Biomarkers for determining treatment of ulcerative colitis with filgotinib

Abstract

Filgotinib or a pharmaceutically acceptable salt thereof for use in a method of treating ulcerative colitis is provided, along with methods of deciding whether to continue treating ulcerative colitis in a patient with filgotinib or a pharmaceutically acceptable salt. The treatments are based on the assessment of the levels of certain predictive biomarkers in the patient having ulcerative colitis.

Description

[0001] BIOMARKERS FOR DETERMINING TREATMENT OF ULCERATIVE COLITIS WITH FILGOTINIB

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to predictive biomarkers useful in predicting the effectiveness of treatment of ulcerative colitis with filgotinib, a selective JAK inhibitor. The present invention also relates to filgotinib for use in methods of treating ulcerative colitis in patients in need thereof, and methods of treating ulcerative colitis in such patients using filgotinib, wherein filgotinib treatment is either continued or adjusted, depending on the levels of certain predictive biomarkers. The present invention also relates to diagnostic devices and kits that can be used to carry out the methods of the invention.

[0004] BACKGROUND OF THE INVENTION

[0005] Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease characterized by relapsing and remitting mucosal inflammation, starting in the rectum and extending to proximal segments of the colon. The hallmark symptoms of UC are bloody diarrhea, rectal urgency, and tenesmus. The clinical course tends to wax and wane with periods of remission interspersed with periods of active disease. The pathogenesis of UC is multifactorial and comprises immune, genetic, environmental, and microbial components (Feuerstein et al. 2019 Mayo Clinic Proc 94, 1357-1373; Ungaro et al. 2017, Lancet, 389, 1756-1770).

[0006] The main drug classes used for treatment of UC include 5-aminosalicylic acids (5-ASAs), corticosteroids, thiopurines, anti-TNFs, anti-integrins, and Janus kinase (JAK) inhibitors. Filgotinib (FIL) is a potent and highly selective (JAK1) inhibitor. (Rompaey, L. et al. 2013 J Immunol 191 , 3568-3577). FIL has demonstrated efficacy in inducing and maintaining clinical remission in patients with moderately-to-severely active UC (Feagan, B. G. et al. 2021 Lancet 397, 2372- 2384). However, there is variability in responses across the UC patient population to FIL.

[0007] Thus, long-term disease control in UC is still challenging and an unmet need for more effective therapies or better treatment strategies remains. One approach that has been considered in the context of UC treatment is the assessment of biomarkers that may allow for personalised treatments.

[0008] C-reactive protein (CRP), a non-specific biomarker of inflammation, and fecal calprotectin (FCP), a marker of neutrophils, are standardly assessed biomarkers used to monitor disease activity, have been explored as markers to monitor treatment response in UC (Ungaro et al. 2017, Lancet, 389, 1756-1770) to anti-TNF or anti-integrin (Reinisch, W. Et al. 2011 Gut 60, 780; Iwasa, R. Et al. 2015 BMC Gastroenterol. 15, 103; Popa, I. V et al Medicina 56, 628; Magro, F. et al. 2014 J. Crohn’s Colitis 8, 129-136; Bertani, L. et al. 2020 Clin. Transl. Gastroenterol. 11 , e00174; Vos, M. D. et al. 2012 J. Crohn’s Colitis 6, 557-562) and tofacitinib (a JAK inhibitor) (Lees, C. W. et al. 2021 Ther. Adv. Gastroenterol. 14, 17562848211054710; Ishida, N. Et al. 2022 Dig. Dis. Sci. 67, 3984-3992; Sandborn, W. J. Et al. 2021 Inflamm. Bowel Dis. 28, 1338-1347). Although some evidence exists to support CRP and FCP as biomarkers to monitor treatment response to multiple therapeutic modalities in UC, the evidence is insufficient with respect to supporting personalized treatment.

[0009] To the inventors’ knowledge, no biomarkers have yet been identified to monitor or predict treatment response to filgotinib or other JAK inhibitors. Despite the evidence presented above in relation to biologic monoclonal antibody inhibitors of integrins, TNF, or IL-23 , it has not yet been shown that CRP and FCP or any other biomarker independently or as a composite with other variables can be used clinically to identify subpopulations of UC patients with differential longterm benefit to targeted therapies. Accordingly, there is a need in the art for treatment methods that enable predictions of treatment response to be made and, thus, improve the life of patients in need thereof. Specifically predicting responses to filgotinib, is necessary to further develop the potential for precision medicine in UC.

[0010] SUMMARY OF THE INVENTION

[0011] The invention is based on the finding that biomarker(s) can be used to predict the responsiveness of ulcerative colitis to continued treatment with filgotinib.

[0012] The invention provides filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, for use in a method of treating ulcerative colitis in a patient, wherein the method comprises the steps of:

[0013] (i) measuring the level of at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0014] (ii) measuring the level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and

[0015] (iii) if the level of:

[0016] (a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.7 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0017] (b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and / or

[0018] (c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, continuing the administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof.

[0019] In a preferred embodiment, measuring the level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL in step (ii) is at least 4 weeks (for example, at 4 weeks) after administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof.

[0020] In one embodiment the at least one predictive biomarker is SAA1. In another embodiment the at least one predictive biomarker is IL-6. In a further embodiment the at least one predictive biomarker is NGAL.

[0021] In one embodiment, the patient, prior to administration of filgotinib, or a pharmaceutically acceptable salt thereof, is biologic-naive or biologic- experienced.

[0022] In another embodiment the patient has moderately to severely active ulcerative colitis according to the MCS prior to the treatment with filgotinib, or a pharmaceutically acceptable salt.

[0023] In a preferred embodiment, Filgotinib, or a pharmaceutically acceptable salt thereof, is administered in an amount of 100 mg or 200 mg.

[0024] In a still preferred embodiment, Filgotinib, or a pharmaceutically acceptable salt thereof, is administered for at least 10 weeks or at least 58 weeks.

[0025] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 : Schematic illustrating the trial study design. FIL = filgotinib; PBO = placebo. Nonresponders were subjects who achieved neither EBS remission nor MCS response at Week 10.

[0027] Figures 2a-c: Graphs illustrating the effect of filgotinib treatment on serum protein biomarkers, IL-6 (Figure 2a), SAA1 (Figure 2b) and NGAL (Figure 2c), in biologic-naive and biologic- experienced patients. Grey dashes indicate estimated biomarker levels for healthy volunteers. P values reflect filgotinib treatment changes from baseline to week 10 compared with placebo. Abbreviations: Cl, confidence interval; IL, interleukin; LS, least-squares; NGAL, neutrophil gelatinase-associated lipocalin; SAA1 , serum amyloid A1.

[0028] DETAILED DESCRIPTION

[0029] The inventors have identified several biomarkers that are associated with positive clinical responses to filgotinib treatment in patients with ulcerative colitis. In particular, the inventors have found that the clinical outcome for patients undergoing filgotinib treatment at week 10 of treatment can be predicted according to certain biomarkers that are decreased at week 4 following start of treatment relative to baseline levels of the biomarkers prior to treatment with filgotinib.

[0030] The inventors analysed serum samples from ulcerative colitis patients to measure serum protein biomarker levels at baseline (i.e. prior to filgotinib treatment) and at week 4 of treatment with filgotinib. The relative fold changes in protein levels between week 4 and baseline were quantified and differentially expressed proteins associated with either a positive or negative clinical response at week 10 were identified. The inventors found that a more significant reduction in certain biomarkers between baseline and week 4 was associated with clinical outcome at week 10 (as assessed by EBS remission). Three biomarkers were identified (SAA1 , IL-6 and NGAL), with a downregulation of at least 1.7 fold, at least 1.3 fold or at least 1.3 fold in the levels of SAA1 , IL-6 or NGAL, respectively being associated with clinical response to filgotinib treatment at week 10. Accordingly, a comparison of one or more biomarker levels in a UC patient sample prior to filgotinib treatment and the level of the same one or more biomarkers 4 weeks following treatment can be used to predict whether a UC patient will display a positive clinical response to further treatment with filgotinib. This means that an assessment of such biomarkers can be used to direct decisions on subsequent filgotinib treatment. The information provided by an assessment of these biomarker levels in UC patients is therefore advantageous because a patient that is likely to benefit from further treatment to achieve a positive clinical response can continue to be treated, with confidence that the beneficial effects of the drug will outweigh any side effects. Conversely, a patient that is unlikely to benefit from further treatment can adjust the filgotinib treatment regimen (e.g. change the dose, add a further drug, or discontinue the treatment with filgotinib), thereby avoiding any side-effect of administering the drug further. In light of this utility in predicting outcomes to treatment, these biomarkers are referred to as predictive biomarkers herein.

[0031] Predictive biomarkers

[0032] The predictive biomarkers identified by the inventors are downregulated at week 4 when compared to levels of these biomarkers prior to treatment. These biomarkers are summarised in Table 1 below, with sequences of RNA transcript and proteins provided for each biomarker.

[0033] The invention may be carried out by measuring predictive biomarkers, as defined elsewhere herein, and the predictive biomarkers may comprise or consist of any of the sequences of the predictive biomarkers provided in Table 1.

[0034] In certain embodiments wherein a predictive biomarker is SAA1 , SAA1 comprises an RNA sequence of SEQ ID NO: 1 and / or a protein sequence of SEQ ID NO: 2. In certain embodiments wherein a predictive biomarker is I L-6, 1 L-6 comprises an RNA sequence of SEQ I D NO: 11 and / or a protein sequence of SEQ ID NO: 12. In certain embodiments wherein a predictive biomarker is NGAL, NGAL comprises an RNA sequence of SEQ ID NO: 27 and / or a protein sequence of SEQ ID NO: 28.

[0035] The invention may also be carried out by measuring predictive biomarkers having sequences that are at least 98% identical (e.g. at least 99% identical) to any of the sequences specified in Table 1.

[0036]

[0037] The invention provides filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, for use in a method of treating ulcerative colitis in a patient, wherein the method comprises the steps of:

[0038] (i) measuring the level of at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0039] (ii) measuring the level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and

[0040] (iii) if the level of:

[0041] (a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.7 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0042] (b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and / or

[0043] (c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, continuing the administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof.

[0044] The invention also provides a method of deciding whether to continue treating ulcerative colitis in a patient with filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, wherein the method comprises the steps of: (i) measuring the level of at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0045] (ii) measuring the level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and

[0046] (iii) if the level of:

[0047] (a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.7 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0048] (b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and / or

[0049] (c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, continuing the administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof.

[0050] In some embodiments, the at least one predictive biomarker is one predictive biomarker. In some such embodiments, the one predictive biomarker is SAA1. In other embodiments, the one predictive biomarker is IL-6. In other embodiments, the one predictive biomarker is NGAL.

[0051] An assessment of more than one biomarker may increase the predictive value of the assessment of patient responsiveness to the drug, thereby providing increased confidence in the continued treatment of ulcerative colitis with the drug. Accordingly, the invention may be performed using more than one of the predictive biomarkers described in Table 1 above (i.e. using a set of predictive biomarkers). In some embodiments, the predictive biomarker set that is measured in any of the methods described herein includes more than one (e.g. 2 or 3) predictive biomarkers selected from Table 1.

[0052] Thus, in some embodiments, the at least one predictive biomarker is at least two (e.g., two) predictive biomarkers. For example, in some embodiments, the at least one predictive biomarker is at least two (e.g., two) predictive biomarkers selected from the list of SAA1 , IL-6 and NGAL. In some embodiments where the at least one predictive biomarker is two predictive biomarkers any combination of two biomarkers from the immediately preceding list of predictive biomarkers may be used. Accordingly, in some embodiments, the two predictive biomarkers are SAA1 and IL-6. In other embodiments, the two predictive biomarkers are SAA1 and NGAL. In other embodiments, the two predictive biomarkers are IL-6 and NGAL.

[0053] In other embodiments, the at least one predictive biomarker is three predictive biomarkers, wherein the three predictive biomarkers are SAA1 , IL-6 and NGAL.

