Therapies with PPAR agonists and FGFR3 inhibitors

Abstract

Provided are methods of treating subjects in need of an anti-fibroblast growth factor receptor 3 (anti-FGFR3) 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-FGFR3 therapy. The methods can comprise administering to the subject a therapeutically effective amount of PPAR alpha agonist and a bile acid sequestrant. Also provided are compositions comprising an FGFR3 inhibitor, a PPAR alpha agonist, and, optionally, a bile acid sequestrant. The methods attenuate the dysregulation of bile acid biosynthesis caused by FGFR3 inhibition with anti-FGFR3 therapies. The methods reduce the severity and / or incidence of adverse events associated with anti-FGFR3 therapies.

Description

THERAPIES WITH PPAR AGONISTS AND FGFR3 INHIBITORSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Nos. 63 / 739,281, filed December 27, 2024, and 63 / 739,283, filed December 27, 2024, the entireties of which are incorporated by reference herein.TECHNICAL FIELD

[0002] Described herein are methods of treating subjects in need of an anti-fibroblast growth factor receptor 3 (anti-FGFR3) therapy with peroxisome proliferator-activated receptor (PPAR) alpha agonists.BACKGROUND

[0003] The Fibroblast Growth Factor Receptor (FGFR) family plays a critical role in various physiological processes, including cell growth, differentiation, and metabolism. Among its many functions, FGFR signaling has been recognized as a key regulator of bile acid and cholesterol homeostasis, both of which are vital for maintaining metabolic balance and overall liver function. Bile acids are synthesized from cholesterol in the liver and play an essential role in lipid digestion and absorption. Fibroblast growth factor 19 (FGF19) is known to modulate bile acid synthesis and cholesterol homeostasis through its interactions with FGFR4. Binding of FGF19 to FGFR4 stimulates its kinase activity and triggers a signaling pathway that modulates the transcriptional activity of Hepatocyte Nuclear Factor 4a (HNF4A), leading to the downregulation of bile acid synthesis via the inhibition of CYP7A1 expression. This negative feedback loop prevents excessive bile acid production, thus playing a protective role against bile acid toxicity and preserving cholesterol levels within the body.

[0004] HNF4A is a master transcription factor that not only regulates CYP7A1 but also controls the expression of other genes involved in lipid and cholesterol metabolism, including Apolipoprotein A-I (APO Al). APO Al is the main protein component of HDL and facilitates the transport of cholesterol from peripheral tissues to the liver, where it is excreted. This process helps prevent the buildup of cholesterol in arteries, a key factor in the development of atherosclerosis, which is the underlying cause of most cardiovascular diseases. Hence, upregulating APOA1 could have far-reaching benefits, particularly in the management of cardiovascular diseases and conditions associated with dyslipidemia, inflammation, and metabolic imbalances. Thus, by modulating HNF4A activity, FGFR- 1 - 120039.000207\4936-3978-3555.1signaling affects a broad spectrum of metabolic processes related to bile acid homeostasis and cholesterol balance.

[0005] While both FGFR3 and FGFR4 share the ability to bind FGF19, FGFR4 has been believed to be the only receptor in the liver regulating bile acid synthesis in response to FGF19. Recent work provided evidence of redundancy between FGFR4 and FGFR3 in HCC hepatocytes, with FGFR3 also serving as a receptor for FGF19 signaling when FGFR4 is impaired by a specific inhibitor. Here we demonstrate that FGFR3 downstream signaling also regulates CYP7A1 expression and therefore also controls bile acid synthesis, even in the absence of FGFR4 inhibition, thus elucidating a previously unrecognized normal physiological role for FGFR3 with implications for treatments with FGFR3 inhibitors.

[0006] There remains a need for regulating bile acid synthesis in therapies utilizing FGFR3 inhibitors. The present disclosure addresses these needs.SUMMARY

[0007] In meeting these needs, the present disclosure provides a method of treating a subject in need of an anti-FGFR3 therapy. The method comprises administering to the subject a therapeutically effective amount of a PPAR alpha agonist in combination with the anti-FGFR3 therapy.

[0008] The present disclosure also provides a method of treating a subject in need of an anti-FGFR3 therapy comprising administering to the subject the anti-FGFR3 therapy in combination with a therapeutically effective amount of a PPAR alpha agonist and a bile acid sequestrant.

[0009] Also provided are compositions comprising an FGFR3 inhibitor, a PPAR alpha agonist, and a pharmaceutically acceptable excipient.

[0010] Also provided are compositions comprising an FGFR3 inhibitor, a PPAR alpha agonist, a bile acid sequestrant, and a pharmaceutically acceptable excipient.

[0011] The present disclosure also provides kits comprising an FGFR3 inhibitor and a PPAR alpha agonist.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended drawings. For the purpose of- 2 -4886-1054-6423.5120039.000207\4936-3978-3555.1illustrating 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:

[0013] Figure 1 is a pictorial representation of an interplay between FGFR3 and FGFR4 in the regulation of bile acids and cholesterol homeostasis.

[0014] Figure 2 is a bar graph depicting changes in CYP7A1 expression (Relative mRNA express! on / Actin) in Hep3B cells, treated for 24 hours with 40 nM of selective FGFR4 inhibitors (BLU-554 andFGF-401), FGFR1-3 inhibitor tasurgratinib, FGFR3-biased inhibitor Compound 1, or dual FGFR3-4 inhibitors (Compound 2, Compound 3, and Compound 4). Data show that dual FGFR3-4 inhibitors caused significantly higher CYP7A1 expression levels as compared to the upregulated CYP7A1 levels following either selective FGFR4 inhibitors (FGF-401 and BLU-554) orFGFR3 inhibitors (Tasurgratinib and Compound 1) in Hep3B (3 A) and HuH-7 (3B) cells. CYP7A1 expression was much higher in the presence of dual 3 / 4 inhibitors suggesting a synergistic effect of FGFR4 and FGFR3 inhibition in HuH7 cells.

[0015] Figure 3 is a bar graph depicting changes in CYP7A1 expression (Relative mRNA express! on / Actin) HuH-7 cells, treated for 24 hours with 40 nM of selective FGFR4 inhibitors (BLU-554 and FGF-401), FGFR1-3 inhibitor tasurgratinib, FGFR3-biased inhibitor Compound 1, or dual FGFR3-4 inhibitors (Compound 2, Compound 3, and Compound 4). Data show that dual FGFR3-4 inhibitors caused significantly higher CYP7A1 expression levels as compared to the upregulated CYP7A1 levels following either selective FGFR4 inhibitors (FGF-401 and BLU-554) orFGFR3 inhibitors (Tasurgratinib and Compound 1) in Hep3B (3 A) and HuH-7 (3B) cells. CYP7A1 expression was much higher in the presence of dual 3 / 4inhibitors suggesting a synergistic effect of FGFR4 and FGFR3 inhibition in HuH7 cells.

[0016] Figure 4 is a bar graph depicting changes in APOA1 expression (Relative mRNA express! on / Actin) in Hep3B cells, treated for 24 hours with 40 nM of selective FGFR4 inhibitors (BLU-554 andFGF-401), FGFR1-3 inhibitor tasurgratinib, FGFR3-biased inhibitor Compound 1, or dual FGFR3-4 inhibitors (Compound 2, Compound 3, and Compound 4). Data show that dual FGFR3-4 inhibitors caused significantly higher CYP7A1 expression levels as compared to the upregulated CYP7A1 levels following either selective- 3 -4886-1054-6423.5120039.000207\4936-3978-3555.1FGFR4 inhibitors (FGF-401 and BLU-554) or selective FGFR3 inhibitors (Tasurgratinib and Compound 1) in Hep3B cells.

