Combination of an FGFR4 inhibitor with a PPAR agonist

Abstract

Provided are methods of treating subjects in need of an anti-fibroblast growth factor receptor 4 (anti-FGFR4) therapy. The methods comprise administering to the subjects a therapeutically effective amount of a peroxisome proliferator-activated receptor (PPAR) alpha agonist in combination with the anti-FGFR4 therapy. The anti-FGFR4 therapy comprises administering to subjects an FGFR4 inhibitor comprising a compound of Formula I, a pharmaceutically acceptable salt of the compound of Formula I, a compound of Formula II, or a pharmaceutically acceptable salt of the compound of Formula II. Also provided are compositions comprising the FGFR4 inhibitor, a PPAR alpha agonist, and, optionally, a bile acid sequestrant. The methods attenuate the dysregulation of bile acid biosynthesis caused by FGFR4 inhibition with anti-FGFR4 therapies. The methods reduce the severity and / or incidence of adverse events associated with anti-FGFR4 therapies.

Description

COMBINATION OF AN FGFR4 INHIBITOR WITH A PPAR AGONISTCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of United State Provisional Application No. 63 / 600,073, filed November 17, 2023, the entirety of which is incorporated by reference herein.TECHNICAL FIELD

[0002] Described herein are methods of treating subjects in need of an anti- fibroblast growth factor receptor 4 (anti-FGFR4) therapy with peroxisome proliferator- activated receptor (PPAR) alpha agonists.BACKGROUND

[0003] One of the normal physiological roles of FGFR4 is to regulate bile acid synthesis. The FGFR4 stimulation with its ligand, fibroblast growth factor- 19 (FGF19), results in the downstream suppression of cholesterol 7a hydroxylase (CYP7AP) expression. CYP7A1 encodes cytochrome P450 7A1 (Cyp7al, also known as cholesterol 7-alpha- monooxygenase), which catalyzes the rate limiting step in bile acid synthesis. Inhibition of FGFR4 activity results in an increase in bile acid synthesis due to the lack of repression of CYP7A1. High levels of bile acids can lead to liver toxicity and gastrointestinal issues such as diarrhea. Liver toxicity characterized by single cell necrosis, increased bilirubin, severe diarrhea, and decreased food consumption were reported in monkeys given an anti -F GF 19 antibody. In dogs, bile acid sequestration by cholestyramine mitigated FGFR4 inhibition- induced alanine amino transferase (ALT) elevation, an indicator of potential liver toxicity.

[0004] FGFR4 inhibitors are under development for treatment of cancers such as hepatocellular carcinoma (HCC). Amplification of the FGFR4 ligand FGF19 and high expression of FGFR4 are frequently reported in HCC cases, and both have been shown to drive the progression of HCC. FGFR4 has also been implicated in other morbidities, such as in Left Ventricular Hypertrophy (LVH), which is a complication of Chronic Kidney Disease (CKD). Chronic kidney disease is associated with a markedly increased risk of cardiovascular mortality. The dysregulation of bile acids due to FGFR4 inhibition can complicate or even limit therapy.

[0005] There remains a need for regulating bile acid synthesis in therapies utilizing FGFR4 inhibitors. The present disclosure addresses these needs.SUMMARY

[0006] In meeting these needs, the present disclosure provides methods of treating subjects in need of an anti-fibroblast growth factor receptor 4 (anti-FGFR4) therapy. The methods comprise administering to the subjects a therapeutically effective amount of a PPAR alpha agonist in combination with the anti-FGFR4 therapy. The anti-FGFR4 therapy is an FGFR4 inhibitor comprising the compound of Formula I:Formula I (F-I), a pharmaceutically acceptable salt of the compound of Formula I, the compound of Formula II:Formula II (F-II), or a pharmaceutically acceptable salt of the compound of Formula II.

[0007] The present disclosure also provides methods of treating subjects in need of an anti-FGFR4 therapy comprising administering to the subjects an anti-FGFR4 therapy in combination with a therapeutically effective amount of a PPAR alpha agonist and a bile acid sequestrant. The anti-FGFR4 therapy is an FGFR4 inhibitor comprising the compound of Formula I, a pharmaceutically acceptable salt of the compound of Formula I, the compound of Formula II, or a pharmaceutically acceptable salt of the compound of Formula II.

[0008] Also provided are compositions comprising an FGFR4 inhibitor, a PPAR alpha agonist, and a pharmaceutically acceptable excipient. The FGFR4 inhibitor of the compositions comprises the compound of Formula I, a pharmaceutically acceptable salt of the compound of Formula I, the compound of Formula II, or a pharmaceutically acceptable salt of the compound of Formula II.

[0009] Also provided are compositions comprising an FGFR4 inhibitor, a PPAR alpha agonist, a bile acid sequestrant, and a pharmaceutically acceptable excipient. The FGFR4 inhibitor of the compositions comprises the compound of Formula I, a pharmaceutically acceptable salt of the compound of Formula I, the compound of Formula II, or a pharmaceutically acceptable salt of the compound of Formula II.

[0010] The present disclosure also provides kits comprising an FGFR4 inhibitor and a PPAR alpha agonist, wherein the FGFR4 inhibitor comprises the compound of Formula I, a pharmaceutically acceptable salt of the compound of Formula I, the compound of Formula II, or a pharmaceutically acceptable salt of the compound of Formula II.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended drawings. For the purpose of illustrating the disclosed methods, there are shown in the drawings exemplary embodiments of the methods; however, the disclosed methods are not limited to the exemplary embodiments of the methods. In the drawings:

[0012] FIGs. 1 A and IB are bar graphs depicting changes in CYP7A1 expression (Relative mRNA expression / Actin) in Hep3B cells (FIG. 1 A) or HuH-7 cells (FIG. IB) with treatment of increasing concentrations of F-I for 22 hours. Treatment of the cells with F-I resulted in increased CYP7A1 expression in Hep3B (FIG. 1 A) and HuH-7 cells (FIG. IB) in a dose dependent manner, as measured using qPCR. Statistical significance (Mann-Whitney t-test): * p < 0.05, ** p < 0.01, *** p<0.001, **** p < 0.0001.