[0054] Timing between predictive biomarker measurements

[0055] The inventors analysed biomarker levels in serum from ulcerative colitis patients at 4 weeks of treatment and compared these levels with baseline levels of biomarkers in the same ulcerative colitis patients (i.e. the levels of the biomarkers prior to administration of filgotinib). Although the samples were analysed at week 4 of treatment, the levels of predictive biomarkers are expected to show a similar profile at similar timepoints following treatment. This means that biomarker levels do not need to be measured at precisely 4 weeks of treatment in order to predict responsiveness to ongoing treatment with the drug.

[0056] Accordingly, in some embodiments, the level of the at least one predictive biomarker is measured after at least 3 weeks of administration to the patient of the drug. For example, the level of the at least one predictive biomarker is measured at 3 weeks of administration to the patient of the drug. In some embodiments, the level of the at least one predictive biomarker is measured after at least

[0057] 4 weeks of administration to the patient of the drug. For example, the level of the at least one predictive biomarker is measured at 4 weeks of administration to the patient of the drug.

[0058] In some embodiments, the level of the at least one predictive biomarker is measured after at least

[0059] 5 weeks of administration to the patient of the drug. For example, the level of the at least one predictive biomarker is measured at 5 weeks of administration to the patient of the drug.

[0060] Magnitude of predictive biomarker downregulation

[0061] An increased magnitude of downregulation of a predictive biomarker may increase the predictive value of the biomarker assessment and thus allow for more effective treatment of ulcerative colitis patients with the drug.

[0062] The inventors have identified predictive biomarkers according to a 1.7, 1.3 or 1.3 fold decrease in SAA1 , IL-6 and NGAL, respectively, relative to baseline (i.e. prior to treatment) and larger decreases may also be measured and used according to the methods described herein. The level of IL-6, may be downregulated by at least 1 .3 fold, at least 1 .4 fold, at least 1 .5 fold, at least 1.6 fold, at least 1.7 fold, or at least 2 fold relative to the baseline level of IL-6. The level of NGAL, may be downregulated by at least 1.3 fold, at least 1.4 fold, at least 1.5 fold, at least 1.6 fold, at least 1.7 fold, or at least 2 fold relative to the baseline level NGAL. The level of SAA1 , may be downregulated by at least 1.7 fold, at least 1.8 fold, at least 1.9 fold, at least 2.1 fold, at least 2.2 fold, at least 2.7 fold, or at least 3 fold relative to the baseline level of SAA1.

[0063] In some embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0064] In some such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0065] In other such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0066] In other such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0067] In some embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 1.4 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0068] In some such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 1.4 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0069] In other such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 1.4 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0070] In other such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 1.4 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0071] In some embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 1.5 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0072] In some such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 1.5 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0073] In other such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 1.5 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0074] In other such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 1.5 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0075] In some embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 1.6 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0076] In some such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 1.6 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0077] In other such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 1.6 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0078] In other such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 1.6 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0079] In some embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 1.7 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0080] In some such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 1.7 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0081] In other such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 1.7 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0082] In other such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 1.7 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0083] In some embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 2 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0084] In some such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 2 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0085] In other such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 2 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0086] In other such embodiments, wherein the predictive biomarker is IL-6 and the level of IL-6 after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 2 fold less than the level of IL-6 prior to administration to the patient of the drug, administration of the drug is continued.

[0087] In some embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 1.3 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0088] In some such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 1.3 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0089] In other such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 1.3 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0090] In other such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 1.3 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0091] In some embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 1.4 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0092] In some such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 1.4 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0093] In other such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 1.4 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0094] In other such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 1.4 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0095] In some embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 1.5 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0096] In some such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 1.5 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0097] In other such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 1.5 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0098] In other such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 1.5 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0099] In some embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 1.6 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0100] In some such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 1.6 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0101] In other such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 1.6 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0102] In other such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 1.6 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0103] In some embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 1.7 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0104] In some such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 1.7 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0105] In other such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 1.7 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0106] In other such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 1.7 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0107] In some embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 2 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0108] In some such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 2 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0109] In other such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 2 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0110] In other such embodiments, wherein the predictive biomarker is NGAL and the level of NGAL after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 2 fold less than the level of NGAL prior to administration to the patient of the drug, administration of the drug is continued.

[0111] In some embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 1.7 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0112] In some such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least

[0113] 1.7 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0114] In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least

[0115] 1.7 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0116] In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least

[0117] 1.7 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued. In some embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 1.8 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0118] In some such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least

[0119] 1.8 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0120] In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least

[0121] 1.8 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0122] In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least

[0123] 1.8 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0124] In some embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 1.9 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0125] In some such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least

[0126] 1.9 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0127] In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least

[0128] 1.9 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0129] In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least

[0130] 1.9 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0131] In some embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 2.1 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued. In some such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least

[0132] 2.1 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0133] In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least

[0134] 2.1 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0135] In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least

[0136] 2.1 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0137] In some embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 2.2 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0138] In some such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least

[0139] 2.2 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0140] In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least

[0141] 2.2 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0142] In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least

[0143] 2.2 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0144] In some embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 2.7 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0145] In some such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 2.7 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued. In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 2.7 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0146] In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 2.7 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0147] In some embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug is at least 3 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0148] In some such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 3 weeks (for example at 3 weeks) of administration to the patient of the drug is at least 3 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0149] In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 4 weeks (for example at 4 weeks) of administration to the patient of the drug is at least 3 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0150] In other such embodiments, wherein the predictive biomarker is SAA1 and the level of SAA1 after at least 5 weeks (for example at 5 weeks) of administration to the patient of the drug is at least 3 fold less than the level of SAA1 prior to administration to the patient of the drug, administration of the drug is continued.

[0151] Measuring predictive biomarkers

[0152] As described elsewhere herein, the inventors identified predictive biomarkers by measuring protein levels in serum and whole blood samples using enzyme-linked immunosorbent assays. Accordingly, in some embodiments, the biomarker level is assessed according to protein level. Predictive biomarkers are also expressed as RNA, thereby providing an additional or alternative analyte that may be measured.

[0153] Accordingly, in some embodiments, the biomarker level is assessed according to RNA level. In some such embodiments, the biomarker level is assessed according to mRNA level.

[0154] Although the inventors measured predictive biomarkers in serum and whole blood biomarker samples, the invention is not restricted to measurement of predictive biomarkers in such samples. Other samples that may be obtained from ulcerative colitis patients less intrusively (e.g. stool or urine samples) or alternatively, via colonic mucosal biopsies. These may provide a more straightforward implementation of the methods described herein.

[0155] Accordingly, in some embodiments the levels of the at least one predictive biomarker are measured in a blood sample, a stool sample, a urine sample, or a colonic mucosal biopsy sample. In some embodiments the levels of the at least one predictive biomarker are measured in a blood sample.

[0156] In some embodiments the levels of the at least one predictive biomarker are measured in a stool sample.

[0157] In some embodiments the levels of the at least one predictive biomarker are measured in a urine sample.

[0158] In some embodiments the levels of the at least one predictive biomarker are measured in a colonic mucosal biopsy sample.

[0159] In some embodiments, protein levels of the at least one predictive biomarker are measured in a blood sample, a stool sample, a urine sample, or a colonic mucosal biopsy sample

[0160] In some embodiments, protein levels of the at least one predictive biomarker are measured in a blood sample. In some embodiments, protein levels of the at least one predictive biomarker are measured in a stool sample. In some embodiments, protein levels of the at least one predictive biomarker are measured in a urine sample. In some embodiments, protein levels of the at least one predictive biomarker are measured in a colonic mucosal biopsy sample.

[0161] In other embodiments, RNA (e.g. mRNA) levels of the at least one predictive biomarker are measured in a blood sample, a stool sample, a urine sample, or a colonic mucosal biopsy sample. In some embodiments, RNA (e.g. mRNA) levels of the at least one predictive biomarker are measured in a blood sample. In some embodiments, RNA (e.g. mRNA) levels of the at least one predictive biomarker are measured in a stool sample. In some embodiments, RNA (e.g. mRNA) levels of the at least one predictive biomarker are measured in a urine sample. In some embodiments, RNA (e.g. mRNA) levels of the at least one predictive biomarker are measured in a colonic mucosal biopsy sample.

[0162] Protein levels of biomarkers may be measured using any of the methods defined herein. Typically, the same assay is used to measure biomarker protein level prior to treatment with filgotinib in step (i) and following treatment with filgotinib in step (ii). Protein levels of predictive biomarkers may be measured according to any of the amino acid sequences described in Table 1 . However, it is not necessary for the full protein sequence described in T able 1 to be detected in order to measure the level of the corresponding predictive biomarker and sequences having at least 98% (e.g. at least 99%) identity to the sequences described in Table 1 may also be detected.

[0163] Commonly used methods known in the art for the quantification of protein expression levels in a sample are antibody-based methods (i.e. immunoassays), such as enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunofluorescence or other similar methods known in the art. Each of these methods utilizes an antibody that specific for the predictive biomarker protein that is to be measured. Examples of immunoassays include, without limitation immunoblotting assays (Western blots), enzyme linked immunosorbent assays (ELISAs) (e.g., sandwich ELISAs), radioimmunoassays, electrochemiluminescence-based detection assays, magnetic immunoassays, lateral flow assays, and related techniques, in some embodiments, the protein level of the at least one predictive biomarker is measured using an ELISA. ELISAs are known in the art (see, e.g., Crowther, John R (2009). “The ELISA Guidebook.” 2nd ed. Humana Press and Lequin R (2005). “Enzyme immunoassay (EIA) / enzyme-linked immunosorbent assay (ELISA)”. Clin. Chem. 51 (12): 2415-8) and exemplary ELISAs are described herein. Kits for performing ELISAs are also known in the art and commercially available (see, e.g., ELISA kits from Life Technologies and BD Biosciences). An ELISA may also be in the format of a sandwich ELISA, in which a first binding agent that specifically binds a protein of the biomarker set is immobilized on a support member. The support member can then be incubated with a biological sample as described herein for a suitable period of time under conditions that allow for the formation of complex between the binding agent and the protein in the sample. Such a complex can then be detected using a detection agent that binds the protein, the binding agent-protein complex, or the binding agent. The detection agent can be conjugated to a label, which can release a signal directly or indirectly. The intensity of the signal represents the level of the protein in the sample. In some embodiments, the detection agent is detected and its level represents the level of the protein in the sample.

[0164] Alternatively, an ELISA may also be in the format of a digital beaded ELISA, in which a first binding agent that specifically binds a protein of interest (e.g. a predictive biomarker as defined herein) is immobilized on a paramagnetic bead. The support member can then be incubated with a biological sample as described herein for a suitable period of time under conditions that allow for the formation of complex between the binding agent and the protein in the sample. A detection agent is then added that binds the protein or the binding agent-protein complex. The objective is to form an immunocomplex consisting of the bead, bound protein, and detection agent. The detection agent can be conjugated to a label, which can release a signal directly or indirectly. At low concentrations, each bead will contain one bound biomarker protein, or none. The immunocomplex is then loaded into arrays containing microwells, wherein each well is large enough to hold one bead. The signal is amplified enzymatically with fluorescent substrate, and the fluorescence signal is imaged to quantify the amount of protein in the sample.

[0165] Additional suitable immunoassays for detecting a biomarker provided herein will be apparent to those of skill in the art. It will be apparent to those of skill in the art that this disclosure is not limited to immunoassays, however, and that detection assays that rely on a chromogenic substrate can also be useful for the detection and / or quantification of predictive biomarkers as provided herein.

[0166] Any other binding agent that specifically binds to a desired protein may be used in the methods described herein to measure the protein level of the at least one predictive biomarker. For example, in some embodiments, the binding agent is an aptamer antibody that specifically binds to a desired protein. In some embodiments, a sample may be contacted, simultaneously or sequentially, with more than one binding agent that bind different proteins (e.g., multiplexed analysis, for example the SOMAScan™ assay (SOMALogic)). The biological sample is contacted with a binding agent under appropriate conditions. In general, the term “contact” refers to an exposure of the binding agent with the biological sample or agent for a suitable period sufficient for the formation of complexes between the agent and the protein in the sample, if any. In some embodiments, the contacting is performed by capillary action in which a biological sample or agent is moved across a surface of the support membrane.