[0017] Figure 5 is a bar graph depicting changes in APOA1 expression (Relative mRNA express! on / Actin) in HuH-7 cells, treated for 24 hours with 40 nM of selective FGFR4 inhibitors (BLU-554 and FGF-401), FGFR1-3 inhibitor tasurgratinib, FGFR3-biased inhibitor Compound 1, or dual FGFR3-4 inhibitors (Compound 2, Compound 3, and Compound 4). Data show that dual FGFR3-4 inhibitors caused significantly higher CYP7A1 expression levels as compared to the upregulated CYP7A1 levels following either selective FGFR4 inhibitors (FGF-401 and BLU-554) or selective FGFR3 inhibitors (Tasurgratinib and Compound 1) in HuH-7 cells.

[0018] Figure 6 is a bar graph depicting changes in CYP7A1 expression (Relative mRNA expression / Actin) in Hep3B cells with treatment of increasing concentrations of Compound 1 (an FGFR3-biased inhibitor) for 24 hours. Treatment of the cells with Compound 1 (20 nM, 40 nM, and 60 nM) resulted in increased CYP7A1 expression in Hep3B in a dose dependent manner, as measured using qPCR.

[0019] Figure 7 is a bar graph depicting changes in CYP7A1 expression (Relative mRNA expression / Actin) in HuH-7 cells with treatment of increasing concentrations of Compound 1 (an FGFR3-biased inhibitor) for 24 hours. Treatment of the cells with Compound 1 (20 nM, 40 nM, and 60 nM) resulted in increased CYP7A1 expression in HuH-7 in a dose dependent manner, as measured using qPCR.

[0020] Figure 8 is a bar graph depicting changes in APOA1 expression (Relative mRNA expression / Actin) in Hep3B cells with treatment of increasing concentrations of Compound 1 (an FGFR3-biased inhibitor) for 24 hours. Treatment of the cells with Compound 1 (20 nM, 40 nM, and 60 nM) resulted in increased APOA1 expression in Hep3B in a dose dependent manner, as measured using qPCR.

[0021] Figure 9 is a bar graph depicting changes in APOA1 expression (Relative mRNA expression / Actin) in HuH-7 cells with treatment of increasing concentrations of Compound 1 (an FGFR3-biased inhibitor) for 24 hours. Treatment of the cells with Compound 1 (20 nM, 40 nM, and 60 nM) resulted in increased APOA1 expression in HuH-7 in a dose dependent manner, as measured using qPCR.

[0022] Figure 10 is a bar graph depicting changes in CYP7A1 expression (Relative mRNA expression / Actin) in HCC (Hep3B) cells treated with 60 nM of Compound 1 for 24- 4 - 4886-1054-6423.5120039.000207\4936-3978-3555.1hours in combination with increasing concentrations of Fenofibrate (2 uM, 5 uM, and 10 uM) for 24 hours. In Hep3B cells, combination with Fenofibrate resulted in reversal of CYP7A1 expression increase caused by Compound 1.

[0023] Figure 11 is a bar graph depicting changes in CYP7A1 expression (Relative mRNA express! on / Actin) in HCC cells (HuH-7) treated with 60 nM of Compound 1 for 24 hours in combination with increasing concentrations of Fenofibrate (2 uM, 5 uM, and 10 uM) for 24 hours. In HuH-7 cells, combination with Fenofibrate resulted in reversal of CYP7A1 expression increase caused by Compound 1.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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- 5 - 4886-1054-6423.5120039.000207\4936-3978-3555.1disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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 two endpoints. For example, the expression “from about 2 to about 4” also discloses the range- 6 - 4886-1054-6423.5120039.000207\4936-3978-3555.1“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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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-FGFR3 therapy.

[0037] The terms “effective amount” and “therapeutically effective amount” are used interchangeably herein and refer to an amount of the drug effective to achieve a- 7 -4886-1054-6423.5120039.000207\4936-3978-3555.1particular biological or therapeutic result such as, but not limited to, amelioration of one or more 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-FGFR3 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.

[0038] 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.

[0039] As used herein, the term “small molecule” refers to a molecule having a molecular weight of less than 1000 gram / mol.Combination Therapies

[0040] Provided are methods of treating a subject in need of an anti-FGFR3 therapy. According to the disclosure, an anti-FGFR3 therapy can be selective against FGFR3 over other FGFRs (for example, selective for FGFR3 over FGFR1, FGFR2, and FGFR4; a selective anti-FGFR3 therapy), can be a dual anti-FGFR3-4 therapy, or can be a pan anti-FGFR1-4 therapy (non-selective for FGFR3 and one or more of FGFR1, FGFR2, and FGFR4, e.g., FGFR1-3 and FGFR1-4). The methods comprise administering to the subject a therapeutically effective amount of a PPAR alpha agonist in combination with the anti-FGFR3 therapy. Also provided are methods of treating a subject comprising administering to the subject a therapeutically effective amount of a PPAR alpha agonist in combination with a means for anti-FGFR3 therapy. Means for anti-FGFR3 therapy are known in the art and include, for example, FGFR3 inhibitors. In some aspects, the means for anti-FGFR3 therapy is an FGFR3 inhibitor that is a selective FGFR3 inhibitor, a dual FGFR3-4 inhibitor, or a pan FGFR1-4 inhibitor.

[0041] In some embodiments, the anti-FGFR3 therapy or the means for anti-FGFR3 therapy an FGFR3 inhibitor. FGFR3 inhibitors include selective FGFR3 inhibitors, dual FGFR3-4 inhibitors, pan FGFR1-4 inhibitors, and combinations thereof. In some aspects, the- 8 -4886-1054-6423.5120039.000207\4936-3978-3555.1FGFR3 inhibitor is a selective FGFR3 inhibitor. According to the disclosure, selective FGFR3 inhibitors inhibit FGFR3 activity more than they inhibit any other FGFR activity. The difference in selectivity of the selective FGFR3 inhibitor will be at least an order of magnitude greater than the activity of the selective FGFR3 inhibitor against any other FGFR (e.g., FGFR1, FGFR2, FGFR4), when tested in assays known to those of ordinary skill in the art.

[0042] In some aspects of the disclosure, the anti FGFR3 therapy or the means for anti-FGFR3 therapy is a dual FGFR3-4 inhibitor. According to the disclosure, dual FGFR3-4 inhibitors inhibit FGFR3 activity and FGFR4 activity more than they inhibit any other FGFR activity. The difference in selectivity of the dual FGFR3-4 inhibitor will be at least an order of magnitude greater than the activity of the dual FGFR3-4 inhibitor against any other FGFR that is not FGFR3 or FGFR4, when tested in assays known to those of ordinary skill in the art. Exemplary dual FGFR3-4 inhibitors are dual FGFR3-4 antagonists that include compounds that can cause inhibition at the receptor (for example, tyrosine kinase inhibitor), degradation of the receptor (protein degraders, e.g., PROTACs), antibodies that directly interact and block receptor-ligand binding, and antibodies that bind and neutralize FGFR3-4 ligands (e.g., anti-FGF 19 antibodies).