[0013] FIGs. 2A and 2B are bar graphs depicting change in CYP7A1 expression (Relative expression / Actin) in Hep3B cells (FIG. 2A) or HuH-7 cells (FIG. 2B) with treatment of 30 nM F-I and increasing concentrations of fenofibrate. Fenofibrate was applied at a concentration of 2, 5, and 10 pM in combination with 30 nM of F-I for 22 hours. Statistical significance (Mann-Whitney t-test): * p < 0.05, ** p < 0.01, *** p<0.001, **** p < 0.0001.

[0014] FIG. 3 is a bar graph depicting change in serum C4 (ng / ml) in male C57BL / 6 mice dosed orally with vehicle, fenofibrate, BLU554, FGF401, F-I, or a combination of fenofibrate and the FGFR4 inhibitor at the doses indicated for 6 days. The mean C4 value for each group of 6 mice is shown with dots representing individual mice, and error bars representing standard error of the mean. Statistical significance (Mann-Whitney t-test): * p < 0.05, ** p < 0.01, ns: not significant.

[0015] FIGs. 4A and 4B are line graphs depicting change in tumor volume (mm3) in athymic nude (Nu / Nu) mice inoculated subcutaneously in the flank with Huh7 cells, a human hepatocellular carcinoma cell line driven by FGF19 overexpression. Once tumors reached about 150 mm3, mice were dosed orally with vehicle, fenofibrate, FGF401, F-I, or a combination of fenofibrate and the FGFR4 inhibitor at the doses indicated for up to 21 days. Data points represent mean tumor volume (n=8 per group) and error bars represent standard error of the mean. The vehicle for fenofibrate, FGF401, and F-I was 0.5% methylcellulose / 0.5% tween 80. In the combination treatment groups, the compounds were formulated and dosed separately.

[0016] FIGs. 5A and 5B are bar graphs depicting changes in CYP7A1 expression (Relative expression / Actin) in Hep3B cells (FIG. 5A) or HuH-7 cells (FIG. 5B) with treatment of increasing concentrations of F-II for 22 hours. Treatment of the cells with F-II resulted in increased CYP7A1 expression in Hep3B (FIG. 5A) and HuH-7 cells (FIG. 5B) in a dose dependent manner, as measured by qPCR. Statistical significance (Mann-Whitney t- test): * p < 0.05, ** p < 0.01, *** p<0.001, **** p < 0.0001, ns: not significant.

[0017] FIGs. 6A and 6B are bar graphs depicting change in CYP7A1 expression (Relative expression / Actin) in Hep3B cells (FIG. 6A) or HuH-7 cells (FIG. 6B) with treatment of F-II (30 nM) in combination with fenofibrate. The treatment resulted in reversal of CYP7A1 expression increase caused by FGFR4 signaling blockade using F-II in both Hep3B (FIG. 6A) and HuH-7 cells (FIG. 6B). Fenofibrate was applied at a concentration of 2, 5, and 10 pM in combination with 30 nM of F-II for 22 hours. mRNA was then isolated and CYP7A1 expression was measured by qPCR. The depicted data represent the fold change compared to vehicle (DMSO) treated cells, and Actin was used as internal control. Statistical significance (Mann-Whitney t-test): * p < 0.05, ** p < 0.01, *** p<0.001, **** p < 0.0001, ns: not significant.

[0018] FIGs. 7A and 7B are bar graphs depicting change in serum C4 (ng / ml, FIG. 7A) and in liver Cyp7al expression (%Actb, FIG. 7B) of male C57BL / 6 mice dosed orally with vehicle, fenofibrate, BLU554, FGF401, F-II, or a combination of fenofibrate and the FGFR4 inhibitor at the doses indicated for 6 days. Before the final day of the study, animals were fasted overnight and serum and livers were collected 4 hours after the final dose. The vehicle for fenofibrate, FGF401, and F-II was 0.5% methylcellulose / 0.5% tween 80, and the vehicle for BLU554 was 80% PEG400 / 4% hydroxypropyl-P-cyclodextrin. When combination treatments were tested, the vehicle treatment groups received both vehicles, formulated separately. In the combination treatment groups, the compounds were formulated and dosed separately. The mean C4 value (FIG. 7A) and liver Cyp7al value (FIG. 7B) for each group of 4 mice is shown with dots representing individual mice, and error bars representing standard error of the mean. Statistical significance (Mann-Whitney t-test): * p < 0.05, ** p < 0.01, ns: not significant.

[0019] FIGs. 8A, 8B, and 8C are line graphs depicting change in tumor volume (mm3) in athymic nude (Nu / Nu) mice inoculated subcutaneously in the flank with Huh7 cells. Once tumors reached about 150 mm3, mice were dosed orally with vehicle, fenofibrate, FGF401, F-II, or a combination of fenofibrate and the FGFR4 inhibitor at the doses indicated for up to 21 days. Data points represent mean tumor volume (n=6 per group) and error barsrepresent standard error of the mean. The FGF401, F-II (20 mg / kg BID) and F-II (25 mg / kg BID) fenofibrate combination groups have overlapping curves and final data points with their respective single agent FGFR4 inhibitor treatment groups. The vehicle for fenofibrate, FGF401, and F-II was 0.5% methylcellulose / 0.5% tween 80, and the vehicle for BLU554 was 80% PEG400 / 4% hydroxypropyl-P-cyclodextrin. In the combination treatment groups, the compounds were formulated and dosed separately.

[0020] FIG. 9 is a bar graph depicting change in serum C4 (ng / ml) in the Nu / Nu mice treated as described for FIGs. 8 A, 8B, and 8C. On the final day of the study, four hours after the final dose, blood was collected for serum C4 analysis. The mean C4 value for each group is shown with dots representing individual mice, and error bars representing standard error of the mean. Statistical significance (Mann-Whitney t-test): * p < 0.05, ** p < 0.01, ns: not significant.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0021] The disclosed compositions and methods may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed compositions and methods are not limited to the specific compositions and methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed compositions and methods.

[0022] Unless specifically stated otherwise, any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the disclosed compositions and methods are not to be constrained by the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement.