[0167] RNA levels of biomarkers may be measured using any of the methods defined herein or known in the art. Typically, the same assay is used to measure biomarker RNA level prior to treatment with filgotinib in step (i) and following treatment with filgotinib in step (ii). RNA levels of predictive biomarkers may be measured according to any of the transcript sequences described in Table 1. However, it is not necessary for the full RNA sequence described in Table 1 to be detected in order to measure the level of the corresponding predictive biomarker and sequences having at least 98% (e.g. at least 99%) identity to the sequences described in Table 1 or may also be detected. Similarly, in, for example, PCR based methods of detection, primers that are capable of amplifying a portion of the sequences described in Table 1 , wherein the portion of the amplified sequence is specific for the predictive biomarker may also be used.

[0168] Commonly used methods known in the art for the quantification of mRNA expression levels in a sample include, without limitation, northern blotting and in situ hybridization; microarrays, RNAse protection assays; and PCR-based methods, such as reverse transcription polymerase chain reaction (RT-PCR), real time quantitative PCR (also referred to as qRT-PCR) and digital PCR. Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes, or DNA-protein duplexes. Representative methods for sequencing-based gene expression analysis include RNA sequencing (RNA-seq), Serial Analysis of Gene Expression (SAGE), and gene expression analysis by massively parallel signature sequencing (MPSS). The measured RNA levels for a given sample may be normalized using methods known to those skilled in the art in order to correct for differing amounts of starting material, varying efficiencies of the extraction and amplification reactions.

[0169] In some embodiments, RNA (e.g. mRNA) levels of the at least one predictive biomarker are measured using RNA-seq.

[0170] RNA-seq may be used to quantify and determine the sequence of RNA transcripts. An RNA-Seq experiment comprises the steps of (i) isolating RNA, (ii) converting the isolated RNA to complementary DNA (cDNA), (iii) preparing a sequencing library, and (iv) sequencing the library, for example on an next generation sequencing platform (e.g Illumina sequencing). First, RNA is extracted from the biological material of choice (e.g., cells, tissues). Second, subsets of RNA molecules are isolated using a specific protocol, such as the poly-A selection protocol to enrich for polyadenylated transcripts or a ribo-depletion protocol to remove ribosomal RNAs. Next, the RNA is converted to complementary DNA (cDNA) by reverse transcription and sequencing adaptors are ligated to the ends of the cDNA fragments. Following amplification by PCR, the RNA- Seq library is ready for sequencing (Kukurba KR, Montgomery SB. RNA Sequencing and Analysis. Cold Spring Harb Protoc. 2015 Apr 13;2015(11):951-69).

[0171] In other embodiments, RNA (e.g. mRNA) levels of the at least one predictive biomarker are measured using PCR-based methods. For example, reverse transcription quantitative PCR (RT- PCR followed with qPCR) may be used. The steps for measuring RNA (e.g. mRNA) levels according to these methods are as follows: (i) RT-PCR is used to create a cDNA of the at least one predictive biomarker transcript, (ii) the cDNA of the at least one predictive biomarker transcript is then analysed in a qPCR assay in which a, for example, fluorescence signal is produced as the DNA amplification process progresses; (iii) the qPCR signal is compared to a standard curve to provide a measurement, such as number of copies of RNA present in a sample (Wang et al., PloS ONE 2011 ; 6: e25832; Gallo et al., PloS ONE 2012; 7: e30679.; Sinha et al., The Journal of Allergy and Clin Immunol. 2013; 132: 219-222.). In these methods for assessing RNA (e.g. mRNA levels), synthetic nucleotides (i.e. oligonucleotides) may be used as probes or specific primers for PCR. Such molecules can easily be synthesized by chemical techniques, for example, the phosphotriester method of Matteucci et al. (1981) J. Am. Chem. Soc. 103, 3185-3191 or using automated synthesis methods. Furthermore, Northern blots, microarrays, Invader assays, and RT-PCR combined with capillary electrophoresis have all been used to measure expression levels of RNA in a sample. (See Gene Expression Profiling: Methods and Protocols, Richard A. Shimkets, editor, Humana Press, 2004.)

[0172] In other embodiments, digital PCR may be used to quantify RNA (e.g. mRNA) levels of the at least one predictive biomarker. Digital PCR depends on the ability of PCR to detect a single molecule of a target locus. The sample is greatly diluted and divided into a large number of aliquots, so that some aliquots receive at least one molecule of the target (“positive” aliquots), whilst others do not. The number of positive aliquots, as determined by PCR, then reflects the abundance of the target locus in the sample. If the sample is sufficiently dilute, only a few of the aliquots will be positive, and each of these positive aliquots can be assumed to have contained only a single target molecule. In this case, the process equates to a direct and simple counting of molecules - the “digital” in “digital PCR”. In this way, it is easy to calculate the absolute abundance of the target sequence in the sample. More commonly, though, the abundance of the target sequence is compared to that of a reference sequence analysed in the same way (Day E, Dear PH, McCaughan F. Digital PCR strategies in the development and analysis of molecular biomarkers for personalized medicine. Methods. 2013;59(1):101-107).

[0173] In some embodiments, the RNA level(s) data is generated from a microarray, such as a gene chip. A microarray as employed herein includes RNA or DNA arrays. A gene chip is essentially a microarray — that is to say an array of discrete regions, typically nucleic acids — which are separate from one another and are, for example arrayed at a density of between, about 100 / cm2to 1000 / cm2, but can be arrayed at greater densities such as 10000 / cm2.

[0174] A microarray consists of an arrayed series of a plurality of microscopic spots of nucleotides, called features, each containing a small amount (typically in the range of picomoles) of a specific nucleotide sequence. The specific nucleotide sequence can be a short section of a gene or other nucleotide element that is used as a probe to hybridize a cDNA or cRNA sample under high- stringency conditions. Probe-target hybridization is usually detected and quantified by fluorescence-based detection of fluorophore-labeled targets to determine relative abundance of nucleic acid sequences in the target. The nucleotide probes are typically attached to a solid surface by a covalent bond to a chemical matrix (via epoxy-silane, amino-silane, lysine, polyacrylamide or others). Examples of microarrays used to determine measure nucleic acid levels include U.S. Pat. No. 6,271 ,002, et al; U.S. Pat. Nos. 6,218,122; 6,218,114; or 6,004,755.

[0175] Treatment of ulcerative colitis

[0176] Ulcerative colitis is a chronic idiopathic inflammatory disease characterized by relapsing and remitting mucosal inflammation, starting in the rectum and extending to proximal segments of the colon.

[0177] The inventors used the Mayo Clinical Score (MCS) for ulcerative colitis disease activity for the assessment of disease severity in patients, and also for monitoring patient responsiveness during therapy. The MCS provides a universal metric to encapsulate disease severity of ulcerative colitis at a given time in a single number. The MCS comprises four parts: stool frequency, rectal bleeding, endoscopic findings and a physician’s global assessment, each of which is scored from 0-3. The physician’s global assessment accounts for other signs and symptoms of ulcerative colitis including abdominal pain, physical exam findings (extraintestinal manifestations, fever, tachycardia), functional status, and the patient’s overall sense of well-being. An MCS can range therefore range from 0-12 with higher scores indicating worse severity. A ‘Full’ or ‘Complete’ MCS incorporates all 4 parts. If endoscopic findings are not available, the remaining 3 categories constitute a ‘Partial’ MCS (pMCS).

[0178] Ulcerative colitis can be assessed as being moderately to severely active as defined by a MCS endoscopic subscore of > 2, a rectal bleeding subscore of > 1 , a stool frequency subscore of > 1 , a physician’s global assessment subscore of > 2; and a total MCS of 6-12.

[0179] The inventors assessed biomarker levels at baseline (i.e. prior to treatment), week 4 and at 10 weeks of filgotinib treatment in ulcerative colitis patients having moderately to severely active ulcerative colitis according to the MCS prior to administration of filgotinib. Patients having moderately to severely active ulcerative colitis according to the MCS prior to administration of filgotinib may therefore be particularly amenable to treatment with filgotinib according to any of the therapies described herein.

[0180] Accordingly, in some embodiments, the drug is for use in a method of treating ulcerative colitis in a patient, wherein the patient has moderately to severely active ulcerative colitis according to the MCS prior to the treatment with the drug. In other embodiments, the method of deciding whether to continue treating ulcerative colitis is in a patient that has moderately to severely active ulcerative colitis according to the MCS.

[0181] For example, in some embodiments the drug is for use in a method of treating ulcerative colitis in a patient, wherein the patient has moderately to severely active ulcerative colitis according to the MCS prior to treatment, wherein the method comprises the steps of:

[0182] (i) measuring the level of at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL prior to administration to the patient of the drug,

[0183] (ii) measuring the level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug, and

[0184] (iii) if the level of:

[0185] (a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug, is at least 1.7 fold less than the level of SAA1 prior to administration to the patient of the drug,

[0186] (b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug, is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of the drug, and / or

[0187] (c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug, is at least 1.3 fold less than the level of NGAL prior to administration to the patient of the drug, continuing the administration to the patient of the drug. In other embodiments, the method of deciding whether to continue treating ulcerative colitis in a patient with the drug after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug, is in a patient that has moderately to severely active ulcerative colitis according to the MCS prior to the treatment with the drug, wherein the method comprises the steps of:

[0188] (i) measuring the level of at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL prior to administration to the patient of the drug,

[0189] (ii) measuring the level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug, and

[0190] (iii) if the level of:

[0191] (a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug, is at least 1.7 fold less than the level of SAA1 prior to administration to the patient of the drug,

[0192] (b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug, is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of the drug, and / or

[0193] (c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug, is at least 1.3 fold less than the level of NGAL prior to administration to the patient of the drug, continuing the administration to the patient of the drug.

[0194] The invention includes a step of continuing treatment with the drug if the level of the at least one predictive biomarker is downregulated significantly enough to indicate that the patient will benefit from further treatment with the drug (i.e. the patient is likely to demonstrate a positive clinical response at week 10 following further treatment with the drug). The invention can also be utilized to identity patients that are not likely to demonstrate a positive clinical response at week 10 following further treatment with the drug and thus treatment can be adjusted in these patients (e.g. the dose of the drug can be changed, a further drug may be added to the treatment, or treatment with the drug may be discontinued). Such a adjustment in treatment is advantageous because the patient then avoids further treatment that risks side-effects that would not be outweighed by a significant benefit in continued treatment of ulcerative colitis without adjustment. Accordingly, in some embodiments the drug for use in treating ulcerative colitis or the method of deciding whether to continue treating ulcerative colitis in a patient comprises a step following the measurement of the level of the at least one predictive biomarker after at least 3, at least 4, or at least 5 weeks of administration of the drug, wherein if the level of the at least one predictive biomarker, after at least 3, at least 4, or at least 5 weeks of administration to the patient of the drug, is not at least 1.7, 1.3 or 1.3 fold less than the levels of SAA1 , IL-6, and / or NGAL, respectively, prior to administration to the patient of the drug (as defined elsewhere herein), the administration to the patient of the drug is adjusted (e.g. the dose of the drug is changed, a further drug may be added to the treatment, or treatment with the drug is discontinued).

[0195] In some such embodiments, the drug for use in treating ulcerative colitis or the method of deciding whether to continue treating ulcerative colitis in a patient comprises a step following the measurement of the level of the at least one predictive biomarker after at least 3 weeks (e.g. at 3 weeks) of administration of the drug, wherein if the level of the at least one predictive biomarker after at least 3 weeks (e.g. at 3 weeks) of administration to the patient of the drug, is not at least

[0196] 1.7, 1.3 or 1.3 fold less than the levels of SAA1 , IL-6, and / or NGAL, respectively, prior to administration to the patient of the drug (as defined elsewhere herein), the administration to the patient of the drug is adjusted (e.g. the dose of the drug is changed, a further drug may be added to the treatment, or treatment with the drug is discontinued).