[0043] In some aspects of the disclosure, the anti FGFR3 therapy or the means for anti-FGFR3 therapy is a pan FGFR1-4 inhibitor. According to the disclosure, pan FGFR1-4 inhibitors inhibit FGFR3 activity and one or more of FGFR1, FGFR2, and FGFR4.Exemplary pan FGFR1-4 inhibitors are FGFR1-4 antagonists that include compounds that can cause inhibition at the receptor (for example, tyrosine kinase inhibitor), degradation of the receptor (protein degraders, e.g., PROTACs), antibodies that directly interact and block receptor-ligand binding, and antibodies that bind and neutralize FGFR1-4 ligands (e.g., anti-FGF 19 antibodies).

[0044] The FGFR3 inhibitor can comprise a direct FGFR3 inhibitor, for example, a direct, selective FGFR3 inhibitor, a dual FGFR3-4 inhibitor, or a pan FGFR1-4 inhibitor. The direct FGFR3 inhibitor can contact, interact with, bind to, or otherwise alter (e.g., reduce) the level of FGFR3 activity directly. In some embodiments, anti-FGFR3 therapy or the means for an anti-FGFR3 therapy can be a direct FGFR3 inhibitor, for example, a direct, selective FGFR3 inhibitor, a dual FGFR3-4 inhibitor, or a pan FGFR1-4 inhibitor. Examples of direct FGFR3 inhibitors include small molecule FGFR3 inhibitors, small molecule selective FGFR3- 9 - 4886-1054-6423.5120039.000207\4936-3978-3555.1inhibitors, dual FGFR3-4 inhibitors, pan FGFR1-4 inhibitors, or anti-FGFR3 antibodies or binding fragments thereof.

[0045] The dual FGFR3-4 inhibitor can comprise a direct dual FGFR3-4 inhibitor. The direct dual FGFR3-4 inhibitor can contact, interact with, bind to, or otherwise alter (e.g., reduce) the level of FGFR3 and FGFR4 activity directly. In some embodiments, anti -dual FGFR3-4 therapy or the means for an anti-dual FGFR3-4 therapy can be a direct dual FGFR3-4 inhibitor. Examples of direct dual FGFR3-4 inhibitors include small molecule dual-FGFR3-4 inhibitors, or anti-FGFR3-4 antibodies or binding fragments thereof.

[0046] The FGFR1-4 inhibitor can comprise a direct pan FGFR1-4 inhibitor. The direct pan FGFR1-4 inhibitor can contact, interact with, bind to, or otherwise alter (e.g., reduce) the level of FGFR1-4 activity directly. In some embodiments, anti-pan FGFR1-4 therapy or the means for an anti-pan FGFR1-4 therapy can be a direct pan FGR1-4 inhibitor. Examples of direct pan FGFR1-4 inhibitors include small molecule pan FGFR1-4 inhibitors, or anti-FGFRl-4 antibodies or binding fragments thereof.

[0047] FGFR3 inhibitors can comprise indirect FGFR3 inhibitors, for example, indirect, selective FGFR3 inhibitors, indirect dual FGFR3-4 inhibitors, and indirect pan FGFR1-4 inhibitors. An indirect FGFR3 inhibitor does not contact, interact with, bind to, or otherwise alter (e.g., reduce) the level of FGFR3 activity directly. The indirect FGFR3 inhibitor inhibits the FGFR3 function indirectly, such as by contacting, interacting with, or binding to FGF19, klotho beta (also referred to herein as klotho-P, KLP, or KLB), or other molecules in the FGFR3 signaling pathway. The indirect FGFR3 inhibitor can comprise an FGFR3 signaling inhibitor, for example, a selective FGFR3 signaling inhibitor. An exemplary FGFR3 signaling inhibitor is an inhibitor that inhibits or reduces the levels of a signaling molecule operating upstream or downstream of FGFR3 in the FGFR3 signaling pathway. In some embodiments, anti-FGFR3 therapy or the means for an anti-FGFR3 therapy can be an indirect FGFR3 inhibitor. Examples of indirect FGFR3 inhibitors include anti-FGF19 antibodies or binding fragments thereof and anti-klotho beta antibodies or binding fragments thereof.

[0048] In some aspects of the disclosure, the anti-FGFR3 therapy or means for anti-FGFR3 therapy is an anti-FGF19 antibody. Anti-FGF19 antibodies are described at least in U.S. Patent Nos: 7,678,373; 8,293,241; 8,409,579; and 9,266,955. Anti-klotho beta antibodies are described at least in U.S. Application Publication No: US / 2022 / 0089780.- 10 - 4886-1054-6423.5120039.000207\4936-3978-3555.1Other examples of anti-klotho beta antibodies or binding fragments thereof include antihuman klotho beta antibodies or their binding fragments obtained from Novus Biologicals (catalog numbers: NBP3-09315; MAB58891; MAB5889; and AF5889), from Affinity Biosciences (catalog number DF14991), from Thermo Fisher Scientific (catalog numbers: PA5-119246 and PA5-44023) or from R&D Systems (catalog numbers: AF2619 and MAB3738).

[0049] FGFR3 inhibitors can comprise indirect dual FGFR3-4 inhibitors. An indirect dual FGFR3-4 inhibitor does not contact, interact with, bind to, or otherwise alter (e.g., reduce) the level of FGFR3-4 activity directly. The indirect dual FGFR3-4 inhibitor inhibits the FGFR3-4 function indirectly, such as by contacting, interacting with, or binding to FGF19, klotho beta (also referred to herein as klotho-P, KLp, or KLB), or other molecules in the FGFR3-4 signaling pathway. The indirect dual FGFR3-4 inhibitor can comprise a dual FGFR3-4 signaling inhibitor. An exemplary dual FGFR3-4 signaling inhibitor is an inhibitor that inhibits or reduces the levels of a signaling molecule operating upstream or downstream of FGFR3 and FGFR4 in the FGFR3 and FGFR4 signaling pathways. In some embodiments, anti-dual FGFR3-4 therapy or the means for an anti -dual FGFR3-4 therapy can be an indirect dual FGFR3-4 inhibitor.

[0050] FGFR3 inhibitors can comprise indirect pan FGFR1-4 inhibitors. An indirect pan FGFR1-4 inhibitor does not contact, interact with, bind to, or otherwise alter (e.g., reduce) the level of FGFR1-4 activity directly. The indirect pan FGFR1-4 inhibitor inhibits the FGFR1-4 function indirectly, such as by contacting, interacting with, or binding to FGF19, klotho beta (also referred to herein as klotho-P, KLp, or KLB), or other molecules in the FGFR1-4 signaling pathway. The indirect pan FGFR1-4 inhibitor can comprise a pan FGFR1-4 signaling inhibitor. An exemplary pan FGFRl-4signaling inhibitor is an inhibitor that inhibits or reduces the levels of a signaling molecule operating upstream or downstream of FGFR1-4 in the FGR1-4 signaling pathways. In some embodiments, anti- pan FGFR1-4therapy or the means for an anti- pan FGFRl-4therapy can be an indirect pan FGFR1-4 inhibitor.

[0051] In some embodiments, the anti-FGFR3 therapy or the means for anti-FGFR3 therapy is a direct FGFR3 inhibitor (e.g., a direct, selective FGFR3 inhibitor) and / or an indirect FGFR3 inhibitor (e.g., an indirect, selective FGFR3 inhibitor). The FGFR3 inhibitor can comprise a small molecule, anFGFR3 inhibitor, a selective FGFR3 inhibitor, an anti-- 11 - 4886-1054-6423.5120039.000207\4936-3978-3555.1FGFR3 antibody or binding fragment thereof, or a selective anti-FGFR3 antibody or a binding fragment thereof. The FGFR3 signaling inhibitor can comprise a small molecule, an FGFR3 inhibitor, a selective FGFR3 inhibitor, an anti-FGFR3 antibody or binding fragment thereof, a selective anti-FGFR3 antibody or a binding fragment thereof, an anti-FGF19 antibody or a binding fragment thereof, or an anti-klotho beta antibody or a binding fragment thereof. The small molecule FGFR3 inhibitor includes, but is not limited to compounds described in WO 2024 / 137587, W02024 / 006897, and WO2022 / 147246, incorporated herein in their entireties, Compound 1, LOXO, or a combination thereof.

