Fixed-drug or pharmaceutical composition

Abstract

Provided are a fixed-drug combination comprising bempedoic acid and tolvaptan, a method for treating autosomal dominant polycystic kidney disease (ADPKD) by administering a combination of bempedoic acid and tolvaptan, and a method for treating ADPKD by administering bempedoic acid.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Patent Application No. 63 / 195,843, filed June 2, 2021, and U.S. Patent Application No. 63 / 275,077, filed November 3, 2021, which are incorporated by reference in their entireties herein. [Background technology]

[0002] Autosomal dominant polycystic kidney disease (ADPKD) is a severe genetic disease characterized by the proliferation of cysts in the kidney and subsequent decline in renal function. Approximately 4-7 million people worldwide suffer from ADPKD, making it a serious health concern (Akoh; Current management of autosomal dominant polycystic kidney disease; World J. Nephrol.; 2015; 4(4); 468-79). ADPKD is the most common genetic cause of end-stage renal disease, with a prevalence of 1:500-1:1000, affecting 600,000 people in the United States alone (Gabow; Autosomal dominant polycystic kidney disease; The New England Journal of Medicine; 1993; 329; 332-342). Disease progression is characterized by the expansion of cystic lesions in the kidney and often the liver, leading to progressive decline in renal function and associated increased morbidity and mortality in ADPKD patients (Gabow). Many patients with ADPKD have loss-of-function mutations in the polarity protein polycystin-1 (PKD1), and treatment options are limited (Torres et al.; Tolvaptan in patients with autosomal dominant polycystic kidney disease; N. Engl. J. Med.; 2012; 367; 2407-2418). Therefore, the development of new treatments for ADPKD patients is an important area of ​​research.

[0003] Tolvaptan is the only drug approved by the FDA to treat hyponatremia and ADPKD. Tolvaptan acts in the kidney as an antagonist of vasopressin receptor 2, causing aquaresis (i.e., excretion of water without significant loss of electrolytes) (Torres). Although tolvaptan is effective in improving symptoms and slowing progression of ADPKD, its safety profile is less than ideal. Specifically, monthly liver function tests are required because tolvaptan therapy carries a risk of hepatotoxicity, including acute liver failure requiring transplantation, as a dose-dependent side effect (Wu et al.; Mechanisms of tolvaptan-induced toxicity in HepG2 cells; Biochem. Pharmacol.; 2015; 95; 324-336). The situation that tolvaptan is the only FDA-approved drug for the treatment of ADPKD indicates the need for new therapeutic agents to treat this condition. Summary of the Invention [Problem to be solved by the invention]

[0004] Despite the success of tolvaptan, there remains an unmet need for safe and effective treatment options for patients with ADPKD. [Means for solving the problem]

[0005] The present disclosure provides combination drug therapies including an ATP citrate lyase (ACL) inhibitor (e.g., bempedoic acid) and a vasopressin 2 receptor antagonist (e.g., tolvaptan). The present disclosure also provides methods of using the combination drug therapies described herein, such as for the treatment of autosomal dominant polycystic kidney disease (ADPKD) in a patient in need thereof. The present disclosure further provides methods of using bempedoic acid as a single agent for the treatment of conditions including ADPKD.

[0006] In one aspect, the disclosure provides a fixed-dose combination of bempedoic acid and tolvaptan.

[0007] In various embodiments of the present disclosure, the fixed dose contains about 30 mg to about 240 mg of bempedoic acid. In various embodiments of the present disclosure, the fixed dose contains about 5 mg to about 120 mg of tolvaptan or about 5 mg to about 90 mg of tolvaptan.

[0008] In some embodiments, the disclosure provides fixed dose combinations comprising about 30 mg to about 240 mg of bempedoic acid and about 5 mg to about 90 mg of tolvaptan, as well as fixed dose combinations comprising about 30 mg to about 240 mg of bempedoic acid and about 5 mg to about 60 mg of tolvaptan.

[0009] In various embodiments of the present disclosure, the fixed dose contains about 90 mg, about 60 mg, about 45 mg, about 30 mg, about 15 mg, about 10 mg, or about 5 mg of tolvaptan. In certain embodiments of the present disclosure, the fixed dose contains about 180 mg of bempedoic acid.

[0010] In certain embodiments, the disclosure provides a fixed dose comprising about 180 mg of bempedoic acid and about 5 mg of tolvaptan, a fixed dose comprising about 180 mg of bempedoic acid and about 10 mg of tolvaptan, a fixed dose comprising about 180 mg of bempedoic acid and about 15 mg of tolvaptan, a fixed dose comprising about 180 mg of bempedoic acid and about 30 mg of tolvaptan, a fixed dose comprising about 180 mg of bempedoic acid and about 45 mg of tolvaptan, a fixed dose comprising about 180 mg of bempedoic acid and about 60 mg of tolvaptan, a fixed dose comprising about 180 mg of bempedoic acid and about 90 mg of tolvaptan.

[0011] In various embodiments of the present disclosure, the fixed dose is formulated for oral administration. In certain embodiments of the present disclosure, the fixed dose is formulated as an oral solid dosage form selected from the group consisting of a tablet, a capsule, a softgel capsule, a pill, a solution, and a suspension.

[0012] In another aspect, the present disclosure provides a pharmaceutical composition comprising bempedoic acid, tolvaptan, and one or more pharma- ceutically acceptable excipients.

[0013] In various embodiments of the present disclosure, the pharmaceutical composition comprises about 30 mg to about 240 mg of bempedoic acid. In various embodiments, the pharmaceutical composition comprises about 5 mg to about 120 mg of tolvaptan or about 5 mg to about 90 mg of tolvaptan.

[0014] In some embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg to about 240 mg of bempedoic acid, about 5 mg to about 90 mg of tolvaptan, and one or more pharma- ceutically acceptable excipients, as well as a pharmaceutical composition comprising about 30 mg to about 240 mg of bempedoic acid, about 5 mg to about 60 mg of tolvaptan, and one or more pharma- ceutically acceptable excipients.

[0015] In various embodiments of the present disclosure, the pharmaceutical composition comprises about 90 mg, about 60 mg, about 45 mg, about 30 mg, about 15 mg, about 10 mg, or about 5 mg of tolvaptan. In certain embodiments of the present disclosure, the pharmaceutical composition comprises about 180 mg of bempedoic acid.

[0016] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising about 180 mg of bempedoic acid, about 5 mg of tolvaptan, and one or more pharma- ceutical acceptable excipients; a pharmaceutical composition comprising about 180 mg of bempedoic acid, about 10 mg of tolvaptan, and one or more pharma- ceutical acceptable excipients; a pharmaceutical composition comprising about 180 mg of bempedoic acid, about 15 mg of tolvaptan, and one or more pharma- ceutical acceptable excipients; a pharmaceutical composition comprising about 180 mg of bempedoic acid, about 30 mg of tolvaptan, and one or more pharma- ceutical acceptable excipients; The present invention provides a pharmaceutical composition comprising a tolvaptan and one or more pharma- ceutical acceptable excipients, a pharmaceutical composition comprising about 180 mg of bempedoic acid, about 45 mg of tolvaptan and one or more pharma- ceutical acceptable excipients, a pharmaceutical composition comprising about 180 mg of bempedoic acid, about 60 mg of tolvaptan and one or more pharma- ceutical acceptable excipients, and a pharmaceutical composition comprising about 180 mg of bempedoic acid, about 90 mg of tolvaptan and one or more pharma- ceutical acceptable excipients.

[0017] In various embodiments of the present disclosure, the pharmaceutical composition is formulated for oral administration. In certain embodiments of the present disclosure, the pharmaceutical composition is formulated as an oral solid dosage form selected from the group consisting of a tablet, a capsule, a softgel capsule, a pill, a solution, and a suspension.

[0018] In certain embodiments of the present disclosure, the pharmaceutical composition provides an immediate release of bempedoic acid. In other embodiments of the present disclosure, the pharmaceutical composition provides an extended release of bempedoic acid.

[0019] In another embodiment, the present disclosure provides a method of treating ADPKD in a patient receiving tolvaptan therapy, the method comprising administering to the patient an effective amount of bempedoic acid.In another embodiment, the present disclosure provides a method of slowing the progression of ADPKD in a patient receiving tolvaptan therapy, the method comprising administering to the patient an effective amount of bempedoic acid.In another embodiment, the present disclosure provides a method of preventing renal failure in a patient with ADPKD receiving tolvaptan therapy, the method comprising administering to the patient an effective amount of bempedoic acid.

[0020] In various embodiments of the present disclosure, the effective amount of bempedoic acid is from about 30 mg to about 240 mg. In certain embodiments of the present disclosure, the effective amount of bempedoic acid is about 180 mg.