[0197] In other such embodiments, the drug for use in treating ulcerative colitis or the method of deciding whether to continue treating ulcerative colitis in a patient comprises a step following the measurement of the level of the at least one predictive biomarker after at least 4 weeks (e.g. at 4 weeks) of administration of the drug, wherein if the level of the at least one predictive biomarker after at least 4 weeks (e.g. at 4 weeks) of administration to the patient of the drug, is not at least

[0198] 1.7, 1.3 or 1.3 fold less than the levels of SAA1 , IL-6, and / or NGAL, respectively, prior to administration to the patient of the drug (as defined elsewhere herein), the administration to the patient of the drug is adjusted (e.g. the dose of the drug is changed, a further drug may be added to the treatment, or treatment with the drug is discontinued).

[0199] In other such embodiments, the drug for use in treating ulcerative colitis or the method of deciding whether to continue treating ulcerative colitis in a patient comprises a step following the measurement of the level of the at least one predictive biomarker after at least 5 weeks (e.g. at 5 weeks) of administration of the drug, wherein if the level of the at least one predictive biomarker after at least 5 weeks (e.g. at 5 weeks) of administration to the patient of the drug, is not at least

[0200] 1.7, 1.3 or 1.3 fold less than the levels of SAA1 , IL-6 and NGAL, respectively, prior to administration to the patient of the drug (as defined elsewhere herein), the administration to the patient of the drug is adjusted (e.g. the dose of the drug is changed, a further drug may be added to the treatment, or treatment with the drug is discontinued).

[0201] The inventors assessed the association between biomarkers at baseline (i.e. prior to treatment) and at week 4 of treatment with patients, who were either biologic-naive or biologic-experienced prior to the start of treatment with filgotinib. Biologic-naive patients had no prior therapeutic exposures to a biologic drug prior to the start of treatment with filgotinib. In contrast biologic- experienced patients, had received one or more biologic therapies prior to the start of treatment with filgotinib. As described in the examples, the predictive biomarkers were showed different fold changes in biologic-naive and biologic-experienced. Accordingly, assessment of certain predictive biomarkers described herein may increase the predictive value of the assessment of patient responsiveness to the drug in patients that are biologic-naive or biologic-experienced. Thus, in some embodiments, the patient is biologic-naive prior to treatment with the drug.

[0202] In other embodiments, the patient is biologic-experienced prior to treatment with the drug.

[0203] The methods of the invention involve a step of continuing to administer the drug if the level of at least one predictive biomarker indicate the patient is likely to benefit from continued treatment with the drug. Administration of the drug may be according to a dosing pattern as defined herein. For example, in some embodiments, each dose provides from about 1 to about 500 mg of the drug, with particular doses each providing from about 10 to about 300 mg, more particularly about 25 to about 250 mg, and especially 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg.

[0204] The inventors assessed ulcerative colitis patients during treatment with 100mg or 200mg of filgotinib. Accordingly, in some embodiments, the dose provides about 100 to about 200 mg of the drug.

[0205] In some embodiments, the dose provides about 100 mg (for example 100mg) of the drug. In other embodiments, the dose provides about 200 mg (for example 200mg) of the drug.

[0206] Injection dose levels may range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2g / day or about 1g / day for a 40 to 80 kg human patient.

[0207] With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Also with oral dosing, one to four (1-4) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, dosage regimens can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.

[0208] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0209] The drug can be administered as the sole active agent or it can be administered in combination with other therapeutic agents that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.

[0210] In one embodiment, the drug is administered as a medicament. In a specific embodiment, said medicament additionally comprises a further active ingredient.

[0211] In one embodiment, the drug is co-administered with another therapeutic agent for the treatment and / or prophylaxis of inflammatory bowel disease. Particular agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetic disease modifying, immunomodulatory agents (e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6- mercaptopurine and cyclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).

[0212] By co-administration is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times.

[0213] Diagnostic devices and kits

[0214] The invention also provides a diagnostic device (e.g. a companion diagnostic device) for performing the methods of the invention. Accordingly, the diagnostic devices provided herein can be used to assess the likelihood a patient will benefit from any of the treatments provided herein. The invention also provides kits that include one or more assay reagents for performing any of the methods provided herein. Accordingly, the kits provided herein can be used to assess the likelihood a patient will benefit from any of the treatments provided herein.

[0215] Filgotinib

[0216] The compound cyclopropanecarboxylic acid {5-[4-(1 ,1-dioxo-thiomorpholin-4-ylmethyl)-phenyl]- [1 ,2,4]triazolo[1 ,5-a]pyridin-2-yl}-amide (also known as “filgotinib”, herein referred to as FIL) is a selective JAK inhibitor and has the chemical structure:

[0217] Filgotinib and methods of its preparation and therapeutic use are described in U.S. Patent No. 8,563,545 (based on International Application Publication No. WO2010 / 149769). It is described as being an inhibitor of JAK and as being useful in the treatment of inflammatory conditions, autoimmune diseases, proliferative diseases, allergy, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and / or diseases associated with hypersecretion of IL6 or interferons. The data presented in WO2010 / 149769 demonstrate that despite similar in vitro activities, filgotinib has unexpectedly high in vivo potency compared with structurally similar compounds.

[0218] Salts and crystalline forms of filgotinib are described in International Application Publication No. WO2015 / 117981. In particular, International Application Publication No. WO2015 / 117981 describes a hydrochloric acid salt, and more particularly a hydrochloride trihydrate, of filgotinib. Pharmaceutical compositions comprising filgotinib are described in International Application Publication No. WO2015 / 117980. In particular, International Application Publication No. WO2015 / 117980 describes pharmaceutical compositions comprising a hydrochloric acid salt, and more particularly a hydrochloride trihydrate, of filgotinib.

[0219] Pharmaceutical compositions comprising a therapeutically effective amount of filgotinib maleate Form I are described in International Application Publication No. WO2018 / 169875.

[0220] Any of the forms of filgotinib, or compositions comprising filgotinib, disclosed herein (including those disclosed in the cited documents) can be used in the present disclosure.

[0221] Solid Forms

[0222] In the present disclosure, the filgotinib can be in any solid form, including the solid forms disclosed below. Solid forms of the drug are described in International Application Publication No. WO2015 / 117981 , the contents of which is incorporated by reference. A preferred solid form of the drug is described in International Application Publication No. WO2018 / 169875, the contents of which is also incorporated by reference.

[0223] When employed as a pharmaceutical, the drug may be administered in a pharmaceutically acceptable solid form, which may be a pharmaceutically acceptable salt, solvate, hydrate, and / or adduct and may be a pharmaceutically acceptable solid crystalline or amorphous form. Hereafter, the terms “salt”, “solvate”, “hydrate”, “adduct”, “solid form”, “crystalline form” and “amorphous form” refer to “pharmaceutically acceptable” salts, solvates, hydrates, adducts, solid forms, crystalline forms, and amorphous forms.

[0224] A salt may comprise a salt of: wherein said salt is formed with a salt forming agent selected from hydrobromic acid, hydrochloric acid, sulfuric acid, toluenesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, naphthalene-2-sulfonic acid, naphthalene-1 ,5-disulfonic acid, 1-2-ethane disulfonic acid, methanesulfonic acid, 2-hydroxy ethanesulfonic acid, phosphoric acid, ethane sulfonic acid, malonic acid, 2-5-dihydroxybenzoic acid, and L-Tartaric acid.

[0225] In certain embodiments, the salt is one formed with a salt forming agent selected from hydrobromic acid, and hydrochloric acid, in particular hydrochloric acid.

[0226] In certain embodiments, the salt is one formed with a salt forming agent selected from oxalic acid, maleic acid, or malonic acid, in particular maleic acid.

[0227] In certain embodiments, the salt is one formed with a salt forming agent selected from toluenesulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, and ethanesulfonic acid; in particular toluenesulfonic acid, and benzenesulfonic acid, more particularly toluenesulfonic acid, and most particularly para-toluenesulfonic acid.

[0228] In certain embodiments, the salt is a 3:1 to 1 :3 [filgotinib:salt forming agent] adduct. In a particular embodiment, the salt is a 1 :1 [filgotinib:salt forming agent] adduct. In a more particular embodiment, the salt forming agent is selected from hydrobromic acid, hydrochloric acid, toluenesulfonic acid, and maleic acid. In a most particular embodiment, the salt forming agent is hydrochloric acid.

[0229] In certain embodiments, the salt is a 1 :1 [filgotinib: HCI] adduct.

[0230] In certain embodiments, the salt is a solvate. In a particular embodiment, the salt is a mono-, di-, or trisolvate. In a most particular embodiment, the salt is a trisolvate. Alternatively, the salt is not a solvate.

[0231] In certain embodiments, the salt is a hydrate. In a more particular embodiment, the salt is a mono- , di-, or trihydrate. In a most particular embodiment, the salt is a trihydrate. Alternatively, the salt is anhydrous.

[0232] In certain embodiments, the salt is a solvate of a hydrochloric acid salt of filgotinib. In a particular embodiment, the salt is a hydrate. In a more particular embodiment, the salt is a mono, di, or trihydrate. In a most particular embodiment, the salt is a trihydrate.

[0233] In certain embodiments, the salt is a [filgotinib:Salt forming agent:Solvent] adduct. In a particular embodiment, the salt is a 1:1:0 to 1:1:4 [filgotinib:Salt forming agent:Solvent] adduct. In a more particular embodiment, the salt is a 1:1:0, 1:1:1, 1:1:1.5, 1:1:2, or 1:1:3 [filgotinib:Salt forming agent:Solvent] adduct. In a most particular embodiment, the salt is a 1:1:3 [filgotinib:Salt forming agent:Solvent] adduct.

[0234] In certain embodiments, the salt is a [filgotinib: HCkSolvent] adduct. In a particular embodiment, the salt is a 1:1:0 to 1:1:4 [filgotinib: HCkSolvent] adduct. In a more particular embodiment, the salt is a 1:1:0, 1:1:1, 1:1:1.5, 1:1:2, or 1:1:3 [filgotinib: HCkSolvent] adduct. In a most particular embodiment, the salt is a 1:1:3 [filgotinib: HCkSolvent] adduct. In a further most particular embodiment, the solvent is selected from H2O, MeOH, and HCO2H.

[0235] In certain embodiments, the salt is a [filgotinib: HCI:H2O] adduct. In a particular embodiment, the salt is a 1:1:0 to 1:1:4 [filgotinib: HCI:H2O] adduct, in particular a 1:1:1 to 1:1:4 [filgotinib: HCI:H2O] adduct. In a more particular embodiment, the salt is a 1:1:0, 1:1:1, 1:1:1.5, 1:1:2, or 1:1:3 [filgotinib: HCI:H2O] adduct, in particular a 1:1:1, 1:1:2, or 1:1:3 [filgotinib:HCI: H2O] adduct. In a most particular embodiment, the salt is a 1:1:3 [filgotinib: HCI:H2O] adduct.

[0236] In certain embodiments, the salt exhibits peaks on a XRPD spectrum.

[0237] In certain embodiments, the salt is in a crystalline form.

[0238] In certain embodiments, the salt is a 1:1:0 [filgotinib: HCI:H2O] adduct in a solid crystalline form, wherein the crystalline form is characterized at least by a powder X-ray diffraction peak at any one or more of the following positions: 7.4, 8.9, 12.4, 14.8, 15.1, 16.9, 17.6, 19.4, 20.7, 21.1, 22.8, 24.9, 26.0, 28.6, 29.8, and 32.6° 20 ± 0.2° 20.

[0239] In certain embodiments, the salt is a 1:1:0 [filgotinib: HCI:H2O] adduct in a solid crystalline form, characterized by the XRPD pattern expressed in terms of 2 theta angles as shown in Figure 4 of International Application Publication No. WO2015 / 117981.