[0052] Compound l is a selective FGFR3 small molecule inhibitor and it is represented by the following formula. Pharmaceutically acceptable salts of Compound 1 are included within the scope of this disclosure:Compound 1

[0053] LOXO is represented by the following formula. Pharmaceutically acceptable salts of LOXO are also included within the scope of this disclosure:LOXO

[0054] In some embodiments, the anti-FGFR3 therapy or the means for anti-FGFR3 therapy is a direct dual FGFR3-4 inhibitor and / or an indirect dual FGFR3-4 inhibitor. The dual FGFR3-4 inhibitor can comprise a small molecule dual FGFR3-4 inhibitor, or an antidual FGFR3-4 antibody or a binding fragment thereof. The dual FGFR3-4 signaling inhibitor- 12 - 4886-1054-6423.5120039.000207\4936-3978-3555.1can comprise a small molecule dual FGFR3-4 inhibitor, an anti-FGFR3-4 antibody or a binding fragment thereof, an anti -F GF 19 antibody or a binding fragment thereof, or an anti-klotho beta antibody or a binding fragment thereof. The small molecule dual FGFR3-4 inhibitor includes, but is not limited to compounds described in WO 2024 / 137587, W02024 / 006897, and WO2022 / 147246, incorporated herein in their entireties The small molecule dual FGFR3-4 inhibitor includes, but is not limited to, Compound 2, Compound 3, or Compound 4.

[0055] Compound 2 and Compound 3 are small molecule dual FGFR3-4 inhibitors represented by the following formulas. Pharmaceutically acceptable salts of Compound 2 and Compound 3 are included within the scope of this disclosure:Compound 3

[0056] Compound 4 is also a dual FGFR3-4 small molecule inhibitor that is structurally related to Compounds 2 and 3 and exhibits similar FGFR3-4 binding activity in conventional assays.

[0057] The FGFR3 inhibitor can also comprise a pan FGFR1-4 small molecule inhibitor. Pan FGFR1-4 inhibitors are known in the art and include futibatinib, LY2874455, KIN-3248, AZD4547, and erdafitinib.- 13 - 4886-1054-6423.5120039.000207\4936-3978-3555.1

[0058] The FGFR3 inhibitor can comprise an anti-FGFR3 antibody, for example, aselective anti-FGFR3 antibody or a binding fragment thereof. The anti-FGFR3 antibody can comprise the B-701 antibody (vofatamab) or the binding fragment thereof, MFGR1877S or the binding fragment thereof, or R3Mab or the binding fragment thereof. In other aspects, the FGFR3 inhibitor can comprise an anti-FGFR3-4 antibody or a binding fragment thereof.

[0059] The FGFR3 inhibitor (e.g., a selective FGFR3 inhibitor) or the dual FGFR3-4 inhibitor or the pan FGFR1-4 inhibitor can comprise an antibody-drug conjugate, for example LY3076226.

[0060] The FGFR3 signaling inhibitor can comprise an anti-FGF19 antibody or a binding fragment thereof. The anti-FGF19 antibody can comprise an FGF19 neutralizing antibody.

[0061] The anti-FGFR3 therapy or means for anti-FGFR3 therapy can comprise a combination of an FGFR3 inhibitor and a second chemotherapeutic agent. In some aspects, the anti-FGFR3 therapy or means for anti-FGFR3 therapy can comprise a combination of a selective FGFR3 inhibitor and a second chemotherapeutic agent. In other aspects, the anti-FGFR3 therapy or means for anti-FGFR3 therapy can comprise a combination of a dual FGFR3-4 inhibitor and a second chemotherapeutic agent. In other aspects, the anti-FGFR3 therapy or means for anti-FGFR3 therapy can comprise a combination of a pan FGFR1-4 inhibitor and a second chemotherapeutic agent. In other aspects, the anti-FGFR3 therapy or means for anti-FGFR3 therapy can comprise a combination of a selective FGFR3 inhibitor, a dual FGFR3-4 inhibitor, and a second chemotherapeutic agent. In other aspects, the anti-FGFR3 therapy or means for anti-FGFR3 therapy can comprise a combination of a selective FGFR3 inhibitor, a pan FGFR1-4 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).

[0062] 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- 14 - 4886-1054-6423.5120039.000207\4936-3978-3555.1prodrug, which after absorption is hydrolyzed by tissue and plasma esterases to its principal active metabolite fenofibric acid. Elafibranor is a dual PPARa / 6 agonist. The chemical structures of fenofibrate, fenofibric acid,, ciprofibrate, gemfibrozil, bezafibrate, elafibranor, and pemafibrate are shown below:Fenofibrate CiprofibrateElafibranor Pemafibrate4886-1054-6423.5120039.000207\4936-3978-3555.1

[0063] The disclosed methods can comprise administering the FGFR 3 inhibitor, e.g., a selective FGFR3, dual FGFR3-4, or pan-FGFRl-4 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 FGFR3 inhibitor, e.g., a selective FGFR3,dual FGFR3-4, or pan FGFR1-4 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 theFGFR3 inhibitor, e.g., a selective FGFR3,dual FGFR3-4, or pan FGFR1-4 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.

[0064] The disclosed methods can comprise administering the FGFR3 inhibitor, e.g., a selective FGFR3, dual FGFR3-4, or pan FGFR1-4 inhibitor at an amount of between about 0.01 mg / kg and about 50 mg / kg daily. The FGFR3 inhibitor, e.g., a selective FGFR3, dual FGFR3-4, or pan FGFR1-4 inhibitor can be administered in one or more doses. For example, the disclosed methods can comprise administering the FGFR3 inhibitor, e.g., a selective FGFR3, dual FGFR3-4, or pan FGFR1-4 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, 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.

[0065] In some aspects, the disclosed methods comprise administering the FGFR3 inhibitor, e.g., a selective FGFR3, dual FGFR3-4, or pan FGFR 1-4 inhibitor, orally to the subject in a fed or a fasted state.- 16 - 4886-1054-6423.5120039.000207\4936-3978-3555.1

[0066] In some aspects, the disclosed methods comprise administering the FGFR3 inhibitor, e.g., a selective FGFR3, dual FGFR3-4, or pan FGFR1-4 inhibitor, by injection. In some aspects, the disclosed methods comprise administering the FGFR3 inhibitor, e.g., a selective FGFR3, dual FGFR3-4, or pan FGFR1-4 inhibitor by intravenous injection.

[0067] 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 and about 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..

[0068] 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.

[0069] In some embodiments, the methods further comprising administering to the subject a bile acid sequestrant. In some embodiments, the bile acid sequestrant is- 17 - 4886-1054-6423.5120039.000207\4936-3978-3555.1cholestyramine, colestipol, colesevelam, or a combination thereof. In some embodiments, the bile acid sequestrant is cholestyramine.

[0070] The disclosed methods can comprise administering the PPAR alpha agonist prior to, simultaneously with, or following administration of the anti-FGFR3 therapy, for example a selective FGFR3 inhibitor. 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-FGFR3 therapy, for example, a selective FGFR3 inhibitor.