[0021] In various embodiments of the present disclosure, patients receiving an effective amount of bempedoic acid and tolvaptan therapy experience a smaller annual decrease in estimated glomerular filtration rate than patients not receiving an effective amount of bempedoic acid and tolvaptan therapy, or patients receiving only an effective amount of bempedoic acid, or patients receiving only tolvaptan therapy. In various embodiments of the present disclosure, patients receiving an effective amount of bempedoic acid and tolvaptan therapy experience a smaller annual increase in total kidney volume than patients not receiving an effective amount of bempedoic acid and tolvaptan therapy, or patients receiving only an effective amount of bempedoic acid, or patients receiving only tolvaptan therapy. In various embodiments of the present disclosure, patients receiving an effective amount of bempedoic acid and tolvaptan therapy experience a lower incidence of a composite of clinical endpoints selected from worsening renal function, renal pain, hypertension, and albuminuria than patients not receiving an effective amount of bempedoic acid and tolvaptan therapy, or patients receiving only an effective amount of bempedoic acid, or patients receiving only tolvaptan therapy.

[0022] In various embodiments of the present disclosure, patients receiving an effective amount of bempedoic acid and tolvaptan therapy have higher hepatic AMPK activity than patients not receiving an effective amount of bempedoic acid and tolvaptan therapy or receiving only tolvaptan therapy. In various embodiments of the present disclosure, patients receiving an effective amount of bempedoic acid and tolvaptan therapy have a higher degree of hepatic acetyl-coenzyme A carboxylase (ACC) phosphorylation than patients not receiving an effective amount of bempedoic acid and tolvaptan therapy or receiving only tolvaptan therapy. In various embodiments of the present disclosure, patients receiving an effective amount of bempedoic acid and tolvaptan therapy have higher peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha) activity than patients receiving only tolvaptan therapy.

[0023] In various embodiments of the present disclosure, an effective amount of bempedoic acid is administered orally.

[0024] In another aspect, the disclosure provides a method of treating ADPKD in a patient in need thereof, the method comprising administering to the patient a fixed combination of bempedoic acid and tolvaptan, the fixed combination comprising about 30 mg to about 240 mg of bempedoic acid and about 5 mg to about 90 mg of tolvaptan.In another aspect, the disclosure provides a method of slowing the progression of ADPKD in a patient in need thereof, the method comprising administering to the patient a fixed combination of bempedoic acid and tolvaptan, the fixed combination comprising about 30 mg to about 240 mg of bempedoic acid and about 5 mg to about 90 mg of tolvaptan. In another aspect, the disclosure provides a method of preventing renal failure in a patient having ADPKD, the method comprising administering to the patient a fixed combination of bempedoic acid and tolvaptan, wherein the fixed combination comprises about 30 mg to about 240 mg of bempedoic acid and about 5 mg to about 90 mg of tolvaptan.

[0025] In various embodiments of the present disclosure, patients receiving a fixed-dose combination have a smaller annual loss in estimated glomerular filtration rate than patients not receiving a fixed-dose combination, or patients receiving only about 30 mg to about 240 mg of bempedoic acid, or patients receiving only about 5 mg to about 90 mg of tolvaptan. In various embodiments of the present disclosure, patients receiving a fixed-dose combination have a smaller annual increase in total kidney volume than patients not receiving a fixed-dose combination, or patients receiving only about 30 mg to about 240 mg of bempedoic acid, or patients receiving only about 5 mg to about 90 mg of tolvaptan. In various embodiments of the present disclosure, patients receiving a fixed-dose combination have a lower incidence of a composite of a clinical endpoint selected from worsening renal function, renal pain, hypertension, and albuminuria than patients not receiving a fixed-dose combination, or patients receiving only about 30 mg to about 240 mg of bempedoic acid, or patients receiving only about 5 mg to about 90 mg of tolvaptan.

[0026] In various embodiments of the present disclosure, patients receiving a fixed-dose combination have higher hepatic AMPK activity than patients not receiving a fixed-dose combination or patients receiving only about 5 mg to about 90 mg of tolvaptan. In various embodiments of the present disclosure, patients receiving a fixed-dose combination have higher hepatic ACC phosphorylation than patients not receiving a fixed-dose combination or patients receiving only about 5 mg to about 90 mg of tolvaptan. In various embodiments of the present disclosure, patients receiving a fixed-dose combination have higher peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha) activity than patients receiving only about 5 mg to about 90 mg of tolvaptan.

[0027] In various embodiments of the present disclosure, the fixed dose drug is administered orally.

[0028] In various embodiments of the present disclosure, the fixed dose contains about 180 mg of bempedoic acid. In certain embodiments of the present disclosure, the fixed dose contains about 5 mg, about 10 mg, about 15 mg, about 30 mg, about 45 mg, about 60 mg, or about 90 mg of tolvaptan.

[0029] In another embodiment, the disclosure provides a method of treating ADPKD in a patient in need thereof, the method comprising administering to the patient an effective amount of bempedoic acid and tolvaptan.In another embodiment, the disclosure provides a method of slowing the progression of ADPKD in a patient in need thereof, the method comprising administering to the patient an effective amount of bempedoic acid and tolvaptan.In another embodiment, the disclosure provides a method of preventing renal failure in a patient having ADPKD in need thereof, the method comprising administering to the patient an effective amount of bempedoic acid and tolvaptan.

[0030] In various embodiments of the present disclosure, the effective amount of bempedoic acid and tolvaptan comprises about 30 mg to about 240 mg of bempedoic acid. In various embodiments of the present disclosure, the effective amount of bempedoic acid and tolvaptan comprises about 180 mg of bempedoic acid. In various embodiments of the present disclosure, the effective amount of bempedoic acid and tolvaptan comprises about 5 mg, about 10 mg, about 15 mg, about 30 mg, about 45 mg, about 60 mg, or about 90 mg of tolvaptan.

[0031] In various embodiments of the present disclosure, patients receiving effective amounts of bempedoic acid and tolvaptan experience a smaller annual decrease in estimated glomerular filtration rate than patients receiving a placebo, or patients receiving only bempedoic acid, or patients receiving only tolvaptan. In various embodiments of the present disclosure, patients receiving effective amounts of bempedoic acid and tolvaptan experience a smaller annual increase in total kidney volume than patients receiving a placebo, or patients receiving only bempedoic acid, or patients receiving only tolvaptan. In various embodiments of the present disclosure, patients receiving effective amounts of bempedoic acid and tolvaptan experience a lower incidence of a composite of clinical endpoints selected from worsening renal function, renal pain, hypertension, and albuminuria than patients receiving a placebo, or patients receiving only bempedoic acid, or patients receiving only tolvaptan.

[0032] In various embodiments of the present disclosure, patients receiving effective amounts of bempedoic acid and tolvaptan have higher hepatic AMPK activity than patients receiving a placebo or tolvaptan alone. In various embodiments of the present disclosure, patients receiving effective amounts of bempedoic acid and tolvaptan have higher hepatic ACC phosphorylation than patients receiving a placebo or tolvaptan alone. In various embodiments of the present disclosure, patients receiving effective amounts of bempedoic acid and tolvaptan have higher peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha) activity than patients receiving tolvaptan alone.

[0033] In another embodiment, the present disclosure provides a method for treating ADPKD in a patient in need thereof, comprising administering to the patient an effective amount of bempedoic acid.In another embodiment, the present disclosure provides a method for slowing the progression of ADPKD in a patient in need thereof, comprising administering to the patient an effective amount of bempedoic acid.In another embodiment, the present disclosure provides a method for preventing renal failure in a patient with ADPKD, comprising administering to the patient an effective amount of bempedoic acid.

[0034] In various embodiments of the present disclosure, the effective amount of bempedoic acid is from about 30 mg to about 240 mg. In certain embodiments of the present disclosure, the effective amount of bempedoic acid is about 180 mg.

[0035] In various embodiments of the present disclosure, patients receiving an effective amount of bempedoic acid experience a smaller annual decrease in estimated glomerular filtration rate than patients receiving a placebo, or an equivalent or smaller annual decrease in estimated glomerular filtration rate than patients receiving tolvaptan therapy. In various embodiments, patients receiving an effective amount of bempedoic acid experience a smaller annual increase in total kidney volume than patients receiving a placebo, or an equivalent or smaller annual increase in total kidney volume than patients receiving tolvaptan therapy. In various embodiments of the present disclosure, patients receiving an effective amount of bempedoic acid experience a lower incidence of a composite of clinical endpoints selected from worsening renal function, renal pain, hypertension, and albuminuria than patients receiving a placebo, or an equivalent or lower incidence of a composite of clinical endpoints selected from worsening renal function, renal pain, hypertension, and albuminuria than patients receiving tolvaptan therapy. In various embodiments of the present disclosure, the effective amount of bempedoic acid is administered orally.