[0240] In certain embodiments, the salt is a 1:1:3 [filgotinib: HCI:H2O] adduct in a solid crystalline form, wherein the crystalline form is characterized at least by a powder X-ray diffraction peak at any one or more of the following positions: 7.3, 8.4, 8.8, 10.7, 12.0, 12.2, 13.2, 13.7, 14.5, 16.3, 16.7, 17.6, 19.3, 20.2, 20.6, 21.0, 21.4, 21.8, 22.8, 23.4, 23.9, 24.5, 25.2, 25.7, 25.9, 26.4, 27.2, 27.7, 28.3, 28.6, 28.9, 29.2, 29.6, and 32.7° 20 ± 0.2° 20.

[0241] In certain embodiments, the salt is a 1:1:3 [filgotinib: HCI:H2O] adduct in a solid crystalline form, characterized by the XRPD pattern expressed in terms of 2 theta angles as shown in Figure 5 of International Application Publication No. WO2015 / 117981 and / or Figure 1 of International Application Publication No. WO2015 / 117980.

[0242] In certain embodiments, the 1 :1 :3 [filgotinib: HCkbhO] adduct in a solid crystalline form has a particle size of less than 1000 pM, as measured by laser diffraction. In a particular embodiment, the 1 :1 :3 [filgotinib: HCI: H2O] adduct in a solid crystalline form has a particle size between 50 pm and 800 pm, as measured by laser diffraction. In a more particular embodiment, the 1 :1 :3 [filgotinib: HCI: H2O] adduct in a solid crystalline form has a particle size between 200 pm and 600 pm, as measured by laser diffraction. In a most particular embodiment, the 1 :1 :3 [filgotinib: HCI: H2O] adduct in a solid crystalline form has a particle size between 150 pm and 350 pm, as measured by laser diffraction.

[0243] Particle Size Distribution, as measured by laser diffraction, may be determined using a Sympatec laser diffraction HELOS / BF particle size instrument fitted with RODOS / ASPIROS dry dispersion unit operating at 2.5 Bar with a sled speed of 25mm / s. A combination of R1 0.1 / 0.18pm - 35 pm and R3 0.5 / 0.9pm - 175 pm lenses were used for the determination and Trigger conditions were 1ms, 0.2%.

[0244] In certain embodiments, the salt is a 1 :1 :1 [filgotinib:HCI:MeOH] adduct in a solid crystalline form, wherein the crystalline form is characterized at least by a powder X-ray diffraction peak at any one or more of the following positions: 7.1 , 14.4, 16.6, 17.3, 18.9, 23.4, 24.8, and 29.0° 20 ± 0.2° 20.

[0245] In certain embodiments, the salt is a 1 :1 :1 [filgotinib:HCI:MeOH] adduct in a solid crystalline form, characterized by the XRPD pattern expressed in terms of 2 theta angles as shown in Figure 8 of International Application Publication No. WO2015 / 117981.

[0246] In certain embodiments, the salt is a 1 :1 :1.5 [filgotinib: HCI: HCO2H] adduct in a solid crystalline form, wherein the crystalline form is characterized at least by a powder X-ray diffraction peak at any one or more of the following positions: 7.1 , 14.4, 14.8, 16.4, 17.4, 18.6, 20.8, 23.4, 24.5, 24.9, and 29.0° 20 ± 0.2° 20.

[0247] In certain embodiments, the salt is a 1 :1 :1.5 [filgotinib: HCI: HCO2H] adduct in a solid crystalline form, characterized by the XRPD pattern expressed in terms of 2 theta angles as shown in Figure 9 of International Application Publication No. WO2015 / 117981.

[0248] In certain embodiments, a salt is obtained by combining the drug with an acid selected from hydrobromic acid, hydrochloric acid, sulfuric acid, toluenesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, naphthalene-2-sulfonic acid, naphthalene-1 ,5-disulfonic acid, 1-2-ethane disulfonic acid, methanesulfonic acid, 2-hydroxy ethanesulfonic acid, phosphoric acid, ethane sulfonic acid, malonic acid, 2-5-dihydroxybenzoic acid, and L-Tartaric acid, in an inert solvent and precipitating said salt from said solvent. In a particular embodiment, the salt is obtained by adding the drug and a salt forming agent in a suitable solvent in order to achieve full dissolution, followed by a controlled solvent evaporation in order to achieve supersaturation, and thus crystallization of the corresponding salt.

[0249] In certain embodiments, the salt is obtained by mixing the drug and an acid in a molar ratio of between 5:1 and 1 :5 of the drug:acid. In a particular embodiment, the salt is obtained by mixing the drug and an acid in a molar ratio of between 2:1 and 1 :2 of the drug:acid. In a more particular embodiment, the salt is obtained by mixing the drug and an acid in a molar ratio of 1 :1 of the drug:acid.

[0250] In certain embodiments, pharmaceutical compositions comprising a therapeutically effective amount of filgotinib maleate Form I are provided for use in the present invention. In a particular embodiment filgotinib maleate Form I is characterized by an XRPD pattern comprising peaks at 8.2, 11.9, 16.4, and 18.9 °20 ± 0.2 °20 as determined on a diffractometer using Cu-Ka radiation. In a more particular embodiment filgotinib maleate Form I is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 28.9, 16.4, 8.2, 18.9, 20.0, 11.9, 14.9, 18.1 , 20.5, and 22.6 °20 ± 0.2 °20 as determined on a diffractometer using Cu-Ka radiation. In certain embodiments filgotinib maleate Form I is characterized by an XRPD pattern substantially the same as shown in FIG. 1 of International Application Publication No. WO2018 / 169875. In certain embodiments filgotinib maleate Form I is characterized by a differential scanning calorimetry (DSC) curve substantially the same as shown in FIG. 2 of International Application Publication No. WO2018 / 169875. In certain embodiments filgotinib maleate Form I is characterized by thermogravimetric analysis (TGA) comprising a thermogram substantially the same as shown in FIG. 2 of International Application Publication No. WO 2018 / 169875. In certain embodiments filgotinib maleate Form I is characterized by a proton nuclear magnetic resonance spectrum (1H NMR) substantially the same as shown in FIG. 3 of International Application Publication No. WO2018 / 169875.

[0251] Prodrugs, metabolites, derivatives

[0252] In the present disclosure, the filgotinib can be administered in free form or in the form of a pharmaceutically acceptable prodrug, metabolite, or derivative thereof.

[0253] The term “prodrug” as used herein, represents a compound that is transformed in vivo into the drug. Such a transformation can be affected, for example, by hydrolysis in blood or enzymatic transformation of the prodrug form to the parent form in blood or tissue. Prodrugs of the drug may be, for example, amides or esters. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and Judkins et al., Synthetic Communications 26(23):4351-4367, 1996, the contents of which is incorporated by reference. The term “metabolite” as used herein, represents a compound into which the drug is transformed in vivo. In humans, filgotinib is metabolized to form the following active metabolite:

[0254] This molecule also inhibited JAK1 signaling, but was approximately 20-fold less potent and was about 10-fold more abundant than filgotinib. Though the potency of this metabolite is lower than filgotinib, the overall exposure and peak plasma concentration in humans is higher than seen in all tested animal species. As a consequence, dedicated pharmacology and toxicology studies have been performed with this metabolite. Results from pharmacodynamics (PD) testing in healthy volunteers suggest that the clinical activity of filgotinib could result from the combination of filgotinib and this metabolite. This metabolite is described in International Application Publication No. WO 2013 / 189771 , the contents of which is incorporated by reference.

[0255] Derivatives of filgotinib include acid and acid derivative forms, both of which have activity, but filgotinib in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985).

[0256] Pharmaceutical Compositions

[0257] In the present disclosure, the filgotinib can be in any pharmaceutical composition, including the compositions disclosed below. Pharmaceutical compositions comprising the drug are described in International Application Publication No. WO 2015 / 117980, the contents of which is incorporated by reference. A preferred pharmaceutical composition comprising the drug is described in International Application Publication No. WO 2018 / 169875, the contents of which is also incorporated by reference.

[0258] Generally, the drug is administered in a pharmaceutically effective amount. The amount of the drug actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like. A pharmaceutical composition may comprise:

[0259] (i) the drug, preferably a hydrochloric acid salt of filgotinib or a solvate or hydrate of this acid addition salt: inert solid diluent.

[0260] A pharmaceutical composition may comprise: (i) the drug, preferably a hydrochloric acid salt of filgotinib or a solvate or hydrate of this acid addition salt; (ii) an inert solid diluent; and (iii) a lubricant.

[0261] A pharmaceutical composition may comprise: (i) the drug, preferably a hydrochloric acid salt of filgotinib or a solvate or hydrate of this acid addition salt; (ii) an inert solid diluent; (iii) a lubricant; and (iv) a non-ionic disintegrant.

[0262] A pharmaceutical composition may comprised) the drug, preferably a hydrochloric acid salt of filgotinib or a solvate or hydrate of this acid addition salt; (ii) an inert solid diluent; (iii) a lubricant; (iv) a non-ionic disintegrant; and (v) a glidant.

[0263] In a more preferred embodiment the pharmaceutical composition comprises filgotinib, preferably filgotinib maleate salt. In a still preferred embodiment, the pharmaceutical composition comprises filgotinib maleate salt Form I, as described in International Application Publication No. WO 2018 / 169875.

[0264] In certain embodiments, the pharmaceutical composition comprises the drug in any of the solid forms described herein.

[0265] In certain embodiments, the pharmaceutical composition comprises a hydrochloric acid salt of filgotinib, wherein the salt shows peaks on a powder X-ray diffraction spectrum.

[0266] In certain embodiments, the pharmaceutical composition comprises a hydrochloric acid salt of filgotinib, wherein the salt is in a solid crystalline form.

[0267] In certain embodiments, the drug, in particular, the hydrochloric acid salt of filgotinib, constitutes from 1-50.1% by weight of the pharmaceutical composition. In a particular embodiment, the drug, in particular the hydrochloric acid salt of filgotinib, constitutes from 1-50%, 5-45%, 10-40%, 15- 35%, or 20-30%, by weight of the pharmaceutical composition. In a most particular embodiment, the drug, in particular the hydrochloric acid salt of filgotinib, constitutes from 22.5-27.5% by weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprising the drug, in particular the hydrochloric acid salt of filgotinib, comprises less than 2% of any further ionic excipients. In a particular embodiment, the pharmaceutical composition comprising the drug, in particular the hydrochloric acid salt of filgotinib, comprises less than 1% of any further ionic excipients. In a more particular embodiment, the pharmaceutical composition comprising the drug, in particular the hydrochloric acid salt of filgotinib, comprises less than 0.5% of any further ionic excipients. In a most particular embodiment, the pharmaceutical composition comprising the drug, in particular the hydrochloric acid salt of filgotinib, is substantially free of any further ionic excipients.

[0268] In certain embodiments, the pharmaceutical composition additionally comprises an inert solid diluent as described herein. In a particular embodiment, the inert solid diluent is selected from cellulose derivatives, lactose, polyols, sugars, dextrin, and starch. In a more particular embodiment, the inert solid diluent is microcrystalline cellulose, mannitol, sorbitol, or lactose. In a most particular embodiment, the inert solid diluent is microcrystalline cellulose.

[0269] In certain embodiments, the inert solid diluent constitutes from 49.9-99% by weight of the pharmaceutical composition. In a particular embodiment, the inert solid diluent constitutes from 49.9-94%, 50-99%, 50-90%, 55-85%, 60-80%, or 65-75%, by weight of the pharmaceutical composition. In a most particular embodiment, the inert solid diluent constitutes from 67.5-72.5% by weight of the pharmaceutical composition.