[0071] The disclosed methods can comprise administering the PPAR alpha agonist prior to, simultaneously with, or following administration of the anti-dual FGFR3-4 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-dual FGFR3-4 therapy.

[0072] The disclosed methods can comprise administering the PPAR alpha agonist prior to, simultaneously with, or following administration of the anti-pan FGFR1-4 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-pan FGFR1-4 therapy.

[0073] Also disclosed are methods treating a subject in need of an anti-FGFR3 therapy comprising administering to the subject the anti-FGFR3 therapy, for example, a selective FGFR3 inhibitor, 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-FGFR3 therapy, for example a selective FGFR3 inhibitor.- 18 - 4886-1054-6423.5120039.000207\4936-3978-3555.1

[0074] Also disclosed are methods treating a subject in need of an anti-FGFR3-4 therapy comprising administering to the subject the anti-dual FGFR3-4 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 antidual FGFR3-4 therapy.

[0075] Also disclosed are methods treating a subject in need of an anti-pan FGFR1- 4 therapy comprising administering to the subject the anti-pan FGFR1-4 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 antipan FGFR1-4 therapy.

[0076] Examples of combination therapies are presented in Tables 1 and 2.Table 1. Representative combination therapies with small molecule FGFR3 inhibitors and PPAR alpha agonist.- 19 - 4886-1054-6423.5120039.000207\4936-3978-3555.1- 20 - 4886-1054-6423.5120039.000207\4936-3978-3555.1“+” indicates a combination therapy of the small molecule FGFR3 / FGFR1-3 / FGFR1-4 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 FGFR3 -selective / FGFR1-3 / FGFR1-4 inhibitor and the PPAR alpha agonistTable 2. Combination therapies with a small molecule FGFR3 inhibitor, PPAR alpha agonist, and a bile acid sequestrant.- 21 - 4886-1054-6423.5120039.000207\4936-3978-3555.1- 22 - 4886-1054-6423.5120039.000207\4936-3978-3555.1- 23 - 4886-1054-6423.5120039.000207\4936-3978-3555.1“+” indicates a combination therapy of the small molecule FGFR3 / FGFR1-3 / FGFR1-4 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 FGFR3 -selective / FGFR1-3 / FGFR1-4 inhibitor and the PPAR alpha agonist

[0077] The disclosed methods are administered to a subject in need of treatment for proliferative disease, metabolic disease, cardiovascular disease, or kidney disease. For example, the disclosed methods can be administered to a subject in need of treatment for- 24 - 4886-1054-6423.5120039.000207\4936-3978-3555.1systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), or muenke syndrome. The subject can be in need of treatment for a proliferative disease that is an FGFR3-associated cancer. An “FGFR3 -associated cancer” refers to cancers associated with or having a dysregulation of the FGFR3 gene, the FGFR3 kinase protein, or expression or activity, or level of any of the same. Non-limiting examples of FGFR3-associated cancer are described herein. As used herein an “FGFR3 -associated cancer” includes but is not limited to breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e.g. non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer and smallcell lung cancer), urothelial cancer (urothelial carcinomas, including upper tract, renal / urothelial / urethral cancer), bladder cancer (e.g. urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e.g. urothelial upper tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g. cutaneous melanoma), head and neck cancer (e.g. oral cancer, head and neck squamous cell carcinoma), thyroid cancer, renal cancer (e.g. renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer. In some aspects, the cancer is breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small -cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small-cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, renal cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, or testicular cancer. In other aspects, the cancer is breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small -cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small-cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer upper tract cancer, urothelial upper tract cancer, or glioblastoma. In other aspects, the cancer is bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer and muscle invasive bladder cancer. In other aspects, the cacer is bladder cancer [including non-muscle invasive bladder cancer (NMIBC) and muscle-- 25 - 4886-1054-6423.5120039.000207\4936-3978-3555.1invasive bladder cancers (MIBC)], urothelial carcinomas [including upper tract, renal / urothelial / urethral cancer], cervival cancer, multiple myeloma, oral cancers, head and neck squamous cell carcinoma, non-small cell lung cancer.

[0078] The disclosed methods can provide one or more of: a reduction in the number of anti-FGFR3 therapy-related adverse events, a reduction in the anti-FGFR3 therapy-related adverse event frequency, a reduction in the anti-FGFR3 therapy-related adverse event severity, an increase in duration of the anti-FGFR3 therapy, an increase in daily dose of the anti-FGFR3 therapy, and an increase in patient compliance of the subject to the anti-FGFR3 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.

[0079] The disclosed methods can provide one or more of: a reduction in the number of anti-dual FGFR3-4 therapy-related adverse events, a reduction in the anti-dual FGFR3-4 therapy-related adverse event frequency, a reduction in the anti-dual FGFR3-4 therapy-related adverse event severity, an increase in duration of the anti -dual FGFR3-4 therapy, an increase in daily dose of the anti-dual FGFR3-4 therapy, and an increase in patient compliance of the subject to the anti -dual FGFR3-4 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.

[0080] The disclosed methods can provide one or more of: a reduction in the number of anti-pan FGFR1-4 therapy-related adverse events, a reduction in the anti-pan FGFR1-4 therapy-related adverse event frequency, a reduction in the anti-pan FGFR1-4 therapy-related adverse event severity, an increase in duration of the anti-pan FGFR1-4 therapy, an increase in daily dose of the anti -pan FGFR1-4 therapy, and an increase in patient compliance of the subject to the anti-pan FGFR1-4 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.- 26 -4886-1054-6423.5120039.000207\4936-3978-3555.1

[0081] 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-FGFR3 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-FGFR3 therapy without the PPAR alpha agonist.Compositions

[0082] Also disclosed are compositions comprising an FGFR3 inhibitor, a PPAR alpha agonist, and a pharmaceutically acceptable excipient. In some aspects, the composition comprise a selective FGFR3 inhibitor, a PPAR alpha agonist, and a pharmaceutically acceptable excipient. The compositions can comprise the FGFR3 inhibitor and the PPAR alpha agonist as a single unit dosage form. In some aspects, the selective FGFR3 inhibitor and the PPAR alpha agonist as a single unit dosage form. Also disclosed are compositions comprising an FGFR3-4 inhibitor, a PPAR alpha agonist, and a pharmaceutically acceptable excipient. The compositions can comprise the FGFR3-4 inhibitor and the PPAR alpha agonist as a single unit dosage form.

[0083] Also disclosed are compositions comprising an FGFR3 inhibitor, a PPAR alpha agonist, a bile acid sequestrant, and a pharmaceutically acceptable excipient. In some aspects, the compositions comprise a selective FGFR3 inhibitor, a PPAR alpha agonist, a bile acid sequestrant, and a pharmaceutically acceptable excipient. The disclosed compositions can comprise the FGFR3 inhibitor, the PPAR alpha agonist, the bile acid sequestrant, and the pharmaceutically acceptable excipient in a single unit dosage form. In some aspect, he disclosed compositions comprise the selective FGFR3 inhibitor, the PPAR alpha agonist, the4886-1054-6423.5120039.000207\4936-3978-3555.1bile acid sequestrant, and the pharmaceutically acceptable excipient in a single unit dosage form. Also disclosed are compositions comprising a dual FGFR3-4 inhibitor, a PPAR alpha agonist, a bile acid sequestrant, and a pharmaceutically acceptable excipient. The disclosed compositions can comprise the dual FGFR3-4 inhibitor, the PPAR alpha agonist, the bile acid sequestrant, and the pharmaceutically acceptable excipient in a single unit dosage form. Also disclosed are compositions comprising a pan FGFR1-4 inhibitor, a PPAR alpha agonist, a bile acid sequestrant, and a pharmaceutically acceptable excipient. The disclosed compositions can comprise the FGFR1-4 inhibitor, the PPAR alpha agonist, the bile acid sequestrant, and the pharmaceutically acceptable excipient in a single unit dosage form.