[0036] In various embodiments of the present disclosure, the patient is a human. [Brief description of the drawings]

[0037] [Figure 1A]Immunoblot assay showing fatty acid transport protein 2 (FATP2, also known as very long chain acyl-CoA synthetase (ACSVL1) and / or gene SLC27A2) protein expression in homogenates of different mouse tissues (liver, lung, kidney, spleen and muscle), a proximal tubule (PT)-derived kidney cell line (S3, PKD1 Null) and an inner medullary collecting duct (IMCD)-derived kidney cell line (IMCD3[WT] and ID1-3E5[PKD]). [Figure 1B] Immunoblot assay showing FATP2a 70 kDa and FATP2b 55 kDa isoform expression in homogenates of kidney tissue from wild-type and ADPKD mutant (Pkd1RC / RC) mice. [Figure 1C] Immunoblot assay showing ATP citrate lyase (ACLY) protein expression and activity in inner medullary collecting duct-derived Pkd1- / - mouse kidney epithelial cells compared to wild type. [Figure 1D] This is a histogram comparing the ratio of phosphorylated ACLY to total ACLY expression in IMCD-derived wild-type cells and PKD1 knockout cells. [Figure 1E] Immunoblot assay showing ACLY protein expression and activity in Pkd1-heterozygous and Pkd1-null mouse kidney epithelial cells derived from the proximal tubule (PT) compared to wild type. [Figure 1F] This is a histogram comparing the ratio of phosphorylated ACLY to total ACLY expression in PT-derived Pkd1-heterozygous cells and Pkd1-null cells. [Figure 2A] Photographs comparing cyst growth in 3D cultures of PT-derived Pkd1− / − cells untreated, treated with ETC-1002, or treated with SB-204990, with or without metformin. [Figure 2B] A plot comparing cyst area in 3D cultures of PT-derived Pkd1− / − cells untreated, treated with ETC-1002, or treated with SB-204990, with or without metformin. [Figure 2C]Photographs comparing cyst growth in 3D cultures of IMCD-derived Pkd1− / − cells, untreated or treated with ETC-1002, with or without metformin. [Figure 2D] A plot comparing cyst area in 3D cultures of IMCD-derived Pkd1− / − cells untreated or treated with ETC-1002, with or without metformin. [Figure 3A] Shown are images of H&E staining of kidney sections from postnatal day 22 Cre+ mice treated with vehicle, bempedoic acid or tolvaptan, as well as images of kidney sections from uninduced control mice without PKD. [Figure 3B] FIG. 1 is a histogram comparing total kidney weight to body weight in an early-onset, rapidly progressive ADPKD mouse model in groups treated with vehicle, tolvaptan 30 mg / kg / d, tolvaptan 100 mg / kg / d, bempedoic acid 30 mg / kg / d, tolvaptan 30 mg / kg / d + bempedoic acid 30 mg / kg / d, and tolvaptan 100 mg / kg / d + bempedoic acid 30 mg / kg / d, as well as uninduced, untreated controls without PKD. [Figure 3C] FIG. 1 is a histogram comparing blood urea nitrogen (BUN) in an early-onset, rapidly progressive ADPKD mouse model treated with vehicle, tolvaptan 30 mg / kg / d, tolvaptan 100 mg / kg / d, bempedoic acid 30 mg / kg / d, tolvaptan 30 mg / kg / d + bempedoic acid 30 mg / kg / d, or tolvaptan 100 mg / kg / d + bempedoic acid 30 mg / kg / d, and an uninduced, untreated control group without PKD. [Figure 4A] Immunoblot assay of kidney lysates from treatment groups described in Figures 3B and 3C comparing kidney injury molecule-1 (KIM-1) expression relative to total protein expression between treatment groups. [Figure 4B] 3C is a histogram comparing kidney injury molecule-1 (KIM-1) expression in kidney lysates relative to total protein expression between the treatment groups described in FIG. 3B and FIG. 3C. [Figure 5A]Immunoblot assay of kidney lysates from treatment groups described in Figures 3B and 3C comparing AMPK-pThr172 expression relative to total protein expression between treatment groups. [Figure 5B] FIG. 3C is a histogram comparing kidney lysate Thr172 expression relative to total protein expression between the treatment groups described in FIG. 3B and FIG. 3C. [Figure 6A] FIG. 3B and FIG. 3C are immunoblot assays of kidney lysates from the treatment groups described in FIG. 3B and FIG. 3C, comparing pP70S6K expression relative to total protein expression between treatment groups. [Figure 6B] FIG. 3C is a histogram comparing pP70S6K expression in kidney lysates relative to total protein expression between the treatment groups described in FIG. 3B and FIG. 3C. [Figure 7A] Immunoblot assay of kidney lysates from treatment groups described in Figures 3B and 3C comparing pERK expression relative to total protein expression between treatment groups. [Figure 7B] FIG. 3C is a histogram comparing pERK expression in kidney lysates relative to total protein expression between the treatment groups described in FIG. 3B and FIG. 3C. [Figure 8A] Immunoblot assay of kidney lysates from treatment groups described in Figures 3B and 3C comparing pACLY expression relative to total protein expression between treatment groups. [Figure 8B] FIG. 3C is a histogram comparing pACLY expression in kidney lysates relative to total protein expression between the treatment groups described in FIG. 3B and FIG. 3C. [Figure 9A] Immunoblot assay of kidney lysates from treatment groups described in Figures 3B and 3C comparing NGAL expression relative to total protein expression between treatment groups. [Figure 9B] FIG. 3C is a histogram comparing NGAL expression in kidney lysates relative to total protein expression between the treatment groups described in FIG. 3B and FIG. 3C. [Figure 10A]Immunoblot assay of liver lysates from treatment groups described in Figures 3B and 3C receiving vehicle, bempedoic acid 30 mg / kg / d, tolvaptan 100 mg / kg / d, or tolvaptan 100 mg / kg / d + bempedoic acid 30 mg / kg / d, comparing pACLY expression relative to total protein expression between treatment groups. [Figure 10B] FIG. 10B is a histogram comparing pACLY expression in liver lysates relative to total protein expression between the treatment groups described in FIG. 10A. [Figure 11A] Immunoblot assay of liver lysates from treatment groups described in Figures 3B and 3C administered vehicle, bempedoic acid 30 mg / kg / d, tolvaptan 100 mg / kg / d, or tolvaptan 100 mg / kg / d + bempedoic acid 30 mg / kg / d, comparing FATP2 expression relative to total protein expression between treatment groups. [Figure 11B] FIG. 11B is a histogram comparing FATP2 expression in liver lysates relative to total protein expression between the treatment groups described in FIG. 11A. [Figure 12A] Immunoblot assay of liver lysates from treatment groups described in Figures 3B and 3C administered vehicle, bempedoic acid 30 mg / kg / d, tolvaptan 100 mg / kg / d, or tolvaptan 100 mg / kg / d + bempedoic acid 30 mg / kg / d, comparing pThr172 expression relative to total protein expression between treatment groups. [Figure 12B] FIG. 12B is a histogram comparing pThr172 expression in liver lysates relative to total protein expression between the treatment groups described in FIG. 12A. [Figure 13A] Immunoblot assay of liver lysates from treatment groups described in Figures 3B and 3C administered vehicle, bempedoic acid 30 mg / kg / d, tolvaptan 100 mg / kg / d, or tolvaptan 100 mg / kg / d + bempedoic acid 30 mg / kg / d, comparing pACC expression relative to total protein expression between treatment groups. [Figure 13B] FIG. 13B is a histogram comparing pACC expression in liver lysates relative to total protein expression between the treatment groups described in FIG. 13A. [Figure 14A]Immunoblot assay of liver lysates from treatment groups described in Figures 3B and 3C that received vehicle, bempedoic acid 30 mg / kg / d, tolvaptan 100 mg / kg / d, or tolvaptan 100 mg / kg / d + bempedoic acid 30 mg / kg / d, comparing PGC1α expression relative to total protein expression between treatment groups. [Figure 14B] FIG. 14B is a histogram comparing PGC1α expression in liver lysates relative to total protein expression between the treatment groups described in FIG. 14A. [Figure 15A] Immunoblot assay of liver lysates from treatment groups described in Figures 3B and 3C administered vehicle, bempedoic acid 30 mg / kg / d, tolvaptan 100 mg / kg / d, or tolvaptan 100 mg / kg / d + bempedoic acid 30 mg / kg / d, comparing cleaved Cas3 expression relative to total protein expression between treatment groups. [Figure 15B] FIG. 15B is a histogram comparing cleaved Cas3 expression in liver lysates versus total protein expression between the treatment groups described in FIG. [Figure 16] Histograms comparing total kidney weight as a percentage of body weight in late-onset and slow-onset ADPKD mouse models. Mice were divided into three groups. Two groups were sacrificed at different time points after PKD induction, and both were divided into subgroups that received either bempedoic acid or control. One group was sacrificed at the same time as PKD induction to serve as a control and to facilitate interpretation of the magnitude of the treatment effect. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] definition To facilitate the understanding of this disclosure, a number of terms and phrases are defined below.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Abbreviations used herein have their conventional meanings in the chemical and biological arts. Chemical structures and formulas described herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0040] Throughout this specification, when compositions and kits are described as having, comprising, or consisting of certain components, or processes and methods are described as having, comprising, or consisting of certain steps, it is further contemplated that there are compositions and kits of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

[0041] In this application, when an element or component is said to be included in and / or selected from a list of recited elements or components, it is to be understood that the element or component may be any one of the recited elements or components, or the element or component may be selected from a group consisting of two or more of the recited elements or components.

[0042] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein, whether express or implied herein, can be combined in various ways without departing from the spirit and scope of the present disclosure. For example, where reference is made to a particular compound, that compound can be used in various embodiments of the compositions of the present disclosure and / or in the methods of the present disclosure, unless otherwise understood from the context. In other words, within this application, the embodiments have been described and depicted in a manner that allows the present application to be written and drawn in a clear and concise manner, but it is intended and understood that the embodiments can be combined or separated in various ways without departing from the present teachings and disclosure(s). For example, it will be understood that all features described and depicted herein are applicable to all aspects of the disclosure(s) described and depicted herein.