[0023] Throughout this text, the descriptions refer to compositions and methods of using said compositions. Where the disclosure describes or claims a feature or embodiment associated with a composition, such a feature or embodiment is equally applicable to the methods of using said composition. Likewise, where the disclosure describes or claims a feature or embodiment associated with a method of using a composition, such a feature or embodiment is equally applicable to the composition.

[0024] It is to be appreciated that certain features of the disclosed compositions and methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0025] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0027] As used herein, the term “substantial” or “substantially” refers to a degree of similarity, difference, increase, or decrease, as in a comparison to a known value. Substantial can include at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% similarity, difference, increase, or decrease, as in a comparison to a known value.

[0028] It is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise. The term “about” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ± 10%, ± 5%, ± 1%, or ± 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. The modifier “about” should also be considered as disclosing the range defined by the absolute values of the twoendpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9-1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.

[0029] As used herein, approximating language may be applied to modify any quantitative representation that may vary without resulting in a change in the basic function to which it is related. All ranges are combinable.

[0030] Further, the term “comprising” should be understood as having its open- ended meaning of “including,” but the term also includes the closed meaning of the term “consisting.” For example, a composition that comprises components A and B may be a composition that includes A, B, and other components, but may also be a composition made of A and B only.

[0031] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a cell” includes a combination of two or more cells, and the like.

[0032] As used herein, the terms “individual”, “patient” and “subject”, are used interchangeably to refer to a member of any animal species including, but not limited to, birds, humans and other primates, and other mammals including commercially relevant mammals or animal models such as mice, rats, monkeys, cattle, pigs, horses, sheep, cats, and dogs. Preferably, the subject is a human.

[0033] As used herein, the terms “treat,” “treatment,” and the like, mean the methods or steps taken to provide relief from or alleviation of the number, severity, and / or frequency of one or more symptoms of a disease in a subject. As used herein, “treat” and “treatment” may include the prevention, management, prophylactic treatment, and / or inhibition or reduction of the number, severity, and / or frequency of one or more symptoms of a disease in a subject. Also as used herein, “treat” and “treatment” may refer to the prevention, management, prophylactic treatment, and / or inhibition or reduction of the number, severity, and / or frequency of one or more adverse events arising from an anti- FGFR4 therapy.

[0034] The terms “effective amount” and “therapeutically effective amount” are used interchangeably herein and refer to an amount of the drug effective to achieve a particular biological or therapeutic result such as, but not limited to, amelioration of one ormore symptoms of a disease, alleviation of the number, severity, and / or frequency of one or more symptoms of a disease in a subject. The terms “effective amount” and “therapeutically effective amount” are used interchangeably herein and refer to an amount of the drug effective to achieve a particular biological or therapeutic result such as, but not limited to, amelioration of one or more adverse events arising from an anti-FGFR4 therapy. A therapeutically effective amount of drug may vary according to factors such as the disease state, age, sex, body surface area, and body weight of the subject, and the ability of the drug to elicit a desired response in the subject.

[0035] As used herein, the term “in need of,” in the context of a subject “in need of’ refers to a need for a therapy for treatment of a disease or condition or for the treatment of an adverse event arising from an anti-FGFR therapy.

[0036] As used herein, the term “small molecule” refers to a molecule having a molecular weight of less than 1000 gram / mol.Combination Therapies

[0037] Provided are methods of treating a subject in need of an anti-FGFR4 therapy. The methods comprise administering to the subject a therapeutically effective amount of a PPAR alpha agonist in combination with the anti-FGFR4 therapy.

[0038] In some embodiments, the anti-FGFR4 therapy is an FGFR4 inhibitor. The FGFR4 inhibitor can comprise the compound of Formula I (also referred to herein as “F-I”), a pharmaceutically acceptable salt of the compound of F-I, the compound of Formula II (also referred to herein as “F-II”), or a pharmaceutically acceptable salt of the compound of F-II.

[0039] The anti-FGFR4 therapy can comprise a combination of an FGFR4 inhibitor and a second chemotherapeutic agent. In some embodiments, the second chemotherapeutic agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is an antibody or a binding fragment of an antibody. The immune checkpoint inhibitor can comprise the antibody or the binding fragment of an antibody that binds programmed death- 1 (PD1), programmed death ligand- 1 (PD-L1), programmed death ligand- 2 (PD-L2), or cytotoxic T-lymphocyte-associated antigen 4 (CTLA4).

[0040] In some embodiments, the PPAR-alpha agonist is a small molecule. In some embodiments, the PPAR-alpha agonist is fenofibrate, fenofibric acid, ciprofibrate, gemfibrozil, bezafibrate, elafibranor, pemafibrate, or a combination thereof. Fenofibrate is a prodrug, which after absorption is hydrolyzed by tissue and plasma esterases to its principal active metabolite fenofibric acid. Elafibranor is a dual PPARa / 5 agonist. The chemicalstructures of fenofibrate, fenofibric acid, ciprofibrate, gemfibrozil, bezafibrate, elafibranor, and pemafibrate are shown below:

[0041] The disclosed methods can comprise administering the FGFR4 inhibitor at amount of between about 0.5 mg and about 3000 mg daily, in one or more doses. For example, the disclosed methods can comprise administering the FGFR4 inhibitor at an amount between about 0.5 mg and about 3000 mg, about 1 mg and about 2500 mg, about 5 mg and about 2000 mg, about 10 mg and about 3000 mg, about 15 mg and about 3000 mg,about 20 mg and about 3000 mg, about 25 mg and about 3000 mg, about 30 mg and about 3000 mg, about 35 mg and about 3000 mg, about 50 mg and about 3000 mg, about 45 mg and about 3000 mg, or about 50 mg and about 3000 mg, daily, in one or more doses. The disclosed methods can comprise administering the FGFR4 inhibitor at an amount between about 0.5 mg and about 2500 mg, about 1 mg and about 2000 mg, about 5 mg and about 1500 mg, about 10 mg and about 1000 mg, about 15 mg and about 500 mg, about 20 mg and about 250 mg, about 25 mg and about 200 mg, about 30 mg and about 150 mg, about 35 mg and about 100 mg, about 40 mg and about 100 mg, about 45 mg and about 100 mg, or about 50 mg and about 100 mg, daily, in one or more doses.