[0084] In some embodiments, the FGFR3 inhibitor in the compositions is a small molecule FGFR3 inhibitor. In some embodiments, the small molecule FGFR3 inhibitor is a compound described in WO 2024 / 137587, W02024 / 006897, and WO2022 / 147246, incorporated herein in their entireties, Compound 1, LOXO, or a combination thereof or a combination thereof.

[0085] In some embodiments, the FGFR3 inhibitor in the compositions is an anti-FGFR3 antibody or a binding fragment thereof, or an anti-FGF19 antibody or a binding fragment thereof. In some embodiments, the anti-FGFR3 antibody is B-701 antibody or the binding fragment thereof, MFGR1877S or the binding fragment thereof, or R3Mab or the binding fragment thereof.

[0086] 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

[0087] Also provided are kits comprising an FGFR3 inhibitor and a PPAR alpha agonist. The kits can comprise the FGFR3 inhibitor (e.g., a selective FGFR3 inhibitor or an FGFR3-4 inhibitor) as a single unit dosage form and the PPAR alpha as a single unit dosage form. The kits can comprise the FGFR3 inhibitor (e.g., a selective FGFR3 inhibitor or an FGFR3-4 inhibitor) and the PPAR alpha on the same blister pack. The kits can further comprise a bile acid sequestrant.

[0088] The kits can comprise instructions for use and a dosing chart with dosing and regimen recommendations.- 28 - 4886-1054-6423.5120039.000207\4936-3978-3555.1EXAMPLES

[0089] Selective FGFR3, dualFGFR3-4, and pan FGFR1-4 inhibitors are under development. Selective FGFR3 inhibitors are under development for treatment of solid tumors including bladder cancer, and are under development for treatment of skeletal disorders including Achondroplasia and Hypochondroplasia. The dysregulation of bile acids due to FGFR3 or FGFR3-4 inhibition can complicate or even limit the anti-FGFR3 (or FGFR3-4) therapy in subjects.

[0090] FGFR3, in collaboration with FGFR4, regulates bile acid and cholesterol homeostasis through FGF19 signaling. Activation of FGFR3 and FGFR4 by FGF19 suppresses both bile acid synthesis and HDL biosynthesis. See, e.g., Figure 1.

[0091] Example 1. Changes in CYP7A1 expression (Relative mRNA expression / Actin) in Hep3B cells were studied. Hep3B cells were treated for 24 hours with 40 nM of selective FGFR4 inhibitors (BLU-554 and FGF-401), FGFR1-3 inhibitor tasurgratinib, Compound 1, Compound 2, Compound 3, and Compound 4. After 24 hours, mRNA was then isolated and CYP7A1 expression was measured using TaqMan™ qPCR Assays (CYP7A1 assay ID: Hs00167982_ml, ACTNB assay ID: Hs99999903_ml). Data show that dual FGFR3-4 inhibitors (Compounds 2, 3, and 4) caused significantly higher CYP7A1 expression levels as compared to the upregulated CYP7A1 levels following either selective FGFR4 inhibitors (FGF-401 and BLU-554) or FGFR3 inhibitors (Tasurgratinib and compound 1) in Hep3B cells. CYP7A1 expression was much higher in the presence of dual 4 / 3 inhibitors suggesting a synergistic effect of FGFR4 and FGFR3 inhibition in Hep3B cells. See Figure 2.

[0092] Example 2. Changes in CYP7A1 expression (Relative mRNA expression / Actin) in HuH-7 cells were studied. HuH-7 cells were treated for 24 hours with 40 nM of selective FGFR4 inhibitors (BLU-554 and FGF-401), FGFR1-3 inhibitor tasurgratinib, Compound 1, Compound 2, Compound 3, and Compound 4. After 24 hours, mRNA was then isolated and CYP7A1 expression was measured using TaqMan™ qPCR Assays (CYP7A1 assay ID: Hs00167982_ml, ACTNB assay ID: Hs99999903_ml). Data show that dual FGFR3-4 inhibitors (Compounds 2, 3, and 4) caused significantly higher CYP7A1 expression levels as compared to the upregulated CYP7A1 levels following either selective FGFR4 inhibitors (FGF-401 and BLU-554) or FGFR3 inhibitors (Tasurgratinib and Compound 1) in- 29 - 4886-1054-6423.5120039.000207\4936-3978-3555.1HuH-7 cells. CYP7A1 expression was much higher in the presence of dual 4 / 3 inhibitors suggesting a synergistic effect of FGFR4 and FGFR3 inhibition in HuH-7 cells. See Figure 3.

[0093] Example 3. Changes in APOA1 expression (Relative mRNA expression / Actin) in Hep3B cells were studied. Hep3B cells, treated for 24 hours with 40 nM of selective FGFR4 inhibitors (BLU-554 and FGF-401), FGFR1-3 inhibitor tasurgratinib, Compound 1, Compound 2, Compound 3, and Compound 4. After 24 hours, mRNA was then isolated and APOA1 expression was measured using TaqMan™ qPCR Assays (APOA1 assay ID: Hs00163641_m, ACTNB assay ID: Hs99999903_ml). Data show that dual FGFR3-4 inhibitors (Compounds 2, 3, and 4) caused significantly higher APOA-1 expression levels as compared to the upregulated APOA-1 levels following either selective FGFR4 inhibitors (FGF-401 and BLU-554) or selective FGFR3 inhibitors (Tasurgratinib and compound 1) in Hep3B cells. See Figure 4.

[0094] Example 4. Changes in APOA1 expression (Relative mRNA expression / Actin) in HuH-7 cells were studied. HuH-7 cells, treated for 24 hours with 40 nM of selective FGFR4 inhibitors (BLU-554 and FGF-401), FGFR1-3 inhibitor tasurgratinib, Compound 1, Compound 2, Compound 3, and Compound 4. After 24 hours, mRNA was then isolated and APOA1 expression was measured using TaqMan™ qPCR Assays (APOA1 assay ID: Hs00163641_m, ACTNB assay ID: Hs99999903_ml). Data show that dual FGFR3-4 inhibitors (Compounds 2, 3, and 4) caused significantly higher APOA-1 expression levels as compared to the upregulated APOA-1 levels following either selective FGFR4 inhibitors (FGF-401 and BLU-554) or selective FGFR3 inhibitors (Tasurgratinib and compound 1) in HuH-7 cells. See Figure 5.

[0095] Example 5. Changes in CYP7A1 expression (Relative mRNA expression / Actin) in Hep3B cells were studied. Hep3B cells were treated with increasing concentrations of Compound 1 for 24 hours. Treatment of Hep3B cells with Compound 1 (20 nM [+], 40 nM [++], and 60 nM [+++]) resulted in increased CYP7A1 expression in a dose dependent manner, as measured using qPCR. See Figure 6.