[0043] The articles "a" and "an" are used in this disclosure, unless the context is inappropriate, to refer to one or to more than one (i.e., to at least one) of the grammatical subject of the article. By way of example, "a component" refers to one component or to more than one component.

[0044] In this disclosure, the term "and / or" is used to mean either "and" or "or," unless otherwise indicated.

[0045] The phrase "at least one" should be understood to include each of the recited items thereafter individually, and various combinations of two or more recited items, unless otherwise understood from context and usage. Additionally, the phrase "and / or" in the context of more than two recited items should be understood to have the same meaning, unless otherwise understood from context.

[0046] Use of the terms "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing" is to be generally understood as open-ended and open-ended, including grammatical equivalents thereof, and not excluding, for example, additional, unrepeated elements or steps, unless otherwise stated or understood from the context.

[0047] When the use of the term "about" precedes a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless otherwise indicated or inferred from the context.

[0048] It should be understood that the steps or order for performing certain operations is not critical so long as the present disclosure remains operable. Moreover, two or more steps or operations may be conducted simultaneously.

[0049] At various places in the present specification, variables or parameters are disclosed in groups or ranges. It is specifically intended herein to include the individual subcombinations of the members of such groups or ranges. For example, an integer ranging from 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer ranging from 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0050] The use of any and all examples or exemplary language herein, such as "such as" or "including," is intended merely to better describe the disclosure and does not pose a limitation on the scope of the disclosure unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0051] As a general matter, compositions specifying percentages are by weight unless otherwise specified. Further, if no definition is given for a variable, the prior definition of that variable is controlling.

[0052] As used herein, a "pharmaceutical composition" or "pharmaceutical formulation" refers to a combination of an active agent with a carrier, inert or active, making the composition particularly suitable for diagnostic or therapeutic uses in vivo or ex vivo.

[0053] As used herein, the phrases "pharmacologically acceptable" and "pharmacologically acceptable" refer to compounds, molecular entities, compositions, materials and / or dosage forms that do not produce adverse, allergic or other untoward reactions when administered to animals or humans. When administered to humans, the formulations must meet the standards of sterility, pyrogenicity, general safety and purity required by regulatory agencies that evaluate the safety and effectiveness of drugs and pharmaceutical products, such as the U.S. Food and Drug Administration. "Pharmaceutically acceptable" and "pharmacologically acceptable" may mean approved or approvable by a federal or state regulatory agency or a corresponding regulatory agency in a country other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and more particularly in humans.

[0054] As used herein, "pharmaceutical acceptable salt" refers to any salt of an acidic or basic group that may be present in a compound of the present disclosure (e.g., bempedoic acid), which salt is compatible with pharmaceutical administration. For example, one or both of the carboxylic acid groups of bempedoic acid can be converted into a pharmaceutical acceptable salt(s).

[0055] As known to those skilled in the art, the "salts" of compounds can be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid. Other acids, such as oxalic acid, are not themselves pharmaceutically acceptable, but can be used in the preparation of salts useful as intermediates to obtain the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0056] Examples of bases include alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and bases of the formula NW4 + (Wherein, W is C 1~4 alkyl), and the like.

[0057] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include Na + , K + , Ca 2+ , NH4 +and NW4 + (Where, W is C 1~4 Illustrative examples of suitable cations include the anions of the compounds of the present disclosure combined with appropriate cations such as, for example, an alkyl group.

[0058] For therapeutic use, the salts of the compounds of the disclosure are contemplated as pharma-ceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharma-ceutically acceptable compound.

[0059] As used herein, "carrier" refers to a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent, such as bempedoic acid or a pharma- ceutically acceptable salt thereof, from one organ or part of the body to another.

[0060] As used herein, "pharmaceutical acceptable excipient" refers to a substance that aids in the administration and / or absorption of an active agent by a patient and may be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the patient.Non-limiting examples of pharmaceutical acceptable excipients include water, NaCl, normal saline such as phosphate buffered saline, emulsions (e.g., oil / water or water / oil emulsions), lactated Ringer's solution, normal sucrose, normal glucose, premixed drugs, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohol, oils, gelatin, lactose, carbohydrates such as amylose or starch, fatty acid esters, hydroxypropylmethylcellulose, polyvinylpyrrolidine, and colorants. Such formulations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents and / or aromatic substances that do not dramatically react with the compounds of the present disclosure. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0061] As used herein, "treat," "treating," or "treatment" includes actions occurring during a patient's illness with a particular disease, disorder, or condition that reduce the severity of the disease, disorder, or condition or slow or retard the progression of the disease, disorder, or condition (e.g., cause improvement, alleviate, reduce, modulate, ameliorate, or eliminate the symptom, disease, disorder, etc.), or alleviate, reduce, modulate, ameliorate, or eliminate the symptom. Treating is curing, ameliorating, or at least partially ameliorating the disorder. In certain embodiments, treating is curing the disease.

[0062] As used herein, "alleviation" or "reduction" of a "symptom" or "symptoms" (and grammatical equivalents of this phrase) refers to a decrease in the severity or frequency of a symptom or elimination of a symptom. For example, "reduction" or "decrease" of polycystic kidney disease means a decrease in the rate of growth of kidney cysts or a decrease in the rate of loss of kidney function.

[0063] As used herein, a "lowering" or "decrease" of an elevated laboratory biomarker / parameter or vital sign associated with a disease disclosed herein may refer, for example, to a drop in the elevated laboratory biomarker / parameter or vital sign to a predetermined, clinically relevant endpoint (e.g., a clinically normal level).

[0064] As used herein, "subject" and "patient" are used interchangeably and refer to an organism treated by the methods and compositions of the present disclosure. Such organisms are preferably mammals (e.g., humans, mice, rats, guinea pigs, dogs, cats, horses, cows, pigs, or non-human primates such as monkeys, chimpanzees, baboons, and rhesus monkeys), and more preferably, humans.

[0065] As used herein, "solid dosage form" refers to a pharmaceutical dosage in solid form, such as, for example, tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalants and chewables.

[0066] As used herein, "immediate release" refers to a dosage form that has not been manipulated to modify or control the release of the active ingredient.

[0067] As used herein, "extended release" refers to a dosage form designed to release drug at a predetermined (not necessarily constant) rate to maintain a desired range of drug concentration with minimal side effects for a particular period of time, e.g., 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, etc. This can be accomplished by a variety of formulations, as exemplified by bempedoic acid extended release formulations such as those described in International Publication WO2019 / 161307A1.

[0068] As used herein, "fixed-dose combination" refers to a formulation in which the active ingredients (e.g., bempedoic acid and tolvaptan) are administered simultaneously to a patient in the form of a single entity or dosage.

[0069] As used herein, "administering" refers to oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intraarticular administration, intrathecal administration, intracranial administration, intranasal administration or subcutaneous administration, or implantation of a sustained release device, such as a mini-osmotic pump, into a patient. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of administration include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. Co-administration means administration of a composition described herein simultaneously with, immediately prior to, or immediately following administration of one or more additional therapies (e.g., bempedoic acid and tolvaptan). Tolvaptan or a pharma- ceutically acceptable salt thereof can be administered alone or co-administered to a patient. Co-administration is meant to include simultaneous or sequential administration alone or in combination (multiple compounds or agents). Thus, the formulation can be combined with other active agents, if desired (e.g., to reduce metabolic degradation).

[0070] As used herein, "disease," "disorder," "condition," or "illness" may be used interchangeably herein, unless otherwise understood from the context, and refer to a patient or a condition or health symptom of a patient that may be treated with a compound, pharmaceutical substance, pharmaceutical composition, or method provided herein.

[0071] As used herein, an "effective amount" or a "therapeutically effective amount" refers to an amount of a compound (e.g., bempedoic acid or tolvaptan), combination of compounds (e.g., bempedoic acid and tolvaptan), pharmaceutical composition (e.g., a pharmaceutical composition of the disclosure), or fixed-dose combination (e.g., a fixed-dose combination of the disclosure) sufficient to produce a beneficial or desired result. An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration. Abbreviation ADPKD: Autosomal dominant polycystic kidney disease PKD: Polycystic Kidney Disease ACL / pACLY: ATP citrate lyase / phosphorylated ATP citrate lyase ACLY: ATP citrate lyase FATP2: fatty acid transport protein 2 ACSVL1: very long chain acyl-CoA synthetase BUN: Blood urea nitrogen TKV: Total kidney volume eGFR: Estimated glomerular filtration rate KIM-1: Kidney injury molecule-1 AMPK: AMP-activated protein kinase Thr 172 / pThr 172 : Phosphorylated AMPKα P70S6K / pP70S6K: ribosomal protein S6 kinase β-1 / phosphorylated ribosomal protein S6 kinase β-1 ERK / pERK: extracellular signal-regulated kinase / phosphorylated extracellular signal-regulated kinase PKD1: Polycystin 1 PT: Proximal tubule IMCD: inner medullary collecting duct BA: bempedoic acid HDL-C: high-density lipoprotein cholesterol CRP: C-reactive protein LDL-C: low-density lipoprotein cholesterol VLDL: very low density lipoprotein A1c / hbA1c: glycated hemoglobin hsCRP: high-sensitivity C-reactive protein apoB: apolipoprotein B apoA1: apolipoprotein A1

[0072] Bempedoic acid Bempedoic acid is a nonstatin indicated as an adjunct to diet and maximally tolerated statin therapy in the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require further reduction of LDL-C. The drug acts by inhibiting ATP citrate lyase (ACL). In vivo, it acts as a prodrug and is converted to the active species bempedoic acid-CoA by endogenous hepatic acyl-coenzyme (CoA) synthetase (ACS) activity. Formation of the active species requires a specific ACS isozyme, very long chain acyl-CoA synthetase (ACSVL1). Bempedoic acid can also activate the metabolic sensor AMPK.