[0042] The disclosed methods can comprise administering the FGFR4 inhibitor at an amount of between about 0.01 mg / kg and about 50 mg / kg daily. The FGFR4 inhibitor can be administered in one or more doses. For example, the disclosed methods can comprise administering the FGFR4 inhibitor at an amount between about 0.01 mg / kg and about 50 mg / kg, about 0.05 mg / kg and about 50 mg / kg, about 0.1 mg / kg and about 50 mg / kg, about 0.5 mg / kg and about 50 mg / kg, about 1 mg / kg and about 50 mg / kg, about 5 mg / kg and about 50 mg / kg, about 10 mg / kg and about 50 mg / kg, about 15 mg / kg and about 50 mg / kg, about 20 mg / kg and about 50 mg / kg, about 25 mg / kg and about 50 mg / kg, about 30 mg / kg and about 50 mg / kg, about 35 mg / kg and about 50 mg / kg, about 40 mg / kg and about 50 mg / kg, or about 45 mg / kg and about 50 mg / kg, daily, in one or more doses.

[0043] In some aspects, the disclosed methods comprise administering the FGFR4 inhibitor orally to the subject in a fed or a fasted state.

[0044] In some aspects, the disclosed methods comprise administering the FGFR4 inhibitor by injection. In some aspects, the disclosed methods comprise administering the FGFR4 inhibitor by intravenous injection.

[0045] The disclosed methods can comprise administering the PPAR alpha agonist at an amount between about 0.05 mg and about 3000 mg daily in one or more doses. For example, the disclosed methods can comprise administering the PPAR alpha agonist at an amount between about 0.05 mg and about 3000 mg, about 0.1 mg and about 3000 mg, about 1 mg and about 2500 mg, about 5 mg and about 2000 mg, about 10 mg and about 3000 mg, about 15 mg and about 3000 mg, about 20 mg and about 3000 mg, about 25 mg and about 3000 mg, about 30 mg and about 3000 mg, about 35 mg and about 3000 mg, about 50 mg and about 3000 mg, about 45 mg and about 3000 mg, or about 50 mg and about 3000 mg, daily, in one or more doses. The disclosed methods can comprise administering the PPAR alpha agonist at an amount between about 0.05 mg and about 2500 mg, about 0.1 mg andabout 2000 mg, about 1 mg and about 2000 mg, about 5 mg and about 1500 mg, about 10 mg and about 1000 mg, about 15 mg and about 500 mg, about 20 mg and about 250 mg, about 25 mg and about 200 mg, about 30 mg and about 150 mg, about 35 mg and about 100 mg, about 40 mg and about 100 mg, about 45 mg and about 100 mg, or about 50 mg and about 100 mg, daily, in one or more doses..

[0046] The disclosed methods can comprise administering the PPAR alpha agonist at an amount between about 0.001 mg / kg and about 50 mg / kg daily. For example, the disclosed methods can comprise administering the PPAR alpha agonist at an amount between about 0.001 mg / kg and about 50 mg / kg, about 0.005 mg / kg and about 50 mg / kg, about 0.01 mg / kg and about 50 mg / kg, about 0.05 mg / kg and about 50 mg / kg, about 0.1 mg / kg and about 50 mg / kg, about 0.5 mg / kg and about 50 mg / kg, about 1 mg / kg and about 50 mg / kg, about 5 mg / kg and about 50 mg / kg, about 10 mg / kg and about 50 mg / kg, about 15 mg / kg and about 50 mg / kg, about20 mg / kg and about 50 mg / kg, about 25 mg / kg and about 50 mg / kg, about 30 mg / kg and about 50 mg / kg, about 35 mg / kg and about 50 mg / kg, about 40 mg / kg and about 50 mg / kg, or about 45 mg / kg and about 50 mg / kg, daily, in one or more doses.

[0047] In some embodiments, the methods further comprise administering to the subject a bile acid sequestrant. In some embodiments, the bile acid sequestrant is cholestyramine, colestipol, colesevelam, or a combination thereof. In some embodiments, the bile acid sequestrant is cholestyramine.

[0048] The disclosed methods can comprise administering the PPAR alpha agonist prior to, simultaneously with, or following administration of the anti-FGFR4 therapy. In those methods wherein a bile acid sequestrant is further administered, the bile acid sequestrant can be administered prior to, simultaneously with, or following administration of the PPAR alpha agonist. In those methods wherein a bile acid sequestrant is further administered, the bile acid sequestrant can be administered prior to, simultaneously with, or following administration of the anti-FGFR4 therapy.

[0049] Also disclosed are methods treating a subject in need of an anti-FGFR4 therapy comprising administering to the subject the anti-FGFR4 therapy in combination with a therapeutically effective amount of a PPAR alpha agonist and a bile acid sequestrant. The disclosed methods can comprise administering the PPAR alpha agonist and the bile acid sequestrant prior to, simultaneously with, or following administration of the anti-FGFR4 therapy.

[0050] Examples of combination therapies are presented in Tables 1 and 2.Table 1. Representative combination therapies with the small molecule FGFR4 inhibitor F-I or F-II and PPAR alpha agonist.“+” indicates a combination therapy of the small molecule FGFR4 inhibitor and the PPAR alpha agonist“+ / -“ indicates an inclusion (+) or exclusion (-) of the specific PPAR alpha agonist in the combination therapy of the small molecule FGFR4 inhibitor and the PPAR alpha agonistTable 2. Combination therapies of PPAR alpha agonist, a bile acid sequestrant, and a small molecule FGFR4 inhibitor F-I or F-II.“+” indicates a combination therapy of the small molecule FGFR4 inhibitor, the PPAR alpha agonist, and a bile acid sequestrant indicates an inclusion (+) or exclusion (-) of the specific PPAR alpha agonist in the combination therapy of the small molecule FGFR4 inhibitor, the PPAR alpha agonist, and a bile acid sequestrant

[0051] The disclosed methods are administered to a subject in need of treatment for proliferative disease, metabolic disease, cardiovascular disease, or kidney disease. The subject can be in need of treatment for a proliferative disease that is an FGFR4-mediated cancer, hepatocellular carcinoma, cholangiocarcinoma, or a solid tumor. The subject can be in need of treatment for a metabolic disease, for example non-alcoholic steatohepatitis (NASH) or diabetes. The subject can be in need of treatment for type 2 diabetes. The subjectcan be in need of treatment for concentric cardiac hypertrophy. The subject can be in need of treatment for cardiovascular disease. The subject can be in need of treatment for chronic kidney disease. The subject can be in need of treatment for left ventricular hypertrophy.