[0096] Example 6. Changes in CYP7A1 expression (Relative mRNA expression / Actin) in HuH-7 cells were studied. HuH-7 cells were treated with increasing concentrations ofCompound 1 for 24 hours. Treatment of HuH-7 cells with Compound 1 (20 nM [+], 40 nM [++], and 60 nM [+++]) resulted in increased CYP7A1 expression in a dose dependent manner, as measured using qPCR. See Figure 7.- 30 -4886-1054-6423.5120039.000207\4936-3978-3555.1

[0097] Example 7. Changes in APOA1 expression (Relative mRNA expression / Actin) in Hep3B cells was studied. Hep3B cells were treated with increasing concentrations of Compound 1 for 24 hours. Treatment of Hep3B cells with Compound 1 (20 nM [+], 40 nM [++], and 60 nM [+++]) resulted in increased APOA1 expression in a dose dependent manner, as measured using qPCR. See Figure 8.

[0098] Example 8. Changes in APOA1 expression (Relative mRNA expression / Actin) in HuH-7 cells was studied. HuH-7 cells were treated with increasing concentrations of Compound 1 for 24 hours. Treatment of HuH-7 cells with Compound 1 (20 nM [+], 40 nM [++], and 60 nM [+++]) resulted in increased APOA1 expression in a dose dependent manner, as measured using qPCR. See Figure 9.

[0099] Example 9. Changes in CYP7A1 expression (Relative mRNA expression / Actin) in Hep3B cells was studied. Hep3B cells were treated with 60 nM of Compound 1 for 24 hours in combination with increasing concentrations of Fenofibrate (2 uM [+], 5 uM [++], and 10 uM [+++]) for 24 hours. Combination with Fenofibrate resulted in reversal of CYP7A1 expression increase caused by Compound 1. See Figure 10.

[0100] Example 10. Changes in CYP7A1 expression (Relative mRNA expression / Actin) in HuH-7 cells was studied. HuH-7 cells were treated with 60 nM of Compound 1 for 24 hours in combination with increasing concentrations of Fenofibrate (2 uM [+], 5 uM [++], and 10 uM [+++]) for 24 hours. Combination with Fenofibrate resulted in reversal of CYP7A1 expression increase caused by Compound 1. See Figure 11.

[0101] Example 11. Changes in CYP7A1 expression (Relative mRNA expression / Actin) in Hep3B cells is studied. Hep3B cells are treated with increasing concentrations of LOXO for 24 hours. Treatment of Hep3B cells with LOXO (20 nM [+], 40 nM [++], and 60 nM [+++]) results in increased CYP7A1 expression, as measured using qPCR.

[0102] Example 12. Changes in CYP7A1 expression (Relative mRNA expression / Actin) in HuH-7 cells is studied. HuH-7 cells are treated with increasing concentrations of LOXO for 24 hours. Treatment of HuH-7 cells with LOXO (20 nM [+], 40 nM [++], and 60 nM [+++]) results in increased CYP7A1 expression, as measured using qPCR.

[0103] Example 13. Changes in APOA1 expression (Relative mRNA expression / Actin) in Hep3B cells is studied. Hep3B cells are treated with increasing- 31 -4886-1054-6423.5120039.000207\4936-3978-3555.1concentrations of LOXO for 24 hours. Treatment of Hep3B cells with LOXO (20 nM [+], 40 nM [++], and 60 nM [+++]) results in increased APOA1 expression, as measured using qPCR.

[0104] Example 14. Changes in APOA1 expression (Relative mRNA expression / Actin) in HuH-7 cells is studied. HuH-7 cells are treated with increasing concentrations of LOXO for 24 hours. Treatment of HuH-7 cells with LOXO (20 nM [+], 40 nM [++], and 60 nM [+++]) results in increased APOA1 expression, as measured using qPCR.

[0105] Example 15. Changes in CYP7A1 expression (Relative mRNA expression / Actin) in Hep3B cells is studied. Hep3B cells are treated with 60 nM of LOXO for 24 hours in combination with increasing concentrations of Fenofibrate (2 uM [+], 5 uM [++], and 10 uM [+++]) for 24 hours. Combination with Fenofibrate results in reversal of CYP7A1 expression increase by LOXO.

[0106] Example 16. Changes in CYP7A1 expression (Relative mRNA expression / Actin) in HuH-7 cells is studied. HuH-7 cells are treated with 60 nM of LOXO for 24 hours in combination with increasing concentrations of Fenofibrate (2 uM [+], 5 uM [++], and 10 uM [+++]) for 24 hours. Combination with Fenofibrate results in reversal of CYP7A1 expression increase by LOXO.- 32 - 4886-1054-6423.5120039.000207\4936-3978-3555.1

Claims

What is claimed:

1. A method of treating a subject in need of an anti-fibroblast growth factor receptor 3 (anti- FGFR3) therapy comprising administering to the subject a therapeutically effective amount of a peroxisome proliferator-activated receptor (PPAR) alpha agonist in combination with the anti-FGFR3 therapy.

2. The method of claim 1, wherein the anti-FGFR3 therapy is an FGFR3 inhibitor comprising a small molecule selective FGFR3 inhibitor, a selective anti-FGFR3 antibody or a binding fragment thereof, an anti-FGF19 antibody or a binding fragment thereof, or an anti-klotho beta antibody or a binding fragment thereof.

3. The method of claim 1, wherein the anti-FGFR3 therapy is a dual FGFR3-4 inhibitor comprising a small molecule dual FGFR3-4 inhibitor, an anti -dual FGFR3-4 antibody or a binding fragment thereof, an anti-FGF19 antibody or a binding fragment thereof, or an anti-klotho beta antibody or a binding fragment thereof.

4. The method of claim 1, wherein the anti-FGFR3 therapy is a pan FGFR1-4 inhibitor comprising a small molecule pan FGFR1-4 inhibitor, an anti-pan FGFR1-4 antibody or a binding fragment thereof, an anti-FGF19 antibody or a binding fragment thereof, or an anti-klotho beta antibody or a binding fragment thereof5. The method of claim 2 or claim 3 or claim 4, wherein the anti-FGFR3 therapy is Compound 1, Compound 2, Compound 3, or a combination thereof.

6. The method of claim 2 or claim 3 or claim 4, wherein the anti-FGFR3 antibody is a humanized anti-FGFR3 antibody or a binding fragment thereof.

7. The method of claim 6, wherein the humanized anti-FGFR3 antibody is B-701 antibody (vofatamab) or the binding fragment thereof, MFGR1877S or the binding fragment thereof, or R3Mab or the binding fragment thereof.- 33 - 4886-1054-6423.5120039.000207\4936-3978-3555.

18. The method of any one of the preceding claims, wherein the anti-FGFR3 therapy comprises a combination of a selective FGFR3 inhibitor and a second chemotherapeutic agent.

9. The method of any one of claims 1-7, wherein the anti-FGFR3 therapy comprises a combination of a FGFR3-4 inhibitor and a second chemotherapeutic agent.

10. The method of claim 8 or claim 9, wherein the second chemotherapeutic agent is an immune checkpoint inhibitor.

11. The method of claim 10, wherein the immune checkpoint inhibitor is an antibody or a binding fragment of an antibody.

12. The method of claim 11, 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).

13. The method of any one of the preceding claims, wherein the PPAR-alpha agonist is a small molecule.

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

15. The method of any one of claims 2-14, wherein the selective FGFR3 inhibitor or the FGFR3-4 inhibitor is administered at a dose of between about 0.5 mg and about 3000 mg daily.

16. The method of any one of claims 2-14, wherein the selective FGFR3 inhibitor or the FGFR3-4 inhibitor is administered at a dose of between about 0.01 mg / kg and about 50 mg / kg daily.- 34 - 4886-1054-6423.5120039.000207\4936-3978-3555.

117. The method of any one of claims 2-16, wherein the selective FGFR3 inhibitor or the FGFR3-4 inhibitor is administered to the subject in a fed or a fasted state orally or by an injection.