[0073] Bempedoic acid has the structure of formula (I). JPEG2024521354000001.jpg32170

[0074] Bempedoic acid and methods for its synthesis are disclosed in U.S. Patent No. 7,335,799 and International Publication No. WO2020 / 257571A1, each of which is incorporated herein by reference. Bempedoic acid is also known by the trade names ETC-1002, ESP-55016, or Nexletol® and Nilemdo®, the latter of which is a fixed-dose combination of bempedoic acid and ezetimibe.

[0075] In various embodiments, bempedoic acid or a pharma- ceutically acceptable salt thereof can be used for the treatment and / or prevention of various diseases and disorders described herein. Methods of treating a disease or disorder generally consist of administering to a patient in need thereof a therapeutically effective amount of bempedoic acid or a pharma- ceutically acceptable salt thereof to treat the disease or disorder.

[0076] Examples of diseases and disorders include, but are not limited to, cardiovascular disease, atrial fibrillation, blood clotting, coronary heart disease, hypercoagulability conditions, ischemia, myocardial infarction, myopathy, myositis, pulmonary embolism, stroke, peripheral vascular disease, dyslipidemia, lipoprotein dyscrasias, glucose metabolism disorders, Alzheimer's disease, Parkinson's disease, diabetic nephropathy, diabetic retinopathy, insulin resistance, metabolic syndrome disorders (e.g., Syndrome X), Galactosemia, HIV infection, peroxisome proliferator-activated receptor-associated disorders, sepsis, thrombotic disorders, obesity, pancreatitis, hypertension, kidney disease, cancer, inflammation (e.g., hepatitis), inflammatory muscle diseases (e.g., polymyalgia rheumatica, polymyositis, fibrosis), impotence, gastrointestinal disorders, irritable bowel syndrome, inflammatory bowel disease, inflammatory diseases (e.g., asthma, vasculitis, ulcerative colitis, Crohn's disease, Kawasaki disease, Wegener's granulomatosis, (RA), systemic lupus erythematosus Examples of the conditions that may be affected include chronic hepatitis (SLE), multiple sclerosis (MS), autoimmune chronic hepatitis), arthritis (e.g., rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis), osteoporosis, soft tissue rheumatism (e.g., tendinitis), bursitis, autoimmune diseases (e.g., systemic lupus and lupus erythematosus), scleroderma, ankylosing spondylitis, gout, pseudogout, non-insulin-dependent diabetes mellitus, diabetes mellitus (e.g., type 2), polycystic ovarian disease, hyperlipidemia (e.g., primary hyperlipidemia, familial hypercholesterolemia (FH), hypercholesterolemia Frederickson type IIa, hypercholesterolemia Frederickson type IIb, familial combined hyperlipidemia (FCH)), lipoprotein lipase deficiency (e.g., hypertriglyceridemia, hypoalphalipoproteinemia, hypercholesterolemia), lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, and lipoprotein abnormalities associated with Alzheimer's disease. In certain embodiments, the methods include treating and / or preventing hyperlipidemia, such as primary hyperlipidemia, hi some embodiments, the methods include treating and / or preventing cardiovascular disease.

[0077] In certain embodiments, bempedoic acid or a pharma- ceutically acceptable salt thereof can be used for the treatment or prevention of one or more of high levels of low density lipoprotein cholesterol (LDL-C), high levels of apolipoprotein B (apoB), high levels of lipoprotein(a) (Lp(a)), high levels of very low density lipoprotein (VLDL), high levels of non-high density lipoprotein cholesterol (non-HDL-C), high levels of serum total cholesterol (TC), high levels of high sensitivity c-reactive protein (hsCRP), high levels of fibrinogen, high levels of insulin, high levels of glucose, and low levels of high density lipoprotein cholesterol (HDL-C). In other words, the methods of the present disclosure can include lowering LDL-C, lowering apoB, lowering Lp(a), lowering VLDL, lowering non-HDL-C, lowering TC, and / or lowering hsCRP. The disclosed methods can include inhibiting ATP citrate lyase (ACL), inhibiting cholesterol synthesis, and / or suppressing fatty acid biosynthesis. In some embodiments, bempedoic acid or a pharma- ceutically acceptable salt thereof can be used to treat non-insulin-dependent diabetes without weight gain.

[0078] In certain embodiments, bempedoic acid or a pharma- ceutically acceptable salt thereof can be used for the treatment or prevention of various diseases and conditions, including, but not limited to, aging, Alzheimer's disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, glucose metabolism disorders, dyslipidemia, lipoprotein disorders, bile production promotion, hypertension, impotence, inflammation, insulin resistance, biliary lipid clearance, C-reactive protein clearance, obesity, biliary oxysterol clearance, pancreatitis, Parkinson's disease, peroxisome proliferator-activated receptor-associated disorders, biliary phospholipid clearance, renal disease, rhabdomyolysis, sepsis, sleep apnea, syndrome X, and thrombotic disorders.

[0079] In certain embodiments, the disorder is selected from the group consisting of lipodystrophy, lysosomal acid lipase deficiency, and glycogen storage disease, hi some embodiments, the patient is an adult human.

[0080] In certain embodiments, bempedoic acid or a pharma- ceutically acceptable salt thereof can be used for the treatment or prevention of ADPKD.

[0081] In certain embodiments, the fixed doses and pharmaceutical compositions disclosed herein comprise bempedoic acid in its free acid form.

[0082] In certain embodiments, the fixed doses and pharmaceutical compositions disclosed herein comprise a crystalline form of bempedoic acid.

[0083] In certain embodiments, the fixed doses and pharmaceutical compositions disclosed herein contain bempedoic acid in a highly pure crystalline form.

[0084] In certain embodiments, the fixed doses and pharmaceutical compositions disclosed herein comprise a pharmaceutical ingredient that includes bempedoic acid.

[0085] In various embodiments, the pharmaceutical material generally comprises a crystalline form of the compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the pharmaceutical material comprises a compound of formula (I) or a pharma- ceutically acceptable salt thereof in an amount of more than 99.0% by weight based on the total weight of the pharmaceutical material. In some embodiments, the amount of the compound of formula (I) in the pharmaceutical material is more than about 99.1% by weight, more than about 99.2% by weight, more than about 99.3% by weight, more than about 99.4% by weight, more than about 99.5% by weight, more than about 99.6% by weight, more than about 99.7% by weight, more than about 99.8% by weight, more than about 99.85% by weight, more than about 99.9% by weight, more than about 99.95% by weight, or more than about 99.98% by weight. In some embodiments, the pharmaceutical material comprises a compound of formula (I) in an amount of more than 99.5% by weight based on the total weight of the pharmaceutical material. In some embodiments, the pharmaceutical substance comprises greater than 99.7% by weight of the compound of formula (I), based on the total weight of the pharmaceutical substance. In some embodiments, the pharmaceutical substance comprises greater than 99.9% by weight of the compound of formula (I), based on the total weight of the pharmaceutical substance.

[0086] In certain embodiments, the pharmaceutical material comprises a compound of formula (I) in an amount of about 98% by weight to about 102% by weight based on the total weight of the pharmaceutical material (anhydrous, solvent-free basis) as determined by high performance liquid chromatography (HPLC) assay.

[0087] In certain embodiments, the HPLC assay comprises one or more of the following: (i) Waters XBridge BEH C18 column (4.6 mm i.d. × 150 mm, 2.5 pm); (ii) a column temperature of about 40° C.; (iii) a mobile phase consisting of about 0.05% phosphoric acid in water / acetonitrile (about 50:50); (iv) isocratic elution; (v) a flow rate of about 1.2 mL / min; (vi) sample temperature at room temperature; (vii) Detection at 215 nm and (viii) The retention time of the compound of formula (I) is about 4.6 minutes. In some embodiments, the HPLC assay comprises each of the above, ie, (i)-(viii).

[0088] In certain embodiments, the crystalline form of the compound of formula (I) may be a crystalline form of the compound of formula (I) as characterized in International Publication Nos. WO2020 / 257571A1 and WO2020 / 257573A1, each of which is incorporated herein by reference. The crystalline form of the compound of formula (I) may be characterized, for example, by a powder X-ray diffraction pattern or peak(s), and / or other characteristic properties such as melting point and hygroscopicity. Crystalline forms of bempedoic acid include, but are not limited to, co-crystals (e.g., aspartame co-crystals and palmitic acid co-crystals), crystalline salts (e.g., ammonium salts, sodium salts, potassium salts, calcium salts, lysine salts, diethylamine salts, ethylenediamine salts, piperazine salts, betaine salts, tromethamine salts, isonicotinamide salts).