[0052] The disclosed methods can provide one or more of: a reduction in the number of anti-FGFR4 therapy-related adverse events, a reduction in the anti-FGFR4 therapy-related adverse event frequency, a reduction in the anti-FGFR4 therapy -related adverse event severity, an increase in duration of the anti-FGFR4 therapy, an increase in daily dose of the anti-FGFR4 therapy, and an increase in patient compliance of the subject to the anti-FGFR4 therapy. In some embodiments, the adverse event is diarrhea, nausea, vomiting, increased level of aspartate transaminase (AST), increased level of alanine transaminase (ALT), increased level of gamma-glutamyl transferase (GGT), increased level of serum bilirubin, increased prothrombin time (PT), or a combination thereof.

[0053] In some embodiments, the methods provide a reduction in serum levels of C4 (7-alpha-hydroxy-4-cholestene-3-one), a bile acid, or a combination thereof. The methods can provide a reduction in serum level of C4 by between about 5% and about 95% in the subject as compared to that in a subject receiving the anti-FGFR4 therapy without the PPAR alpha agonist. For example, the methods can provide a reduction in serum level of C4 by between about 5% and about 10%, between about 5% and about 15%, between about 5% and about 20%, between about 5% and about 25%, between about 5% and about 30%, between about 5% and about 35%, between about 5% and about 40%, between about 5% and about 45%, between about 5% and about 50%, between 5% and about 55%, between about 5% and about 60%, between about 5% and about 65%, between about 5% and about 70%, between about 5% and about 75%, between about 5% and about 80%, between about 5% and about 85%, between about 5% and about 90%, or between about 5% and about 95% in the subject as compared to the serum level of C4 in a subject receiving the anti-FGFR4 therapy without the PPAR alpha agonist.Compositions

[0054] Also disclosed are compositions comprising an FGFR4 inhibitor F-I, a pharmaceutically acceptable salt of the compound of F-I, F-II, or a pharmaceutically acceptable salt of the compound of F-II. The compositions can comprise the FGFR4 inhibitor, a PPAR alpha agonist, and a pharmaceutically acceptable excipient. The compositions can comprise the FGFR4 inhibitor and the PPAR alpha agonist as a single unit dosage form.

[0055] Also disclosed are compositions comprising the FGFR4 inhibitor, a PPAR alpha agonist, a bile acid sequestrant, and a pharmaceutically acceptable excipient. The disclosed compositions can comprise the FGFR4 inhibitor, the PPAR alpha agonist, the bile acid sequestrant, and the pharmaceutically acceptable excipient in a single unit dosage form.

[0056] In some embodiments, the PPAR alpha agonist in the compositions is fenofibrate, fenofibric acid, ciprofibrate, gemfibrozil, bezafibrate, elafibranor, pemafibrate, or a combination thereof. In some embodiments, the bile acid sequestrant is cholestyramine, colestipol, colesevelam, or a combination thereof.Kits

[0057] Also provided are kits comprising the FGFR4 inhibitor and a PPAR alpha agonist. The kits can comprise the FGFR4 inhibitor F-I, a pharmaceutically acceptable salt of the compound of F-I, F-II, or a pharmaceutically acceptable salt of the compound of F-II. The kits can comprise the FGFR4 inhibitor as a single unit dosage form and the PPAR alpha as a single unit dosage form. The kits can comprise the FGFR4 inhibitor and the PPAR alpha on the same blister pack. The kits can further comprise a bile acid sequestrant.

[0058] The kits can comprise instructions for use and a dosing chart with dosing and regimen recommendations.EXAMPLES

[0059] FGFR4 inhibitors are under development for treatment of cancers such as hepatocellular carcinoma (HCC), treatment of solid tumors, CKD, and cardiovascular conditions. The dysregulation of bile acids due to FGFR4 inhibition can complicate or even limit the anti-FGFR4 therapy in subjects.Example 1. In vitro and in vivo studies with F-IMaterials and Methods

[0060] For serum C4 studies, male C57BL / 6 mice were dosed orally with vehicle, fenofibrate, BLU554, FGF401, F-I, or a combination of fenofibrate and the FGFR4 inhibitor at the doses indicated for 6 days. Before the final day of the study, animals were fasted overnight and serum was collected 4 hours after the final dose. The vehicle for fenofibrate, FGF401, and F-I was 0.5% methylcellulose / 0.5% tween 80, and the vehicle for BLU554 was 80% PEG400 / 4% hydroxypropyl-P-cyclodextrin. When combination treatments were tested, the vehicle treatment groups received both vehicles, formulated separately. In the combination treatment groups, the compounds were formulated and dosed separately.

[0061] Serum C4 (7-alpha-hydroxy-4-cholestene-3-one) analyses were carried out on an Agilent 6495 triple quadrupole mass spectrometer with jet stream source coupled to an Agilent 1290 UPLC stack. Data was processed using TargetLynx™ data processing software (Waters Corporation, Milford, MA). Calibration curves were generated using reference standard (7A4C; Sigma-Aldrich®, St. Louis, MO). Calibration range was from 0.5ng / ml - 200 ng / ml with an internal deuterated standard (7A4C-D7; Avanti® Polar Lipids, Alabaster, AL) concentration of 100 ng / ml.