[0270] The pharmaceutical compositions typically additionally comprise a lubricant as described herein. In a particular embodiment, the lubricant is other than magnesium stearate. More generally, in a particular embodiment the lubricant is other than an alkali metal salt or alkaline earth metal salt of stearic acid or other fatty acids, carboxylic acids or sulphonic acids. For example, the lubricant may be other than a metal salt of a fatty acid, carboxylic acid or sulphonic acid. In a particular embodiment, the lubricant is a non-ionic lubricant. In a particular embodiment, the lubricant is selected from vegetable oils, animal oils, polyethyleneglycol, and glycerolesters. In a more particular embodiment, the lubricant is a vegetable oil (e.g. LubritabRTM), glycerol dibehenate, or PEG 10,000. In a most particular embodiment, the lubricant is glycerol dibehenate.

[0271] In certain embodiments, the lubricant constitutes from 0.1-5% by weight of the pharmaceutical composition. In a particular embodiment, the lubricant constitutes from 0.5-4% by weight of the pharmaceutical composition. In a more particular embodiment, the lubricant constitutes from 1- 3% by weight of the pharmaceutical composition. In a most particular embodiment, the lubricant constitutes from 1.5-2.5% by weight of the pharmaceutical composition.

[0272] In certain embodiments, the pharmaceutical composition additionally comprises a disintegrant as described herein. The disintegrant may be a non-ionic disintegrant. In a particular embodiment, the disintegrant is selected from starch, cellulose, guar gum, and polyvinyl polymers. In a more particular embodiment, the disintegrant is Crospovidone (Polyvinylpolypyrrolidone), pregelatinised starch, or microcrystalline cellulose. In a most particular embodiment, the disintegrant is Crospovidone.

[0273] In certain embodiments, the disintegrant constitutes from 0.1-10% by weight of the pharmaceutical composition. In a particular embodiment, the disintegrant constitutes from 0.1-5% by weight of the pharmaceutical composition. In a more particular embodiment, the disintegrant constitutes from 0.5-4% % by weight of the pharmaceutical composition. In a more particular embodiment, the disintegrant constitutes from 1-3% % by weight of the pharmaceutical composition. In a most particular embodiment, the disintegrant constitutes from 1.5-2.5% % by weight of the pharmaceutical composition.

[0274] In certain embodiments, the pharmaceutical composition additionally comprises a glidant as described herein. In a particular embodiment, the glidant is silica, colloidal silicon dioxide talc, cellulose, and starch. In a most particular embodiment, the glidant is colloidal silicon dioxide.

[0275] In certain embodiments, the glidant constitutes from 0.1-1 % by weight of the pharmaceutical composition. In a particular embodiment, the glidant constitutes from 0.1-0.5% by weight of the pharmaceutical composition. In a more particular embodiment, the glidant constitutes from 0.2- 0.3% by weight of the pharmaceutical composition.

[0276] The pharmaceutical compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the drug may be formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.

[0277] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term ‘unit dosage forms’ refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the drug is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0278] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavouring agents and the like. Solid forms may include, for example, any of the following ingredients or salts of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatine; an excipient such as starch or lactose, a disintegrant such as alginic acid, Sodium starch glycolate (or Primogel), or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, or orange flavouring.

[0279] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the drug in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0280] Transdermal compositions are typically formulated as a topical ointment or cream containing the drug, generally in an amount ranging from about 0.01 to about 20% by weight, in particular from about 0.1 to about 20% by weight, more particularly from about 0.1 to about 10% by weight, and most particularly from about 0.5 to about 15% by weight. When formulated as an ointment, the drug will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the drug may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the drug or the formulation.

[0281] The drug can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0282] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0283] The drug can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0284] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared. The present invention, however, is not limited to the following pharmaceutical compositions.

[0285] Formulation 1 - Tablets

[0286] The drug may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of the drug per tablet) in a tablet press.

[0287] Formulation 2 - Capsules

[0288] The drug may be admixed as a dry powder with a starch diluent in an approximate 1 :1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of the drug per capsule). Formulation 3 - Liquid

[0289] The drug (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water. Sodium benzoate (10 mg), flavouring agent, and colorant may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.

[0290] Formulation 4 - Tablets

[0291] The drug may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of lubritab may be added as a lubricant. The mixture may be formed into 25-900 mg tablets (8-300 mg of the drug per tablet) in a tablet press.

[0292] Formulation 5 - Injection

[0293] The drug may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg / mL.

[0294] Formulation 6 - Topical

[0295] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of the drug (50 g), methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.

[0296] The pharmaceutical compositions described herein are generally for oral administration. Pharmaceutical compositions intended for oral administration may further comprise sweetening agents, flavouring agents, colorants, coating agents, and / or preserving agents in order to provide a palatable preparation. In certain embodiments, the pharmaceutical compositions are in the form of a tablet. Tablets may be prepared by compression or molding. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as, for example, a powder or granules, optionally mixed with a binder, lubricant, inert diluent, or preserving agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored.

[0297] The amount of the drug that is combined with the carrier material to produce a single dosage form will vary depending upon the patient treated. In certain embodiments, pharmaceutical compositions comprise about 127.24 mg of filgotinib maleate Form I. In certain embodiments, pharmaceutical compositions comprise about 127.2 mg of filgotinib maleate Form I. In certain embodiments, pharmaceutical compositions comprise about 127 mg of filgotinib maleate Form I. In certain embodiments, pharmaceutical compositions comprise about 254.48 mg of filgotinib maleate Form I. In certain embodiments, pharmaceutical compositions comprise about 254.5 mg of filgotinib maleate Form I. In certain embodiments, pharmaceutical compositions comprise about 254 mg of filgotinib maleate Form I.

[0298] “Filgotinib maleate Form I” is described above and is further characterized in International Application Publication No. WO 2018 / 169875.

[0299] DEFINITIONS

[0300] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those person’s skill in the art to which this disclosure pertains.

[0301] The terms "comprising", "having", "including" and "containing" are to be understood as open terms (meaning "including, but not limited to") and are to be considered as a support also for terms such as "essentially consist of', "essentially consisting of", "consist of" or "consisting of'.

[0302] The terms "essentially consists of", "essentially consisting of" are to be understood as semi-closed terms, meanings that no other ingredient affecting the novel characteristics of the invention is included (therefore optional excipients can be included).

[0303] The terms "consists of', "consisting of' are to be understood as closed terms.

[0304] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[0305] When ranges are referred to herein, for example but without limitation, ‘1 to 10’, the citation of a range should be considered a representation of each member of said range.

[0306] The term “about” refers to a range of ±10%, unless otherwise specified.

[0307] The term “the drug” refers to filgotinib and its pharmaceutically acceptable salts, solvates, hydrates, prodrugs, metabolites, and derivatives thereof. It will be appreciated that the drug may be metabolized to yield biologically active metabolites. In certain embodiments, the drug is filgotinib or a pharmaceutically acceptable salt thereof.

[0308] The term “RNA level” refers to detecting and / or quantifying the RNA or mRNA of a specific gene (biomarker). For example, the RNA level of a biomarker may be determined and / or quantified as the increased expression or reduced expression of the RNA or mRNA in a sample as compared to a control sample (such as the baseline RNA level of the biomarker prior to administration of FIL or a reference value). The RNA level may be determined to be present or absent, greater than or less than a control, or given a numerical value for the amount of RNA, such as the copies of RNA per microliter. The RNA level can be quantified, by absolute or relative quantification. Absolute quantification may be accomplished by inclusion of known concentration(s) of one or more target nucleic acids and referencing the hybridization intensity of unknowns with the known target nucleic acids (e.g. through generation of a standard curve). Alternatively, relative quantification can be accomplished by comparison of hybridization signals between two or more genes, or between treatment / no treatment to quantify the changes in hybridization intensity and, by implication, in transcription level. Methods for detecting and / or quantifying RNA levels are described elsewhere herein.

[0309] The term “protein level” refers to detecting and / or quantifying a protein biomarker. For example, the protein level of a biomarker may be determined and / or quantified as the increased expression or reduced expression of the protein in a sample as compared to a control sample (such as the baseline protein level of the biomarker prior to administration of Fl L or a reference value). The protein level may be determined to be present or absent, greater than or less than a control, or given a numerical value for the amount of protein, such as picograms of protein per microliter. The protein level can be quantified, by absolute or relative quantification. Absolute quantification may be accomplished using various techniques, for example using an Enzyme-Linked Immunosorbent Assay (ELISA), via the inclusion of known concentration(s) of the protein and referencing the absorbance values of the unknown protein concentrations with the known proteins (e.g. through the generation of a standard curve). Alternatively, relative quantification can be accomplished by comparison of absorbance signals between two or more proteins, or between treatment / no treatment or different time points throughout treatment. Methods for detecting and / or quantifying protein levels are described elsewhere herein.

[0310] The term “biomarkers" (short for biological markers) is a substance (for example a transcript, i.e. mRNA, or a protein) whose detection indicates a particular biological state, such as, for example, the responsiveness to a treatment. Biomarkers can be determined individually or in combination with other biomarkers simultaneously. The term “predictive biomarker” or “predictive biomarker set” refers to a biomarker or set of biomarkers that can be used to predict the outcome of a certain treatment, for example, administration of filgotinib in the treatment of ulcerative colitis.

[0311] The terms “up-regulation” and “up-regulated” and any variations thereof are used interchangeably to refer to a level of a biomarker in a biological sample that is greater than a level of the biomarker that may be detected at another time point, e.g. a different stage of treatment. For example, the level of a biomarker may be measured prior to the administration of the drug (to provide a baseline level) and subsequently measured at a greater level at a timepoint (e.g. 10 weeks) after administration of the drug. The terms may also refer to a value or level of a biomarker in a biological sample that is greater than a value or level of the biomarker that is detected in a reference biological sample.

[0312] The terms "down-regulation" and "down-regulated" and any variations thereof are used interchangeably to refer to a value or level of a biomarker in a biological sample that is less than a level of the biomarker that may be detected at a another time point, e.g. a different stage of treatment. For example, the level of a biomarker may be measured prior to the administration of the drug (to provide a baseline level) and subsequently measured at a lower level at a timepoint (e.g. 10 weeks) after administration of the drug. The terms may also refer to a value or level of a biomarker in a biological sample that is less than a value or level of the biomarker that is detected in a reference biological sample.

[0313] Identity with respect to a sequence is defined herein as the percentage of nucleic acid or amino acid residues in the candidate sequence that are identical with the reference amino acid sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity.

[0314] Sequence identity can be determined by standard methods that are commonly used to compare the similarity in position of the amino acids of two polypeptides or the nucleic acids of two polynucleotides. For example, using a computer program such as BLAST or FASTA, two polypeptides are aligned for optimal matching of their respective amino acids. The programs provide a default opening penalty and a default gap penalty, and a scoring matrix such as PAM 250 [a standard scoring matrix; see Dayhoff et al., in Atlas of Protein Sequence and Structure, vol. 5, supp. 3 (1978)] can be used in conjunction with the computer program. The percent identity can be calculated as: the total number of identical matches multiplied by 100 and then divided by the sum of the length of the longer sequence within the matched span and the number of gaps introduced into the shorter sequences in order to align the two sequences.

[0315] The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.

[0316] ‘Therapeutically effective amount’ refers to an amount that is sufficient to effect treatment, as defined below, when administered to a subject, e.g. a human, in need of such treatment. The therapeutically effective amount will vary depending upon the subject being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

[0317] ‘T reating’ or ‘treatment’ of any disease or disorder refers to obtaining beneficial or desired results. Beneficial or desired results include, but are not limited to, alleviation of a symptom and / or diminishment of the extent of a symptom associated with a disease or condition. In some embodiments, “treatment” or “treating” includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing the extend or severity of one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); c) relieving the disease or condition (e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival); and d) ameliorating at least one physical parameter, which may not be discernible by the subject, or modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.

[0318] The term ‘changing the dose’ means increasing the dose of Filgotinib administered to the patient, or decreasing the dose of Filgotinib administered to the patient, or increasing or decreasing the frequency of administration (e.g. switching from once-a-day to twice-a-day dosing) or modifying the timing of administration (e.g. before / after meals, at bedtime).