[0089] Tolvaptan Tolvaptan is a vasopressin receptor 2 antagonist indicated for the treatment of patients with hypersystolic hyponatremia and hypoxemia and those at risk for ADPKD. It increases blood sodium concentration by promoting aquaresis without significant sodium loss, thus assisting in hyponatremia (Dubois et al., Tolvaptan; British J. of Clin. Pharmacol.; 2012; 73(1); 9-11). In patients with ADPKD, tolvaptan may slow the increase in kidney volume and reduce pain and decline in renal function associated with disease progression (Sans-Atxer et al., Tolvaptan in the treatment of autosomal dominant polycystic kidney disease; patient selection and special considerations; J. Nephrol. Renovasc. Dis.; 2018; 11: 41-51).

[0090] Tolvaptan can be used in the fixed doses, pharmaceutical compositions and methods of treatment described herein. In various embodiments, the fixed doses and pharmaceutical compositions provided herein comprise tolvaptan or a pharma- ceutical acceptable salt thereof. Tolvaptan has the structure of formula (II): JPEG2024521354000002.jpg39170

[0091] Tolvaptan and methods for its manufacture are disclosed, for example, in U.S. Patent Nos. 8,501,730 and 10,905,694, which are incorporated herein by reference. Tolvaptan can be administered in an oral dosage form. Tolvaptan is also known by the names OPC-41061, Jynarque®, and Samsca®.

[0092] In various embodiments, tolvaptan or a pharma- ceutically acceptable salt thereof can be used for the treatment or prevention of various diseases and disorders described herein. Methods of preventing or treating a disease or disorder generally involve administering to a patient in need thereof a therapeutically effective amount of tolvaptan or a pharma- ceutically acceptable salt thereof to prevent or treat the disease or disorder.

[0093] Examples of diseases and disorders include, but are not limited to, hyponatremia and ADPKD.

[0094] In certain embodiments, the fixed doses and pharmaceutical compositions disclosed herein comprise tolvaptan in its free acid / free base form.

[0095] Fixed-drug combinations Fixed-dose combinations generally including bempedoic acid and tolvaptan are disclosed herein.

[0096] In some embodiments, the fixed dose combination may comprise about 30 mg to about 300 mg, about 60 mg to about 300 mg, about 90 mg to about 300 mg, about 120 mg to about 300 mg, about 150 mg to about 300 mg, about 180 mg to about 300 mg, about 210 mg to about 300 mg, about 240 mg to about 300 mg, about 270 mg to about 300 mg, about 30 mg to about 270 mg, about 60 mg to about 300 mg, about 70 mg to about 300 mg, about 80 mg to about 300 mg, about 90 mg to about 300 mg, about 120 mg to about 300 mg, about 150 mg to about 300 mg, about 180 mg to about 300 mg, about 210 mg to about 300 mg, about 240 mg to about 300 mg, about 270 mg to about 300 mg, about 30 mg to about 270 mg, about 60 mg to about 300 mg, about 15 ...180 mg to about 300 mg, about 210 mg to about 300 mg, about 240 mg to about 300 mg, about 270 mg to about 300 mg, about 30 mg to about 270 mg, about 60 mg to about 300 mg, about 150 mg to about 300 mg, about 250 mg to about 30 mg to about 270 mg, about 90 mg to about 270 mg, about 120 mg to about 270 mg, about 150 mg to about 270 mg, about 180 mg to about 270 mg, about 210 mg to about 270 mg, about 240 mg to about 270 mg, about 30 mg to about 240 mg, about 60 mg to about 240 mg, about 90 mg to about 240 mg, about 120 mg to about 240 mg, about 150 mg to about 240 mg g, about 180 mg to about 240 mg, about 210 mg to about 240 mg, about 30 mg to about 210 mg, about 60 mg to about 210 mg, about 90 mg to about 210 mg, about 120 mg to about 210 mg, about 150 mg to about 210 mg, about 180 mg to about 210 mg, about 30 mg to about 180 mg, about 60 mg to about 180 mg, about 90 mg to about 180 mg, about 120 mg to about In some embodiments, the fixed dose comprises about 30 mg to about 240 mg of bempedoic acid. In some embodiments, the fixed dose comprises about 120 mg to about 240 mg of bempedoic acid.

[0097] In some embodiments, the fixed dose contains about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg of bempedoic acid.

[0098] In some embodiments, the fixed dose combination may comprise from about 5 mg to about 120 mg, from about 5 mg to about 110 mg, from about 5 mg to about 100 mg, from about 5 mg to about 90 mg, from about 5 mg to about 80 mg, from about 5 mg to about 70 mg, from about 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5 mg to about 40 mg, from about 5 mg to about 30 mg, from about 5 mg to about 20 mg, from about 5 mg to about 10 mg, from about 15 mg to about 90 mg, from about 15 mg to about 80 mg, from about 15 mg to about 70 mg, from about 15 mg to about 60 mg, from about 15 mg to about 50 mg, from about 15 mg to about 40 mg, from about 15 mg to about 30mg, about 15mg to about 20mg, about 25mg to about 90mg, about 35mg to about 90mg, about 45mg to about 90mg, about 55mg to about 90mg, about 65mg to about 90mg, about 75mg to about 90mg, about 85mg to about 90mg, about 10mg to about 110mg, about 15mg to about 105mg, about 20mg to about 100mg, about 25mg to about 95mg, about 30mg to about 90mg, about 35mg to about 85mg, about 40mg to about 80mg, about 45mg to about 75mg, about 50mg to about 70mg, or about 55mg to about 65mg of tolvaptan. In some embodiments, the fixed dose contains about 5mg to about 120mg of tolvaptan. In some embodiments, the fixed dose contains about 5mg to about 90mg of tolvaptan.

[0099] In some embodiments, the fixed dose contains about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 120 mg of tolvaptan.

[0100] In certain embodiments, the fixed dose comprises about 30 mg to about 240 mg of bempedoic acid and about 5 mg to about 90 mg of tolvaptan. In certain embodiments, the fixed dose comprises about 120 mg to about 240 mg of bempedoic acid and about 5 mg to about 90 mg of tolvaptan. In certain embodiments, the fixed dose comprises about 30 mg to about 240 mg of bempedoic acid and about 5 mg to about 60 mg of tolvaptan. In certain embodiments, the fixed dose comprises about 120 mg to about 240 mg of bempedoic acid and about 5 mg to about 60 mg of tolvaptan.

[0101] In some embodiments, the fixed dose contains about 90 mg, about 60 mg, about 45 mg, about 30 mg, about 15 mg, about 10 mg, or about 5 mg of tolvaptan. In certain embodiments, the fixed dose contains about 180 mg of bempedoic acid.

[0102] In certain embodiments, the fixed dose combination comprises about 180 mg of bempedoic acid and about 5 mg of tolvaptan, about 180 mg of bempedoic acid and about 10 mg of tolvaptan, about 180 mg of bempedoic acid and about 15 mg of tolvaptan, about 180 mg of bempedoic acid and about 30 mg of tolvaptan, about 180 mg of bempedoic acid and about 45 mg of tolvaptan, about 180 mg of bempedoic acid and about 60 mg of tolvaptan, or about 180 mg of bempedoic acid and about 90 mg of tolvaptan.

[0103] In some embodiments, the fixed doses disclosed herein are formulated for oral administration.In some embodiments, the fixed doses disclosed herein are formulated as oral dosage forms.Examples of oral dosage forms include, but are not limited to, drenches, tablets, capsules, softgel capsules, cachets, pills, emulsions, lozenges, solutions, suspensions, boluses, powders, elixirs or syrups, pastilles, mouthwashes, granules, or pastes for application to the tongue.In some embodiments, the fixed doses are formulated as tablets.

[0104] In certain embodiments, the liquid dosage form of the fixed-dose combination described herein comprises one of an inert diluent, a solubilizing agent, and an emulsifying agent. In certain embodiments, the oral suspension of the pharmaceutical composition of the present disclosure comprises one or more suspending agents, including, but not limited to, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0105] In certain embodiments, the fixed dose combinations provided herein can be used to treat the diseases, disorders, or conditions described herein.

[0106] Pharmaceutical Compositions Also disclosed herein are pharmaceutical compositions that generally include bempedoic acid and / or tolvaptan and one or more pharma- ceutically acceptable excipients.

[0107] In certain embodiments, the pharmaceutical compositions described herein can be administered in unit dosage form and can be prepared by any method known in the art of pharmacy. The amount of bempedoic acid and tolvaptan compounds, or pharma- ceutically acceptable salts thereof, present in a single dosage form can vary depending on the patient being treated and / or the particular mode of administration.

[0108] In certain embodiments, tolvaptan and bempedoic acid can be combined in a single pharmaceutical composition for simultaneous administration, hi certain embodiments, tolvaptan and bempedoic acid can be formulated as individual pharmaceutical compositions for separate administration.

[0109] In certain embodiments, the amounts of bempedoic acid and tolvaptan, or pharma- ceutically acceptable salts thereof, that can be combined with a pharma- ceutically acceptable carrier to produce a single dosage form will generally be the amounts of the bempedoic acid and tolvaptan compounds, or pharma- ceutically acceptable salts thereof, that produce a therapeutic effect.