[0062] For liver Cyp7al expression experiment, snap frozen liver tissues were homogenized in RNA lysis buffer and mRNA was then isolated using PureLink™ RNA Kit (Invitrogen, 12183025), followed by conversion of RNA into cDNA using High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, 4374967). Liver Cyp7al expression was measured using TaqMan™ qPCR Assays (Cyp7al assay ID: Mm00484150_ml, Actb (used as internal control) assay ID: Mm00607939_sl).

[0063] For tumor regression studies, athymic nude (Nu / Nu) mice were inoculated subcutaneously in the flank with Huh7 cells, a human hepatocellular carcinoma cell line driven by FGF19 overexpression. Tumor sizes [tumor volume (mm3) = (a x Z>2 / 2); where a represents the length, and b the width of the tumor as determined by caliper measurements] and body weights were measured two or three times weekly. Once tumors reached about 150 mm3, mice were dosed orally with vehicle, fenofibrate, FGF401, F-I, or a combination of fenofibrate and the FGFR4 inhibitor at the doses indicated for up to 21 days. The vehicle for fenofibrate, FGF401, and F-I was 0.5% methylcellulose / 0.5% tween 80. In the combination treatment groups, the compounds were formulated and dosed separately.Results

[0064] Treatment of FGFR4+ / FGF19+ HCC cell lines with F-I induced CYP7A1 upregulation in a dose-dependent manner. Changes in CYP7A1 expression (Relative mRNA expression / Actin) in Hep3B cells or HuH-7 cells with treatment of increasing concentrations of F-I for 22 hours are shown in FIGs. 1 A and IB. Treatment of the cells with F-I resulted in increased CYP7A1 expression in Hep3B (FIG. 1 A) and HuH-7 cells (FIG. IB) in a dose dependent manner, as measured using qPCR.

[0065] Combination of fenofibrate with F-I reversed F-I-induced CYP7A1 upregulation in FGFR4+ / FGF19+ HCC cell lines. Treatment of the cells with F-I (30 nM) in combination with fenofibrate resulted in reversal of CYP7A1 expression increase caused by FGFR4 signaling blockade using F-I in both Hep3B (FIG. 2A) and HuH-7 cells (FIG. 2B). Fenofibrate was applied at a concentration of 2, 5, and 10 pM in combination with 30 nM of F-I for 22 hours. mRNA was then isolated and CYP7A1 expression was measured using qPCR. The depicted data represent the fold change compared to vehicle (DMSO) treated cells, and Actin was used as internal control.

[0066] The effect of combination treatment with fenofibrate on serum C4 levels was then studied in vivo in wild-type mice (FIG. 3). BLU554 (30 mg / kg BID and 100 mg / kg BID) and F-I (20 mg / kg BID and 25 mg / kg BID) each increased the level of serum C4, although FGF401 (30 mg / kg BID) did not in this study. Fenofibrate mitigated the FGFR4-inhibitor induced increase in serum C4 when dosed in combination with BLU554 (30 mg / kg BID) and both doses of F-I toward the level observed in vehicle-treated mice. However, fenofibrate did not reduce serum C4 when dosed in combination with BLU554 (100 mg / kg BID). Of note, F- I (25 mg / kg BID) increased the serum C4 to the highest level, while the combination with fenofibrate still effectively reduced C4 to the level observed in the vehicle-treated animals. The results are shown in FIG. 3 and Table 3. The mean C4 value for each group of 6 mice is shown with dots representing individual mice, and error bars representing standard error of the mean.Table 3. Comparison of the serum C4 levels with the different tested treatments.aSEM, standard error of the mean

[0067] Combination treatment with F-I and fenofibrate caused tumor regression in an FGFR4+ / FGF19+ xenograft mouse model. The results are shown in FIGs. 4A and 4B. Percent tumor growth inhibition (TGI) at Day 12 post treatment initiation (at day 22 postinoculation) is shown in Table 4. Data points represent mean tumor volume (n=8 per group) and error bars represent standard error of the mean. Each of the 3 fenofibrate combination groups have overlapping curves and final data points with their respective single agent FGFR4 inhibitor treatment groups.Table 4. Comparison of the percent tumor growth inhibition (TGI) with the different tested treatments.aTGI% = (1-T / C)bStatistical significance versus vehicle group on Day 12 of Treatment (Mann-Whitney t-test)* p < 0.05, ** p < 0.01, ns: not significant; N / A: not applicableExample 2. In vitro and in vivo studies with F-IIMaterials and Methods

[0068] The methods for the CYP7A1 expression analysis in the Hep3B and HuH7 cell lines were performed as described in Example 1 using F-II as the FGFR4 inhibitor.

[0069] Male C57BL / 6 mice were dosed orally with vehicle, fenofibrate, BLU554, FGF401, F-II, or a combination of fenofibrate and the FGFR4 inhibitor at the doses indicated for 6 days. Before the final day of the study, animals were fasted overnight and serum and livers were collected 4 hours after the final dose. The vehicle for fenofibrate, FGF401, and F- II was 0.5% methylcellulose / 0.5% tween 80, and the vehicle for BLU554 was 80% PEG400 / 4% hydroxypropyl-P-cyclodextrin. When combination treatments were tested, the vehicle treatment groups received both vehicles, formulated separately. In the combination treatment groups, the compounds were formulated and dosed separately.

[0070] Serum C4 was measured as described in Example 1.

[0071] Livers were flash frozen in liquid nitrogen, dissociated in RNA lysis buffer using ceramic beads microtubes (19-626, Omni International) in a Bead Mill 24 homogenizer (15-340-163, Fisherbrand™, Fisher Scientific, Pittsburgh, PA). Cell lysis and RNA extraction was performed with the PureLink™ RNA Mini Kit (12183025, ThermoFisher Scientific). RNA was quantified in a Nanodrop Spectrophotomer (840274200, ThermoFisherScientific) and 2 micrograms of RNA were used for reverse transcription in a Mini Amp™ Thermal Cycler (A37834, ThermoFisher Scientific) using the High-Capacity cDNA Reverse Transcription Kit (4368814, Applied Biosystems™, Runcorn, UK). The final cDNA product was diluted 1 :4 in RNAse-free water and used in a multiplexed qPCR using TaqMan™ Fast Advanced Master Mix (4444557, Applied Biosystems™) and TaqMan probes for mouse Actb (4326315E, Applied Biosystems™) and Cyp7al (Mm00484150_ml). The qPCR was run in a QuantStudio™ 6 Pro (A43180, Applied Biosystems™) and Cyp7al expression was calculated with the ACt method.

