 4 AUC: ↔ required upon

Cmax: ↔ co-administration.(Inhibition of OCT2, MATE1,and MATE-2K)

Medicinal product by Effects on medicinal product Recommendationtherapeutic areas/Possible levels. concerningmechanism of interaction Mean percent change in AUC, co-administration with

Cmax filgotinib

ORAL CONTRACEPTIVES

Ethinyl estradiol (0.03 mg Ethinyl estradiol: No dose adjustment issingle dose)/Levonorgestrel AUC: ↔ required upon(0.15 mg single dose) 4 Cmax: ↔ co-administration.

Levonorgestrel:

AUC: ↔

Cmax: ↔

SEDATIVES/HYPNOTICS

Midazolam (2 mg single Midazolam: No dose adjustment isdose) 4,5 AUC: ↔ required upon

Cmax: ↔ co-administration.(Inhibition of CYP3A4)1’OH-midazolam:

AUC: ↔

Cmax: ↔

GS-829845: primary metabolite of filgotinib.1 All interaction studies conducted in healthy volunteers.2 Study conducted with filgotinib 200 mg single dose.3 Study conducted with filgotinib 100 mg single dose.4 Study conducted with filgotinib 200 mg once daily.5 Bioequivalence boundaries are 80 - 125% for midazolam and 1’OH-midazolam.6 As both filgotinib and GS-829845 contribute to efficacy, their exposures were combined into asingle parameter, AUCeff. AUCeff is the combined AUC of filgotinib and GS-829845, adjusted fortheir respective molecular weights and potencies.

Potential for filgotinib to affect other medicinal products

In vitro data indicate that filgotinib and GS-829845 do not inhibit the activity of the following:

CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, UGT1A1, UGT1A4, UGT1A6, UGT1A9, and

UGT2B7 at clinically relevant concentrations. The potential for filgotinib to induce CYP2B6constitutive androstane receptor (CAR) mediated metabolism in vivo is unknown. No conclusion canbe drawn from the in vitro data regarding the potential of filgotinib to inhibit or induce CYP1A2.

In vivo data demonstrated no inhibition or induction of CYP3A4 mediated metabolism.

In vitro studies indicate that filgotinib and GS-829845 are not inhibitors of P-gp, BCRP, OCT1, BSEP,

OAT1, OAT3 or OAT4 at clinically relevant concentrations.

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

The carcinogenic potential of filgotinib was evaluated in a 6-month rasH2 transgenic mouse study anda 2-year rat study. Filgotinib was not carcinogenic in mice at up to 150 mg/kg/day, which resulted inexposures of approximately 25 and 12 times the exposures in humans at the 100 mg and 200 mg oncedaily doses, respectively. In the 2-year rat study, filgotinib treatment resulted in an increase inincidence and decrease in latency of benign Leydig cell tumours at the highest dose of 45 mg/kg/day(exposures of approximately 4.2 times exposures in humans at the 200 mg once daily dose); theclinical relevance of this finding is low.

Filgotinib was not mutagenic or clastogenic in the in vitro bacterial reverse mutation assay, in vitrochromosome aberration assay, and in vivo rat micronucleus assay.

Adverse findings of degeneration/necrosis of incisor ameloblasts were observed in rats at exposures21- to 28-fold greater than clinical exposures at the 200 mg filgotinib dose, with exposure margins atthe no-observed-adverse-effect-level (NOAEL) ranging from 3.5- to 8-fold. The human relevance ofthese dental findings is considered low since in contrast to adult patients, ameloblasts in rats persistinto adulthood to support lifelong continuous incisor growth.

Impaired spermatogenesis and histopathological effects on male reproductive organs (testes andepididymis) were observed with filgotinib in rats and dogs. At the NOAELs in dogs (the mostsensitive species), the exposure margin is 2.7-fold at the 200 mg once daily dose in humans. Theseverity of the histological effects was dose-dependent. Spermatogenic and histopathological effectswere not fully reversible at exposure margins of approximately 7- to 9-fold the exposure at the 200 mgonce daily dose in humans.

Embryo-foetal development studies in rats and rabbits demonstrated embryolethality andteratogenicity at exposures comparable to 200 mg filgotinib once daily dosing in humans. Visceral andskeletal malformations and/or variations were observed at all dose levels of filgotinib.

Filgotinib was administered to pregnant rats at doses of 25, 50, and 100 mg/kg/day. Dose-relatedincreases in the incidence of internal hydrocephaly, dilated ureters, and multiple vertebral anomalieswere seen at all dose levels. At 100 mg/kg/day, an increased number of early and late resorptions werenoted together with a decreased number of viable foetuses. In addition, foetal body weights weredecreased.

In rabbits, filgotinib caused visceral malformations mainly in the lungs and cardiovascular system, at adose level of 60 mg/kg/day. Filgotinib caused skeletal malformations affecting the vertebral columnregion at dose levels of 25 and 60 mg/kg/day, mainly in vertebra, ribs and sternebrae. Fused sternebraealso occurred at 10 mg/kg/day filgotinib. Retarded skeletal ossification was evidenced at60 mg/kg/day.

No adverse effects on pre-/postnatal development were observed in rats in a pre- and postnataldevelopment study of filgotinib and GS-829845. Filgotinib and GS-829845 were detected in nursingrat pups after administration of filgotinib to lactating female rats from gestation day 6 through 10 dayspost-partum at dose levels of 2, 5, and 15 mg/kg/day, likely due to the presence of filgotinib in milk.

At the highest tested dose, maternal systemic exposure (AUC) to filgotinib in rats was approximately2 times the exposure in humans at the 200 mg once daily dose; exposures in nursing pups were lessthan 6% that of maternal exposure on day 10 post-partum. Due to the low exposure of the animals, thepre-/postnatal development study was considered inconclusive.

Microcrystalline cellulose

Lactose monohydrate

Pregelatinised starch

Colloidal silicon dioxide

Fumaric acid

Magnesium stearate

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol

Talc

Iron oxide yellow (E172)

Iron oxide red (E172)

Not applicable.

4 years

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

White, high-density polyethylene (HDPE) bottles, enclosed with a child-resistant polypropylene (PP)screw cap lined with an induction-sealed aluminium foil liner. Each bottle contains either a canister orsachet containing silica gel desiccant.

The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets andouter cartons containing 90 (3 bottles of 30) film-coated tablets.

Not all pack sizes may be marketed.

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

Alfasigma S.p.A.

Via Ragazzi del '99, n. 540133 Bologna

Italy

EU/1/20/1480/001

EU/1/20/1480/002

EU/1/20/1480/003

EU/1/20/1480/004

Date of first authorisation: 24 September 2020

Date of latest renewal:

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

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