[0110] In some embodiments, the pharmaceutical composition comprises about 30 mg to about 300 mg, about 60 mg to about 300 mg, about 90 mg to about 300 mg, about 120 mg to about 300 mg, about 150 mg to about 300 mg, about 180 mg to about 300 mg, about 210 mg to about 300 mg, about 240 mg to about 300 mg, about 270 mg to about 300 mg, about 30 mg to about 270 mg, about 60 mg to about 300 mg, about 70 mg to about 300 mg, about 80 mg to about 300 mg, about 90 mg to about 300 mg, about 120 mg to about 300 mg, about 150 mg to about 300 mg, about 180 mg to about 300 mg, about 210 mg to about 300 mg, about 240 mg to about 300 mg, about 270 mg to about 300 mg, about 30 mg to about 270 mg, about 60 mg to about 300 mg, about 150 mg to about 300 mg, about 250 mg to about 300 mg, about 30 ... mg to about 270 mg, about 90 mg to about 270 mg, about 120 mg to about 270 mg, about 150 mg to about 270 mg, about 180 mg to about 270 mg, about 210 mg to about 270 mg, about 240 mg to about 270 mg, about 30 mg to about 240 mg, about 60 mg to about 240 mg, about 90 mg to about 240 mg, about 120 mg to about 240 mg, about 150 mg to about 240 mg g, about 180 mg to about 240 mg, about 210 mg to about 240 mg, about 30 mg to about 210 mg, about 60 mg to about 210 mg, about 90 mg to about 210 mg, about 120 mg to about 210 mg, about 150 mg to about 210 mg, about 180 mg to about 210 mg, about 30 mg to about 180 mg, about 60 mg to about 180 mg, about 90 mg to about 180 mg, about 120 mg to about 180mg, about 150mg to about 180mg, about 30mg to about 150mg, about 60mg to about 150mg, about 90mg to about 150mg, about 120mg to about 150mg, about 30mg to about 120mg, about 60mg to about 120mg, about 90mg to about 120mg, about 30mg to about 90mg, about 60mg to about 90mg, or about 30mg to about 60mg of bempedoic acid. In some embodiments, the pharmaceutical composition comprises about 30mg to about 240mg of bempedoic acid. In some embodiments, the pharmaceutical composition comprises about 120mg to about 240mg of bempedoic acid.

[0111] In some embodiments, the pharmaceutical composition comprises about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg of bempedoic acid.

[0112] In some embodiments, the pharmaceutical composition comprises about 5 mg to about 120 mg, about 5 mg to about 110 mg, about 5 mg to about 100 mg, about 5 mg to about 90 mg, about 5 mg to about 80 mg, about 5 mg to about 70 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg, about 5 mg to about 10 mg, about 15 mg to about 90 mg, about 15 mg to about 80 mg, about 15 mg to about 70 mg, about 15 mg to about 60 mg, about 15 mg to about 50 mg, about 15 mg to about 40 mg, about 15 mg to about The tolvaptan concentration is about 30 mg, about 15 mg to about 20 mg, about 25 mg to about 90 mg, about 35 mg to about 90 mg, about 45 mg to about 90 mg, about 55 mg to about 90 mg, about 65 mg to about 90 mg, about 75 mg to about 90 mg, about 85 mg to about 90 mg, about 10 mg to about 110 mg, about 15 mg to about 105 mg, about 20 mg to about 100 mg, about 25 mg to about 95 mg, about 30 mg to about 90 mg, about 35 mg to about 85 mg, about 40 mg to about 80 mg, about 45 mg to about 75 mg, about 50 mg to about 70 mg, or about 55 mg to about 65 mg. In some embodiments, the pharmaceutical composition comprises about 5 mg to about 120 mg of tolvaptan. In some embodiments, the pharmaceutical composition comprises about 5 mg to about 90 mg of tolvaptan.

[0113] In some embodiments, the pharmaceutical composition comprises about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg or about 120 mg of tolvaptan.

[0114] In certain embodiments, the pharmaceutical composition comprises about 30 mg to about 240 mg of bempedoic acid, about 5 mg to about 90 mg of tolvaptan, and one or more pharma- ceutically acceptable excipients. In certain embodiments, the pharmaceutical composition comprises about 120 mg to about 240 mg of bempedoic acid, about 5 mg to about 90 mg of tolvaptan, and one or more pharma- ceutically acceptable excipients. In certain embodiments, the pharmaceutical composition comprises about 30 mg to about 240 mg of bempedoic acid, about 5 mg to about 60 mg of tolvaptan, and one or more pharma- ceutically acceptable excipients. In certain embodiments, the pharmaceutical composition comprises about 120 mg to about 240 mg of bempedoic acid, about 5 mg to about 60 mg of tolvaptan, and one or more pharma- ceutically acceptable excipients.

[0115] In some embodiments, the pharmaceutical composition comprises about 90 mg, about 60 mg, about 45 mg, about 30 mg, about 15 mg, about 10 mg, or about 5 mg of tolvaptan. In certain embodiments, the pharmaceutical composition comprises about 180 mg of bempedoic acid.

[0116] In certain embodiments, the pharmaceutical composition comprises about 180 mg of bempedoic acid, about 5 mg of tolvaptan and one or more pharma- ceutically acceptable excipients; about 180 mg of bempedoic acid, about 10 mg of tolvaptan and one or more pharma- ceutically acceptable excipients; about 180 mg of bempedoic acid, about 15 mg of tolvaptan and one or more pharma- ceutically acceptable excipients; about 180 mg of bempedoic acid, about 30 mg of tolvaptan and one or more pharma- ceutically acceptable excipients; about 180 mg of bempedoic acid, about 45 mg of tolvaptan and one or more pharma- ceutically acceptable excipients; about 180 mg of bempedoic acid, about 60 mg of tolvaptan and one or more pharma- ceutically acceptable excipients; or about 180 mg of bempedoic acid, about 90 mg of tolvaptan and one or more pharma- ceutically acceptable excipients.

[0117] In certain embodiments, pharmaceutical compositions generally comprise a fixed dose drug as described herein and one or more pharma- ceutically acceptable excipients.

[0118] In certain embodiments, the solid dosage forms described herein for oral administration are prepared by mixing the pharmaceutical raw materials with one or more pharma- ceutically acceptable excipients. The pharmaceutical excipients may be selected from the group consisting of fillers or extenders, sweeteners, binders, humectants, disintegrants, preservatives, flavors, flavorings, antioxidants, solution retarders, absorption enhancers, wetting agents, absorbents, lubricants, colorants, and release control agents. In some embodiments, when the solid dosage form is a capsule, tablet, or pill, the pharmaceutical compositions described herein may also include a buffering agent. In some embodiments, when the solid dosage form is a gelatin capsule, the pharmaceutical composition may further include one or more excipients selected from lactose, milk sugar, high molecular weight polyethylene glycol, and combinations thereof.

[0119] In certain embodiments, the pharmaceutical composition of the present disclosure may include one or more excipients selected from the group consisting of cyclodextrin, cellulose, liposome, micelle forming agent, and polymer carrier. In some embodiments, the pharmaceutical composition of the present disclosure includes an antibacterial agent, an antifungal agent, or a combination thereof. Examples of antibacterial agents and antifungal agents include, but are not limited to, parabens, chlorobutanol, phenol, and sorbic acid. In some embodiments, the pharmaceutical composition of the present disclosure includes an isotonicity agent.

[0120] In some embodiments, the pharmaceutical composition disclosed herein is formulated for oral administration.In some embodiments, the pharmaceutical composition disclosed herein is formulated as oral dosage form.Examples of oral dosage form include, but are not limited to, drench, tablet, capsule, softgel capsule, cachet, pill, emulsion, lozenge, solution, suspension, bolus, powder, elixir or syrup, pastille, mouthwash, granule or paste for applying to tongue.In some embodiments, the pharmaceutical composition is formulated as tablet.

[0121] In certain embodiments, the liquid dosage form of the pharmaceutical composition described herein comprises one of an inert diluent, a solubilizing agent and an emulsifying agent.In certain embodiments, the oral suspension of the pharmaceutical composition of the present disclosure comprises one or more suspending agents, including ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0122] In some embodiments, the pharmaceutical compositions disclosed herein provide an immediate release of bempedoic acid. In some embodiments, the pharmaceutical compositions disclosed herein provide an extended release of bempedoic acid.

[0123] In certain embodiments, the pharmaceutical compositions described herein can be used for the treatment of a disease, disorder, or condition described herein.

[0124] Methods of Use and Treatment Provided herein is a method of treating ADPKD in a patient receiving tolvaptan therapy, the method comprising administering to the patient an effective amount of bempedoic acid.Also provided herein is a method of slowing the progression of ADPKD in a patient receiving tolvaptan therapy, the method comprising administering to the patient an effective amount of bempedoic acid.Also provided herein is a method of preventing renal failure, reducing total kidney volume and / or slowing the progression of renal dysfunction in a patient with ADPKD receiving tolvaptan therapy, the method comprising administering to the patient an effective amount of bempedoic acid.

[0125] In some embodiments, the effective amount of bempedoic acid is about 30 mg to about 240 mg. In some embodiments, the effective amount of bempedoic acid is about 120 mg to about 240 mg. In certain embodiments, the effective amount of bempedoic acid is about 180 mg.