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

19. The method of any one of claims 1-17, wherein the PPAR alpha agonist is administered at a dose of about 0.001 mg / kg and about 50 mg / kg daily.

20. The method of any one of claims of the preceding claims, further comprising administration to the subject a bile acid sequestrant.

21. The method of claim 20, wherein the bile acid sequestrant is cholestyramine, colestipol, colesevelam, or a combination thereof.

22. The method of claim 20 or 21, wherein the bile acid sequestrant is cholestyramine.

23. The method of any one of the preceding claims, wherein the PPAR alpha agonist is administered prior to, simultaneously with, or following administration of the anti-FGFR3 therapy.

24. The method of any one of claims 20-23, wherein the PPAR alpha agonist and the bile acid sequestrant are administered prior to, simultaneously with, or following administration of the anti-FGFR3 therapy.

25. A method of treating a subject in need of an anti-fibroblast growth factor receptor 3 (anti- FGFR3) therapy comprising administering to the subject an anti-FGFR3 therapy in combination with a therapeutically effective amount of a peroxisome proliferator- activated receptor (PPAR) alpha agonist and a bile acid sequestrant.

26. The method of any one of claims 1-25, wherein the subject is in need of treatment for a skeletal disorder, for example, Achondroplasia or Hypochondroplasia.- 35 - 4886-1054-6423.5120039.000207\4936-3978-3555.

127. The method of any one of claims 1-25, wherein the subject is in need of treatment for a proliferative disease that is an FGFR3 -associated cancer.

28. The method of claim 27, wherein the FGFR3 -associated cancer is breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e.g. non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer and small -cell lung cancer), urothelial cancer, bladder cancer (e.g. urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e.g. urothelial upper tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g. cutaneous melanoma), head and neck cancer (e.g. oral cancer), thyroid cancer, renal cancer (e.g. renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, or testicular cancer.

29. The method of any one of the preceding claims, wherein the method provides one or more of: a reduction in the number of anti-FGFR3 therapy -related adverse events, a reduction in the anti-FGFR3 therapy-related adverse event frequency, a reduction in the anti- FGFR3 therapy-related adverse event severity, an increased duration of the anti-FGFR3 therapy, an increased daily dose of the anti-FGFR3 therapy, and an increases patient compliance of the subject to the anti-FGFR3 therapy.

30. The method of claim 29, 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.

31. The method of any one of the preceding claims, 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.

32. The method of any one of the preceding claims, 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-FGFR3 therapy without the PPAR alpha agonist.- 36 - 4886-1054-6423.5120039.000207\4936-3978-3555.

133. A composition comprising a fibroblast growth factor receptor 3 (FGFR3) inhibitor, a peroximsome proliferator-activated receptor (PPAR) alpha agonist, and a pharmaceutically acceptable excipient.

34. The composition of claim 33, wherein the FGFR3 inhibitor and the PPAR alpha agonist are provided as a single unit dosage form.

35. The composition of claim 33 or 34, wherein the FGFR3 inhibitor comprises a small molecule selective FGFR3 inhibitor, a selective anti-FGFR3 antibody or a binding fragment thereof, an anti-FGF19 antibody or a binding fragment thereof, or an anti-klotho beta antibody or a binding fragment thereof.

36. The composition of claim 33 or 34, wherein the FGFR3 inhibitor comprises a small molecule FGFR3-4 inhibitor, an anti-FGFR3-4 antibody or a binding fragment thereof, an anti-FGF19 antibody or a binding fragment thereof, or an anti-klotho beta antibody or a binding fragment thereof.

37. The composition of any one of claims 35-36, wherein the FGFR3 inhibitor is Compound 1, Compound 2, Compound 3, or a combination thereof.

38. The composition of any one of claims 33-37, wherein the PPAR alpha agonist is fenofibrate, fenofibric acid, ciprofibrate, gemfibrozil, bezafibrate, elafibranor, pemafibrate, or a combination thereof.

39. A composition comprising a fibroblast growth factor receptor 3 (FGFR3) inhibitor, a peroximsome proliferator-activated receptor (PPAR) alpha agonist, a bile acid sequestrant, and a pharmaceutically acceptable excipient.

40. The composition of claim 39, wherein the FGFR3 inhibitor and the PPAR alpha agonist are provided as a single unit dosage form.

41. The composition of claim 39 or 40, wherein the FGFR3 inhibitor comprises a small molecule selective FGFR3 inhibitor, a selective anti-FGFR3 antibody or a binding- 37 - 4886-1054-6423.5120039.000207\4936-3978-3555.1fragment thereof, an anti-FGF19 antibody or a binding fragment thereof, or an anti-klotho beta antibody or a binding fragment thereof.

42. The composition of claim 39 or 40, wherein the FGFR3 inhibitor comprises a small molecule dual FGFR3-4 inhibitor, an anti-FGFR3-4 antibody or a binding fragment thereof, an anti-FGF19 antibody or a binding fragment thereof, or an anti-klotho beta antibody or a binding fragment thereof.

43. The composition of claim 39 or 40, wherein the FGFR3 inhibitor comprises a small molecule pan FGFR1-4 inhibitor, and anti-FGFRl-4 antibody or a binding fragment thereof, an anti-FGF19 antibody or a binding fragment thereof, or an anti-klotho beta antibody or a binding fragment thereof.

44. The composition of any one of claims 41-43, wherein the small molecule FGFR3 inhibitor is Compound 1, Compound 2, Compound 3, or a combination thereof.

45. The composition of any one of claims 39-44, wherein the PPAR alpha agonist is fenofibrate, fenofibric acid, ciprofibrate, gemfibrozil, bezafibrate, elafibranor, pemafibrate, or a combination thereof.

46. The composition of any one of claims 39-45, wherein the bile acid sequestrant is cholestyramine, colestipol, colesevelam, or a combination thereof.

47. The composition of any one of claims 39-46, wherein the bile acid sequestrant is cholestyramine.

48. A kit comprising a fibroblast growth factor receptor 3 (FGFR3) inhibitor and a peroximsome proliferator-activated receptor (PPAR) alpha agonist.

49. The kit of claim 48, wherein the FGFR3 inhibitor is provided as a single unit dosage form and the PPAR alpha is provided as a single unit dosage form.- 38 - 4886-1054-6423.5120039.000207\4936-3978-3555.

150. The kit of claim 48 or 49, wherein the FGFR3 inhibitor comprises a small molecule selective FGFR3 inhibitor, a selective anti-FGFR3 antibody or a binding fragment thereof, an anti-FGF19 antibody or a binding fragment thereof, or an anti-klotho beta antibody or a binding fragment thereof.

51. The kit of claim 48 or 49, wherein the FGFR3 inhibitor comprises a small molecule dual FGFR3-4 inhibitor, an anti -dual FGFR3-4 antibody or a binding fragment thereof, an anti-FGF19 antibody or a binding fragment thereof, or an anti-klotho beta antibody or a binding fragment thereof.

52. The kit of claim 48 or 49, wherein the FGFR3 inhibitor comprises a small molecule pan FGFR1-4 inhibitor, an anti-pan FGFR1-4 antibody or a binding fragment thereof, an anti- FGF19 antibody or a binding fragment thereof, or an anti-klotho beta antibody or a binding fragment thereof.

53. The kit of claim 48-52, wherein the FGFR3 inhibitor and the PPAR alpha agonist are provided in the same blister pack.

54. The kit of any one of claims 48-53, further comprising a bile acid sequestrant.- 39 - 4886-1054-6423.5120039.000207\4936-3978-3555.1

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