[0319] The term ‘pharmaceutical composition’ means a mixture comprising a pharmaceutically acceptable active ingredient, in combination with suitable pharmaceutically acceptable excipients. ‘Pharmaceutical excipients’ are substances other than the pharmaceutically acceptable active ingredient which have been appropriately evaluated for safety and which are intentionally included in an oral solid dosage form. For example, excipients can aid in the processing of the drug delivery system during its manufacture, protect, support or enhance stability, bioavailability or patient acceptability, assist in product identification, or enhance any other attribute of the overall safety, effectiveness or delivery of the drug during storage or use. Examples of excipients include, for example but without limitation inert solid diluents (bulking agent e.g. lactose), binders (e.g. starch), glidants (e.g. colloidal silica), lubricants (e.g. non-ionic lubricants such as vegetable oils), disintegrants (e.g. starch, polyvinylpyrrolidone), coating better polymers (e.g. hydroxypropyl methylcellulose), colorants (e.g. iron oxide), and / or surfactants (e.g. non-ionic surfactants) (Rowe et al., 2009). ‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0320] ‘Pharmaceutically acceptable salt’ is meant to embrace salts including pharmaceutically acceptable salts, solvates, e.g. hydrates, and solvates of the pharmaceutically acceptable salts where the context so permits. Thus, ‘pharmaceutically acceptable salt’ refers to a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2- ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1 -carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0321] The term ‘pharmaceutically acceptable cation’ refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0322] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, excipient or carrier with which the drug is administered.

[0323] As used herein, the term ‘pharmaceutical formulation’ means the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. Examples of formulation include enteral formulations (tablets, capsules), parenteral formulations (liquids, lyophilized powders), or topical formulations (cutaneous, inhalable).

[0324] The terms ‘inert solid diluent’ or ‘solid diluent’ or ‘diluents’ refer to materials used to produce appropriate dosage form size, performance and processing properties for tablets and / or capsules. An inert solid diluent can be also referred to as filler or filler material. Particular examples of diluents include cellulose powdered, silicified microcrystalline cellulose acetate, compressible sugar, confectioner’s sugar, corn starch and pregelatinized starch, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, inhalation lactose, isomalt, kaolin, lactitol, lactose, anhydrous, monohydrate and corn starch, spray dried monohydrate and microcrystalline cellulose, maltodextrin, maltose, mannitol, medium-chain triglycerides, microcrystalline cellulose, polydextrose, polymethacrylates, simethicone, sorbitol, pregelatinized starch, sterilizable maize, sucrose, sugar spheres, sulfobutylether p-cyclodextrin, talc, tragacanth, trehalose, or xylitol. More particular examples of diluents include cellulose powdered, silicified microcrystalline cellulose acetate, compressible sugar, corn starch and pregelatinized starch, dextrose, fructose, glyceryl palmitostearate, anhydrous, monohydrate and corn starch, spray dried monohydrate and microcrystalline cellulose, maltodextrin, maltose, mannitol, medium-chain triglycerides, microcrystalline cellulose, polydextrose, sorbitol, starch, pregelatinized, sucrose, sugar spheres, trehalose, or xylitol.

[0325] ‘Lubricant’ refers to materials that prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall. Particular examples of lubricants include canola oil, hydrogenated castor oil, cottonseed oil, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, medium-chain triglycerides, mineral oil, light mineral oil, octyldodecanol, poloxamer, polyethylene glycol, polyoxyethylene stearates, polyvinyl alcohol, starch, magnesium stearate, or hydrogenated vegetable oil. More particular examples of lubricants include glyceryl behenate, glyceryl monostearate, or hydrogenated vegetable oil.

[0326] ‘Disintegrant’ refers to material that dissolve when wet causing the tablet to break apart in the digestive tract, releasing the active ingredients for absorption. They ensure that when the tablet is in contact with water, it rapidly breaks down into smaller fragments, facilitating dissolution. Particular examples of disintegrants include alginic acid, powdered cellulose, chitosan, colloidal silicon dioxide, corn starch and pregelatinized starch, crospovidone, glycine, guar gum, low- substituted hydroxypropyl cellulose, methylcellulose, microcrystalline cellulose, or povidone.

[0327] The term ‘colorant’ describes an agent that imparts color to a formulation. Particular examples of colorants include iron oxide, or synthetic organic dyes (US Food and Drug administration, Code of Federal Regulations, Title 21 CFR Part73, Subpart B).

[0328] The term ‘coating agent’ refers to an agent that is used to produce a cosmetic or functional layer on the outer surface of a dosage form. Particular examples of coating agent include glucose syrup, maltodextrin, alginates, or carrageenan.

[0329] ‘Glidant’ refers to materials that are used to promote powder flow by reducing interparticle friction and cohesion. These are used in combination with lubricants as they have no ability to reduce die wall friction. Particular examples of glidants include powdered cellulose, colloidal silicon dioxide, hydrophobic colloidal silica, silicon dioxide, or talc. More particular examples of glidants include colloidal silicon dioxide, hydrophobic colloidal silica, silicon dioxide, or talc.

[0330] ‘Flavouring agents’ refers to material that can be used to mask unpleasant tasting active ingredients and improve the acceptance that the patient will complete a course of medication. Flavourings may be natural (e.g. fruit extract) or artificial. Non limiting examples of flavouring agents include mint, peppermint, methyl salicylate, orange, cherry, anise, peach, apricot, liquorice, raspberry, or vanilla.

[0331] ‘Solvate’ refers to forms of a compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The drug may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0332] As used herein, the term ‘isotopic variant’ refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an ‘isotopic variant’ of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be2H / D, any carbon may be13C, or any nitrogen may be15N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and / or substrate tissue distribution studies, will be understood. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as11C,18F,15O and13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0333] ‘Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of TT electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.

[0334] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0335] As used herein, the term ‘biologic-naive’ refers to the exposure status of a patient to the drug, wherein the patient has not had any previous therapeutic exposures to a biologic drug prior to the start of treatment.

[0336] As used herein, the term ‘biologic-experienced’ refers to the exposure status of a patient to the drug, wherein the patient has had previous therapeutic exposures to a biologic drug prior to the start of treatment.

[0337] EMBODIMENTS

[0338] The inventors measured biomarker levels at 4 weeks of filgotinib treatment and identified biomarkers having an at least 1.7, 1.3 or 1.3 fold decrease in the levels of SAA1 , IL-6 and NGAL, respectively, as being associated with positive clinical responses to continued treatment with filgotinib.

[0339] Accordingly, in certain embodiments, the drug is filgotinib or a pharmaceutically acceptable salt thereof, for use in a method of treating ulcerative colitis in a patient, wherein the method comprises the steps of:

[0340] (i) measuring the level of at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0341] (ii) measuring the level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL at 4 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and

[0342] (iii) if the level of:

[0343] (a) SAA1 at 4 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.7 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0344] (b) IL-6 at 4 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and / or

[0345] (c) NGAL at 4 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, continuing the administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof.

[0346] In certain embodiments, the method of deciding whether to continue treating ulcerative colitis in a patient is a method for deciding whether to continue treating ulcerative colitis in a patient with filgotinib or a pharmaceutically acceptable salt thereof after 4 weeks of administration to the patient of filgotinib or a pharmaceutically acceptable salt thereof, wherein the method comprises the steps of: (i) measuring the level of at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0347] (ii) measuring the level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL at 4 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and

[0348] (iii) if the level of:

[0349] (a) SAA1 at 4 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.7 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0350] (b) IL-6 at 4 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and / or

[0351] (c) NGAL at 4 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, continuing the administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof.

[0352] A non-limiting list of embodiments is provided below:

[0353] 1. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, for use in a method of treating ulcerative colitis in a patient, wherein the method comprises the steps of:

[0354] (i) measuring the level of at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0355] (ii) measuring the level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and

[0356] (iii) if the level of:

[0357] (a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.7 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0358] (b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and / or

[0359] (c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, continuing the administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof. A method of deciding whether to continue treating ulcerative colitis in a patient with filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, wherein the method comprises the steps of:

[0360] (i) measuring the level of at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0361] (ii) measuring the level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and

[0362] (iii) if the level of:

[0363] (a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.7 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0364] (b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and / or

[0365] (c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, continuing the administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, for use according to embodiment 1 , or the method of embodiment 2, wherein the method comprises the step of:

[0366] (i) if the level of:

[0367] (a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is not at least 1.7 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0368] (b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is not at least 1.3 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and / or

[0369] (c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is not at least 1.3 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, adjusting the administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof (for example, changing the dose, administering an additional therapeutic agent, or discontinuing the administration). Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, for use according to embodiment 1 or embodiment 3, or the method of embodiment 2 or embodiment 3, wherein measuring the level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL in step (ii) is at least 4 weeks (for example, at 4 weeks) after administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 , 3 and 4, or the method of any of embodiments 2 to 4, wherein the level of SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.8, 1.9, 2.1 , 2.2, 2.7, or 3 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 5, or the method of any of embodiments 2 to 5, wherein the level of IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.4, 1.5, 1.6, 1.7, or 2 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 6, or the method of any of embodiments 2 to 6, wherein the level of NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.4, 1.5, 1.6, 1.7, or 2 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof. 8. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 , 3 and 4, or the method of any of embodiments 2 to 4, wherein the level of:

[0370] (a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.9 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0371] (b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.4 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and / or

[0372] (c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof.

[0373] 9. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 4, or the method of any of embodiments 2 to 4, wherein the level of:

[0374] (a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 2.1 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0375] (b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.4 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and / or

[0376] (c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.4 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 4, or the method of any of embodiments 2 to 4, wherein the level of:

[0377] (a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.9 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0378] (b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.4 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and / or

[0379] (c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.5 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 4, or the method of any of embodiments 2 to 4, wherein the level of:

[0380] (a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 2.7 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof,

[0381] (b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, and / or

[0382] (c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is at least 1.4 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof.

[0383] 12. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 11 , or the method of any of embodiments 2 to 11 , wherein the at least one predictive biomarker is SAA1.

[0384] 13. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 11 , or the method of any of embodiments 2 to 11, wherein the at least one predictive biomarker is IL-6.

[0385] 14. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 11 , or the method of any of embodiments 2 to 12, wherein the at least one predictive biomarker is NGAL.

[0386] 15. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 11 , or the method of any of embodiments 2 to 12, wherein the at least one predictive biomarker is two predictive biomarkers which are SAA1 and IL-6.

[0387] 16. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 11, or the method of any of embodiments 2 to 12, wherein the at least one predictive biomarker is two predictive biomarkers which are SAA1 and NGAL.

[0388] 17. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 11, or the method of any of embodiments 2 to 12, wherein the at least one predictive biomarker is two predictive biomarkers which are IL-6 and NGAL.

[0389] 18. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 11, or the method of any of embodiments 2 to 12, wherein the at least one predictive biomarker is three predictive biomarkers which are SAA1, IL-6, and NGAL. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 18, or the method of any of embodiments 2 to 18, wherein step (i) and step (ii) comprise measuring the levels of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL in a blood sample, a stool sample, a urine sample, or a colonic mucosal biopsy sample. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to embodiment 19, or the method of embodiment 19, wherein step (i) and step (ii) comprise measuring the levels of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL in a blood sample. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to embodiment 19, or the method of embodiment 19, wherein step (i) and step (ii) comprise measuring the levels of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL in a stool sample. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to embodiment 19, or the method of embodiment 19, wherein step (i) and step (ii) comprise measuring the levels of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL in a urine sample. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to embodiment 19, or the method of embodiment 19, wherein step (i) and step (ii) comprise measuring the levels of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL in a colonic mucosal biopsy sample. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 23, or the method of any of embodiments 2 to 23, wherein step (i) and step (ii) comprise measuring the RNA level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to embodiment 24, or the method of embodiment 24, wherein the RNA level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL is measured by RNA-seq.

[0390] 26. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 25, or the method of any of embodiments 2 to 25, wherein step (i) and step (ii) comprise measuring the protein level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL.

[0391] 27. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 26, or the method of any of embodiments 2 to 26, wherein the patient, prior to administration of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is biologic-naive or biologic-experienced.

[0392] 28. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to embodiment 27, or the method of embodiment 27, wherein the patient, prior to administration of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is biologic-naive.