[0072] For tumor regression studies, athymic nude (Nu / Nu) mice were inoculated subcutaneously in the flank with Huh7 cells. Once tumors reached about 150 mm3, mice were dosed orally with vehicle, fenofibrate, FGF401, F-II, or a combination of fenofibrate and the FGFR4 inhibitor at the doses indicated for up to 21 days. Data points represent mean tumor volume (n=6 per group) and error bars represent standard error of the mean. The vehicle for fenofibrate, FGF401, and F-II was 0.5% methylcellulose / 0.5% tween 80, and the vehicle for BLU554 was 80% PEG400 / 4% hydroxypropyl-P-cyclodextrin. In the combination treatment groups, the compounds were formulated and dosed separately.Results

[0073] Treatment of FGFR4+ / FGF19+ HCC cell lines with F-II induced CYP7A1 upregulation in a dose-dependent manner. Changes in CYP7A1 expression (Relative mRNA expression / Actin) in Hep3B cells or HuH-7 cells with treatment of increasing concentrations of F-II for 22 hours is shown in FIGs. 5A and 5B. Treatment of the cells with F-II resulted in increased CYP7A1 expression in Hep3B (FIG. 5A) and HuH-7 cells (FIG. 5B) in a dose dependent manner, as measured using qPCR.

[0074] Combination of fenofibrate with F-II reversed F-II-induced CYP7A1 upregulation in FGFR4+ / FGF19+ HCC cell lines. The treatment of the cells with F-II (30 nM) in combination with fenofibrate resulted in reversal of CYP7A1 expression increase caused by FGFR4 signaling blockade using F-II in both Hep3B (FIG. 6A) and HuH-7 cells (FIG. 6B). Fenofibrate was applied at a concentration of 2, 5, and 10 pM in combination with 30 nM of F-II for 22 hours. mRNA was then isolated and CYP7A1 expression was measured using qPCR. The depicted data represent the fold change compared to vehicle (DMSO) treated cells, and Actin was used as internal control.

[0075] Combination treatment with F-II and fenofibrate mitigated the FGFR4 inhibitor-induced increase in serum C4 and liver Cyp7al in wild-type mice. The results are shown in FIGs. 7 A and 7B and the values for serum C4 are shown in Table 5. The mean C4value (FIG. 7A) and liver Cyp7al value (FIG. 7B) for each group of 4 mice is shown with dots representing individual mice, and error bars representing standard error of the mean.Table 5. Comparison of the serum C4 levels with the different tested treatments.aSEM, standard error of the meanbsingle sampleN / A: not applicable

[0076] Combination treatment with F-II and fenofibrate caused tumor regression in an FGF19+ xenograft mouse model. The results are shown in FIGs. 8A-8C. The FGF401, F- II (20 mg / kg BID) and F-II (25 mg / kg BID) fenofibrate combination groups have overlapping curves and final data points with their respective single agent FGFR4 inhibitor treatment groups. Treatment was started on day 12. Percent tumor growth inhibition (TGI) at Day 18 after treatment initiation (at day 30 post-inoculation) is shown in Table 6.Table 6. Comparison of the percent tumor growth inhibition (TGI) with the different tested treatments.aTGI% = (1-T / C)bStatistical significance versus vehicle on Day 18 of Treatment (Mann-Whitney t-test)* p < 0.05, ** p < 0.01, ns: not significant; N / A: not applicable

[0077] On the final day of the study, 4 hours after the final dose, blood was also collected for serum C4 analysis. The mean C4 value for each group is shown in FIG. 9 with dots representing individual mice, and error bars representing standard error of the mean.

Claims

What is claimed:

1. A method of treating a subject in need of an anti -fibroblast growth factor receptor 4 (anti-FGFR4) therapy comprising administering to the subject a therapeutically effective amount of a peroxisome proliferator-activated receptor (PPAR) alpha agonist in combination with the anti-FGFR4 therapy, wherein the anti- FGFR4 therapy is an FGFR4 inhibitor comprising the compound of Formula I:Formula I, a pharmaceutically acceptable salt of the compound of Formula I, the compound of Formula II:Formula II, or a pharmaceutically acceptable salt of the compound of Formula II.

2. The method of claim 1, wherein the anti-FGFR4 therapy comprises a combination of a FGFR4 inhibitor and a second chemotherapeutic agent.

3. The method of claim 2, wherein the second chemotherapeutic agent is an immune checkpoint inhibitor.

4. The method of claim 3, wherein the immune checkpoint inhibitor is an antibody or a binding fragment of an antibody.

5. The method of claim 4, wherein the antibody or the binding fragment of an antibody binds programmed death- 1 (PD1), programmed death ligand- 1 (PD-L1), programmed death ligand-2 (PD-L2), or cytotoxic T-lymphocyte-associated antigen 4 (CTLA4).

6. The method of any one of claims 1-5, wherein the PPAR-alpha agonist is a small molecule.

7. The method of any one of claims 1-6, wherein the PPAR-alpha agonist is fenofibrate, fenofibric acid, ciprofibrate, gemfibrozil, bezafibrate, elafibranor, pemafibrate, or a combination thereof.

8. The method of any one of claims 1-7, wherein the FGFR4 inhibitor is administered at a dose of between about 0.5 mg and about 3000 mg daily.

9. The method of any one of claims 1-8, wherein the FGFR4 inhibitor is administered at a dose of between about 0.01 mg / kg and about 50 mg / kg daily.

10. The method of any one of claims 1-9, wherein the FGFR4 inhibitor is administered to the subject in a fed or a fasted state orally or by an injection.

11. The method of any one of claims 1-10, wherein the PPAR alpha agonist is administered at a dose of between about 0.05 mg and about 3000 mg daily.

12. The method of any one of claims 1-11, wherein the PPAR alpha agonist is administered at a dose of about 0.001 mg / kg and about 50 mg / kg daily.