[0393] 29. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to embodiment 27, or the method of embodiment 27, wherein the patient, prior to administration of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is biologic-experienced.

[0394] 30. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 29, or the method of any of embodiments 2 to 29, wherein filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is administered in an amount of 100 mg or 200 mg.

[0395] 31. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to embodiment 30, or the method of embodiment 30, wherein filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is administered in an amount of 100 mg. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to embodiment 30, or the method of embodiment 30, wherein filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is administered in an amount of 200 mg. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 , 3 to 27, and 30, or the method of any of embodiments 2 to 27 and 30, wherein filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is administered in an amount of 100 mg and the patient, prior to administration of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is biologic-naive. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 , 3 to 27, and 30, or the method of any of embodiments 2 to 27 and 30, wherein filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is administered in an amount of 100 mg and the patient, prior to administration of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is biologic-experienced. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 , 3 to 27, and 30, or the method of any of embodiments 2 to 27 and 30, wherein filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is administered in an amount of 200 mg and the patient, prior to administration of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is biologic-naive. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 , 3 to 27, and 30, or the method of any of embodiments 2 to 27 and 30, wherein filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is administered in an amount of 200 mg and the patient, prior to administration of filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is biologic-experienced. 37. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 36, or the method of any of embodiments 2 to 36, wherein filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is administered for at least 10 weeks or at least 58 weeks.

[0396] 38. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to embodiment 37, or the method of embodiment 37, wherein filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is administered for at least 10 weeks.

[0397] 39. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to embodiment 37, or the method of embodiment 37, wherein filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, is administered for at least 58 weeks.

[0398] 40. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of embodiments 1 and 3 to 39, or the method of any of embodiments 2 to 39, wherein the filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof is filgotinib, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for example filgotinib or a pharmaceutically acceptable salt thereof.

[0399] 41. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof, for use according to any of embodiments 1 and 3 to 40, or the method of any of embodiments 2 to 40, wherein the patient has moderately to severely active ulcerative colitis according to the MCS prior to the treatment with filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof.

[0400] 42. A diagnostic device (e.g. a companion diagnostic device) for performing the method of any of embodiments 2 to 41.

[0401] 43. A kit comprising one or more assay reagents for performing the method of any of embodiments 2 to 41. EXAMPLES

[0402] Example 1 : Study design and participant selection Details of a phase 2b / 3 trial have been reported previously in Feagan et al. Lancet. 2021 ;397(10292):2372-2384. Briefly, biologic-naive and biologic-experienced patients with moderately to severely active UC were randomized (2:2:1) to receive filgotinib 200 mg, filgotinib 100 mg, or placebo once daily for 10 weeks in two induction studies (Figure 1). Participants were permitted to use concomitant oral corticosteroids (prednisone <30 mg / day or budesonide <9 mg / day) provided the dose was stable for 2 weeks before and 14 weeks after randomization throughout the induction phase, and concomitant immunomodulators (azathioprine, 6- mercaptopurine, or methotrexate) provided the dose was stable for 4 weeks before and 10 weeks after randomization). In the trial induction studies, 659 biologic-naive and 689 biologic-experienced patients were enrolled and randomly assigned to receive filgotinib 200 mg, filgotinib 100 mg, or placebo (full analysis set [FAS]). The biomarker analysis set used in the current analysis (whereby serum and fecal protein biomarker data were available) included 598 biologic-naive (90.7%) and 592 biologic-experienced patients (85.9%). Overall, the biomarker analysis set excluded 158 patients (11.7%) from the FAS. Demographics and disease characteristics were well balanced between the filgotinib 200 mg, filgotinib 100 mg, and placebo arms in both biologic-naive and biologic- experienced patients in the biomarker analysis set (Table 2).

[0403] Table 1 Baseline patient demographics and disease characteristics

[0404] Whole-blood RNA samples were profiled from 574 biologic-naive patients (96.0%) and 575 biologic-experienced patients (97.1%) in the biomarker analysis set and from 19 healthy volunteers. In total, 3211 samples (including 19 from the healthy volunteers) passed quality control and were used for all subsequent analysis.

[0405] The analysis of the trial used serum, stool, and whole-blood samples collected from the induction phase of the trial. The biomarker analysis set presented in the current study excluded patients if they had a record of dose escalation of a non-study concomitant treatment for UC during the induction phase, had insufficient data to evaluate endoscopy / bleeding / stool (EBS) frequency (EBS remission), or failed to follow the clinical study protocol. The trial protocol was reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study site before initiation.

[0406] 2: Protein biomarker collection and assessment

[0407] Measurement of protein levels in serum, whole blood and stool samples using enzyme-linked immunosorbent assay

[0408] Serum and whole-blood samples were collected at baseline and at weeks 4 and 10 following initiation of filgotinib or placebo. Protein biomarkers were measured by enzyme-linked immunosorbent assay at several laboratories.

[0409] Analytes were measured from serum samples collected at baseline, Week 4, and Week 10. Serum protein biomarkers with at least 50% of observations within the limits of quantification and thus included in the analyses were glycoprotein 130, IFN-y, IL-17A, IL-2, IL-10, IL-22, IL-23, IL-5, IL-6, IL-6R, IL-8, neutrophil gelatinase-associated lipocalin (NGAL), serum amyloid A-1 (SAA1), transforming growth factor pi (TGFpi) and tumor necrosis factor a (TNFa), which were measured by Simoa®, a digital, bead-based ELISA (Quanterix, Massachusetts, USA). Further serum protein biomarkers included were oncostatin M (OSM) and calprotectin, which were measured by ELISA (at Nexelis, Seattle, USA), and C-reactive protein (CRP), which was measured from serum at central lab by an IVDR Nephelometric assay (Behring Nephelometer II assay, Siemens, Erlangen, Germany).

[0410] Mediation analysis of serum protein data

[0411] To investigate the mechanism of action of filgotinib in achieving UC clinical improvement, a causal model was used to evaluate whether clinical improvements following filgotinib treatment at week 10 could be driven by an indirect path based on early changes in biomarkers from baseline to week 4. Biomarker values at week 4 were grouped together by an exploratory factor analysis (EFA), and then used to examine downstream associations with clinical changes at week 10. The average causal mediation effect was defined as the expected difference in the potential clinical outcome when the mediator (week 4 biomarker measurements) took the value that would realize under the treatment condition as opposed to the control condition, while the treatment status itself was held constant.

[0412] Results

[0413] Differences in biomarkers from baseline to Week 4 in clinical Individual biomarker levels in patients receiving filgotinib (200 mg or 100 mg) or placebo at baseline and weeks 4 and 10 were plotted (Figures 2a-c) to assess what happens to IL-6, SAA and NGAL biomarkers in clinical responders at week 10 versus non-responders. Additionally, it was assessed whether a decrease in these biomarkers at Week 4 relative to baseline could be indicative of a positive or negative UC clinical outcome at Week 10, as assessed by EBS remission and MCS. EBS remission is defined as an endoscopic subscore of 0 or 1 ; a rectal bleeding subscore of 0; and at least a 1 -point decrease in stool frequency from baseline. A Mayo Clinical Score (MCS) response is defined as a reduction of >3 points in MCS and >30% from baseline with an accompanying decrease in rectal bleeding subscore of >1 point or absolute rectal bleeding subscore of 0 or 1.

[0414] Using the systemic biomarker IL-6 as an example, IL-6 levels at Week 4 of treatment with 200 mg filgotinib were 1.5-fold and 1.1-fold less in responders in the biologic-naive and biologic- experienced group, respectively. In contrast, IL-6 levels at Week 4 of treatment with 200mg filgotinib were 1.2-fold and 1.4-fold less in non-responders in the biologic-naive and biologic- experienced group, respectively. Further administration of 200 mg of filgotinib was associated with reduced IL-6 levels at Week 10 compared with placebo in both biologic-naive and biologic- experienced patients, especially in responders, where levels approached values detected in healthy volunteer samples (Figure 2a).

[0415] Trends similar to those for IL-6 were also observed for SAA and NGAL, where greater fold decreases in biomarker levels were observed at Week 4 relative to baseline in responders compared to non-responders. The fold decreases are summarised in Table 3 below. A reduction of all three biomarkers was also observed at Week 10 of treatment with 200 mg of filgotinib, as can be seen in Figure 2b-c.

[0416] Table 2 Fold decreases in protein levels of SAA1, IL-6 and NGAL relative to baseline FINAL REMARKS

[0417] It will be appreciated by those skilled in the art that the foregoing descriptions are exemplary and explanatory in nature, and intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognize apparent modifications and variations that may be made without departing from the spirit of the invention. All such modifications coming within the scope of the appended claims are intended to be included therein. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents.

[0418] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

[0419] From the foregoing description, various modifications and changes in the compositions and methods of this invention will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein.

[0420] At least some of the chemical names given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control.

[0421] Chemical structures shown herein were prepared using either ChemDraw® or ISIS® / DRAW. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure.

Claims

1. CLAIMS1. Filgotinib, or a pharmaceutically acceptable salt, thereof, for use in a method of treating ulcerative colitis in a patient, wherein the method comprises the steps of:(i) measuring the level of at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof,(ii) measuring the level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof, and(iii) if the level of:(a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof, is at least 1.7 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof,(b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof, is at least 1.3 fold less than the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof, and / or(c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof, is at least 1.3 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof, continuing the administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof.

2. Filgotinib, or a pharmaceutically acceptable salt thereof for use according to claim 1 , wherein the method comprises the step of:(i) if the level of:(a) SAA1 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof, is not at least 1.7 fold less than the level of SAA1 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof,(b) IL-6 after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof, is not at least 1.3 fold lessthan the level of IL-6 prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof, and / or(c) NGAL after at least 3, at least 4, or at least 5 weeks of administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof, is not at least 1.3 fold less than the level of NGAL prior to administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof, adjusting the administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof (for example, changing the dose, administering an additional therapeutic agent, or discontinuing the administration).

3. Filgotinib, or a pharmaceutically acceptable salt, solvate thereof, for use according to claim 1 or claim 2, wherein measuring the level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL in step (ii) is at least 4 weeks (for example, at 4 weeks) after administration to the patient of filgotinib, or a pharmaceutically acceptable salt thereof.

4. Filgotinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 1 to 3, wherein the at least one predictive biomarker is SAA1.

5. Filgotinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 1 to 3, wherein the at least one predictive biomarker is IL-6.

6. Filgotinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 1 to 3, wherein the at least one predictive biomarker is NGAL.

7. Filgotinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 1 to 6, wherein step (i) and step (ii) comprise measuring the levels of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL in a blood sample, a stool sample, a urine sample, or a colonic mucosal biopsy sample.

8. Filgotinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 1 to 7, wherein step (i) and step (ii) comprise measuring the RNA level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL.

9. Filgotinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 1 to 8, wherein step (i) and step (ii) comprise measuring the protein level of the at least one predictive biomarker selected from the list of SAA1 , IL-6 and NGAL.

10. Filgotinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 1 to 9, wherein the patient, prior to administration of filgotinib, or a pharmaceutically acceptable salt thereof, is biologic-naive or biologic- experienced.

11. Filgotinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 1 to 10, wherein filgotinib, or a pharmaceutically acceptable salt thereof, is administered in an amount of 100 mg or 200 mg.

12. Filgotinib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, or metabolite thereof for use according to any of claims 1 to 11 , wherein filgotinib, or a pharmaceutically acceptable salt thereof, is administered for at least 10 weeks or at least 58 weeks.

13. Filgotinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 1 to 12, wherein the filgotinib, or a pharmaceutically acceptable salt thereof is filgotinib, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for example filgotinib or a pharmaceutically acceptable salt thereof.

14. Filgotinib, or a pharmaceutically acceptable salt thereof, for use according to any of claims 1 to 13, wherein the patient has moderately to severely active ulcerative colitis according to the MCS prior to the treatment with filgotinib, or a pharmaceutically acceptable salt.

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