13. The method of any one of claims 1-12, further comprising administering to the subject a bile acid sequestrant.

14. The method of claim 13, wherein the bile acid sequestrant is cholestyramine, colestipol, colesevelam, or a combination thereof.

15. The method of claim 13 or 14, wherein the bile acid sequestrant is cholestyramine.

16. The method of any one of claims 1-15, wherein the PPAR alpha agonist is administered prior to, simultaneously with, or following administration of the anti- FGFR4 therapy.

17. The method of any one of claims 13-16, wherein the PPAR alpha agonist and the bile acid sequestrant are administered prior to, simultaneously with, or following administration of the anti-FGFR4 therapy.

18. A method of treating a subject in need of an anti -fibroblast growth factor receptor 4 (anti-FGFR4) therapy comprising administering to the subject an anti-FGFR4 therapy in combination with a therapeutically effective amount of a peroxisome proliferator- activated receptor (PPAR) alpha agonist and a bile acid sequestrant, wherein the anti- FGFR4 therapy is an FGFR4 inhibitor comprising the compound of Formula I:Formula I, a pharmaceutically acceptable salt of the compound of Formula I, the compound of Formula II:Formula II, or a pharmaceutically acceptable salt of the compound of Formula II.

19. The method of any one of claims 1-18, wherein the subject is in need of treatment for proliferative disease, metabolic disease, cardiovascular disease, or kidney disease.

20. The method of any one of claims 1-19, wherein the subject is in need of treatment for a proliferative disease that is an FGFR4-mediated cancer, hepatocellular carcinoma, cholangiocarcinoma, or a solid tumor.

21. The method of any one of claims 1-20, wherein the subject is in need of treatment for a metabolic disease comprising non-alcoholic steatohepatitis (NASH) or diabetes.

22. The method of any one of claims 1-21, wherein the subject is in need of treatment for type 2 diabetes.

23. The method of any one of claims 1-22, wherein the subject is in need of treatment for concentric cardiac hypertrophy.

24. The method of any one of claims 1-23, wherein the subject is in need of treatment for cardiovascular disease.

25. The method of any one of claims 1-24, wherein the subject is in need of treatment for chronic kidney disease.

26. The method of any one of claims 1- 25, wherein the subject is in need of treatment for left ventricular hypertrophy.

27. The method of any one of claims 1-26, wherein the method provides one or more of: a reduction in the number of anti-FGFR4 therapy-related adverse events, a reduction in the anti-FGFR4 therapy-related adverse event frequency, a reduction in the anti- FGFR4 therapy -related adverse event severity, an increased duration of the anti- FGFR4 therapy, an increased daily dose of the anti-FGFR4 therapy, and an increases patient compliance of the subject to the anti-FGFR4 therapy.

28. The method of claim 27, wherein the adverse event is diarrhea, nausea, vomiting, increased level of aspartate transaminase (AST), increased level of alanine transaminase (ALT), increased level of gamma-glutamyl transferase (GGT), increased level of serum bilirubin, increased prothrombin time (PT), or a combination thereof.

29. The method of any one of claims 1-28, wherein the method provides a reduction in serum levels of C4 (7-alpha-hydroxy-4-cholestene-3-one), a bile acid, or a combination thereof.

30. The method of any one of claims 1-29, wherein the method provides a reduction in serum level of C4 (7-alpha-hydroxy-4-cholestene-3-one) by between about 5% and about 95% in the subject as compared to that in a subject receiving the anti-FGFR4 therapy without the PPAR alpha agonist.

31. A composition comprising a fibroblast growth factor receptor 4 (FGFR4) inhibitor, a peroxisome proliferator-activated receptor (PPAR) alpha agonist, and a pharmaceutically acceptable excipient, wherein the FGFR4 inhibitor comprises the compound of Formula I:Formula I, a pharmaceutically acceptable salt of the compound of Formula I, the compound of Formula II:Formula II, or a pharmaceutically acceptable salt of the compound of Formula II.

32. The composition of claim 31, wherein the FGFR4 inhibitor and the PPAR alpha agonist are provided as a single unit dosage form.

33. The composition of claim 31 or 32, wherein the PPAR alpha agonist is fenofibrate, fenofibric acid, ciprofibrate, gemfibrozil, bezafibrate, elafibranor, pemafibrate, or a combination thereof.

34. A composition comprising a fibroblast growth factor receptor 4 (FGFR4) inhibitor, a peroxisome proliferator-activated receptor (PPAR) alpha agonist, a bile acid sequestrant, and a pharmaceutically acceptable excipient, wherein the FGFR4 inhibitor comprises the compound of Formula I:Formula I, a pharmaceutically acceptable salt of the compound of Formula I, the compound of Formula II:Formula II, or a pharmaceutically acceptable salt of the compound of Formula II.

35. The composition of claim 34, wherein the FGFR4 inhibitor and the PPAR alpha agonist are provided as a single unit dosage form.

36. The composition of claim 34 or 35, wherein the PPAR alpha agonist is fenofibrate, fenofibric acid, ciprofibrate, gemfibrozil, bezafibrate, elafibranor, pemafibrate, or a combination thereof.

37. The composition of any one of claims 34-36, wherein the bile acid sequestrant is cholestyramine, colestipol, colesevelam, or a combination thereof.

38. The composition of any one of claims 34-37, wherein the bile acid sequestrant is cholestyramine.

39. A kit comprising a fibroblast growth factor receptor 4 (FGFR4) inhibitor and a peroxisome proliferator-activated receptor (PPAR) alpha agonist, wherein the FGFR4 inhibitor comprises the compound of Formula I:Formula I, a pharmaceutically acceptable salt of the compound of Formula I, the compound of Formula II:Formula II, or a pharmaceutically acceptable salt of the compound of Formula II.

40. The kit of claim 39, wherein the FGFR4 inhibitor is provided as a single unit dosage form and the PPAR alpha is provided as a single unit dosage form.

41. The kit of claim 39 or 40, wherein the FGFR4 inhibitor and the PPAR alpha agonist are provided on same blister pack.

42. The kit of any one of claims 39-41, further comprising a bile acid sequestrant.

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