[0126] In some embodiments, patients receiving an effective amount of bempedoic acid and tolvaptan therapy have a lower total kidney weight to body weight ratio than patients not receiving an effective amount of bempedoic acid and tolvaptan therapy, or receiving only an effective amount of bempedoic acid, or receiving only tolvaptan therapy. In some embodiments, patients receiving an effective amount of bempedoic acid and tolvaptan therapy have a lower blood urea nitrogen level than patients not receiving an effective amount of bempedoic acid and tolvaptan therapy, or receiving only an effective amount of bempedoic acid, or receiving only tolvaptan therapy.

[0127] In some embodiments, patients receiving an effective amount of bempedoic acid and tolvaptan therapy have a total kidney weight to body weight ratio of about 10 to about 140 percent, about 20 to about 140 percent, about 30 to about 140 percent, about 40 to about 140 percent, about 50 to about 140 percent, about 60 to about 140 percent, about 70 to about 140 percent, about 80 to about 140 percent, about 90 to about 140 percent, about 100 to about 140 percent, about 110 to about 140 percent, about 120 to about 140 percent, about 130 to about 140 percent, about 10 to about 80 percent, about 10 to about 70 percent, about 10 to about 60 percent, about 10 to about 50 percent, about 10 to about 40 percent, about 10 to about 30 percent, about 10 to about 20 percent, about 30 to about 70 percent, about 30 to about 80 percent, about 30 to about 90 percent, about 30 to about 10 ... 0 percent, about 40 to about 70 percent, about 50 to about 70 percent, about 60 to about 70 percent, about 40 to about 60 percent, about 40 to about 50 percent, about 10 to about 20 percent, about 20 to about 30 percent, about 30 to about 40 percent, about 40 to about 50 percent, about 50 to about 60 percent, about 60 to about 70 percent, about 70 to about 80 percent, about 80 to about 90 percent, about 90 to about 100 percent, about 100 to about 110 percent, about 110 to about 120 percent, about 120 to about 130 percent, or about 130 to about 140 percent lower than the total kidney weight to body weight ratio in a patient not receiving an effective amount of bempedoic acid and tolvaptan therapy, or receiving an effective amount of bempedoic acid only, or receiving tolvaptan therapy only.

[0128] In some embodiments, patients receiving an effective amount of bempedoic acid and tolvaptan therapy may have a blood urea nitrogen (BUN) level of about 2 to about 15 mg / dL, about 3 to about 15 mg / dL, about 4 to about 15 mg / dL, about 5 to about 15 mg / dL, about 6 to about 15 mg / dL, about 7 to about 15 mg / dL, about 8 to about 15 mg / dL, about 9 to about 15 mg / dL, about 10 to about 15 mg / dL, about 11 to about 15 mg / dL, about 12 to about 15 mg / dL, about 13 to about 15 mg / dL, about 14 to about 15 mg / dL, about 2 to about 14 mg / dL, about 2 to about 13 mg / dL, about 2 to about 12 mg / dL, about 2 to about 11 mg / dL, about 2 to about 10 mg / dL, about from about 2 to about 9 mg / dL, from about 2 to about 8 mg / dL, from about 2 to about 7 mg / dL, from about 2 to about 6 mg / dL, from about 2 to about 5 mg / dL, from about 2 to about 4 mg / dL, from about 2 to about 3 mg / dL, from about 3 to about 9 mg / dL, from about 4 to about 9 mg / dL, from about 5 to about 9 mg / dL, from about 6 to about 9 mg / dL, from about 7 to about 9 mg / dL, from about 8 to about 9 mg / dL, from about 3 to about 8 mg / dL, from about 3 to about 7 mg / dL, from about 3 to about 6 mg / dL, from about 3 to about 5 mg / dL or from about 3 to about 4 mg / dL lower than the BUN in a patient not receiving an effective amount of bempedoic acid and tolvaptan therapy, or receiving an effective amount of bempedoic acid only, or receiving tolvaptan therapy only.

[0129] In some embodiments, patients receiving an effective amount of bempedoic acid and tolvaptan therapy experience a decrease in estimated glomerular filtration rate (eGFR) of about 0.5 to about 5 mL / min / 1.73 m 2 / year, approx. 1 to approx. 5mL / min / 1.73m 2 / year, approx. 1.5 to approx. 5mL / min / 1.73m 2 / year, approx. 2 to approx. 5mL / min / 1.73m 2 / year, approx. 2.5 to approx. 5mL / min / 1.73m 2 / year, approx. 3 to 5 mL / min / 1.73 m 2 / year, approx. 3.5 to approx. 5mL / min / 1.73m 2 / year, approx. 4 to 5 mL / min / 1.73 m 2 / year, approx. 4.5 to approx. 5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 4.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 4mL / min / 1.73m 2 / year, approx. 0.5 to approx. 3.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 3mL / min / 1.73m 2 / year, approx. 0.5 to approx. 2.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 2mL / min / 1.73m 2 / year, approx. 0.5 to approx. 1.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 1 mL / min / 1.73 m 2 / year, approx. 1.7 to approx. 3.4mL / min / 1.73m 2 / year, approx. 1.9 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.1 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.3 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.5 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.7 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.9 to approx. 3.4mL / min / 1.73m 2 / year, approx. 3.1 to approx. 3.4 mL / min / 1.73 m 2 / year, approx. 3.3 to 3.4 mL / min / 1.73 m 2 / year, approx. 1.7 to approx. 1.9 mL / min / 1.73 m 2 / year, approx. 1.9 to approx. 2.1 mL / min / 1.73 m 2 / year, approx. 2.1 to approx. 2.3 mL / min / 1.73 m 2 / year, approx. 2.3 to approx. 2.5mL / min / 1.73m 2 / year, approx. 2.5 to approx. 2.7 mL / min / 1.73 m 2 / year, approx. 2.7 to approx. 2.9 mL / min / 1.73 m 2 / year, approx. 2.9 to approx. 3.1 mL / min / 1.73 m 2 / year, approx. 3.1 to approx. 3.3 mL / min / 1.73 m 2 / year or about 3.3 to 3.4 mL / min / 1.73 m 2 / year is lower than the eGFR per year in patients not receiving effective doses of bempedoic acid and tolvaptan therapy, or receiving effective doses of bempedoic acid only, or receiving tolvaptan therapy only.

[0130] In some embodiments, a patient receiving an effective amount of bempedoic acid and tolvaptan therapy may receive a 25% to 30% dose at 30° C. In some embodiments, a patient receiving an effective amount of bempedoic acid and tolvaptan therapy may receive a 25% to 30% dose at 30° C. In some embodiments, a patient receiving an effective amount of bempedoic acid and tolvaptan therapy may receive a 25% to 30% dose at 30° C. In some embodiments, a patient receiving an effective amount of bempedoic acid and tolvaptan therapy may receive a 25% to 30% dose at 30° C. percent / year, about 5.5 to about 7 percent / year, about 6 to about 7 percent / year, about 6.5 to about 7 percent / year, about 0 to about 6.5 percent / year, about 0 to about 6 percent / year, about 0 to about 5.5 percent / year, about 0 to about 5 percent / year, about 0 to about 4.5 percent / year, about 0 to about 4 percent / year, about 0 to about 3.5 percent / year, about 0 to about 3 percent / year, about 0 to about 2.5 percent / year, about 0 to about 2 percent / year, 100 to 1500 cents / year, about 0 to about 1.5 percent / year, about 0 to about 1 percent / year, about 0 to about 0.5 percent / year, about 1 to about 5 percent / year, about 1.5 to about 5 percent / year, about 2 to about 5 percent / year, about 2.5 to about 5 percent / year, about 3 to about 5 percent / year, about 3.5 to about 5 percent / year, about 4 to about 5 percent / year, about 4.5 to about 5 percent / year, about 1 to about 1.5 percent / year, about 1.5 to about 2 percent per year, about 2 to about 2.5 percent per year, about 2.5 to about 3 percent per year, about 3 to about 3.5 percent per year, about 3.5 to about 4 percent per year, about 4 to about 4.5 percent per year, or about 4.5 to about 5 percent per year, less than the percent increase in total kidney volume per year in patients not receiving an effective amount of bempedoic acid and tolvaptan therapy, or receiving an effective amount of bempedoic acid only, or receiving tolvaptan therapy only.

[0131] In some embodiments, patients receiving an effective amount of bempedoic acid and tolvaptan therapy have a composite incidence of a clinical endpoint selected from worsening renal function, renal pain, hypertension, and albuminuria of about 5 to about 50 percent, about 10 to about 50 percent, about 15 to about 50 percent, about 20 to about 50 percent, about 25 to about 50 percent, about 30 to about 50 percent, about 35 to about 50 percent, about 40 to about 50 percent, about 45 to about 50 percent, about 5 to about 45 percent, about 5 to about 40 percent, about 5 to about 35 percent, about 5 to about 30 percent, about 5 to about 25 percent, cents, about 5 to about 20 percent, about 5 to about 15 percent, about 5 to about 10 percent, about 15 to about 40 percent, about 20 to about 40 percent, about 25 to about 40 percent, about 30 to about 40 percent, about 35 to about 40 percent, about 15 to about 20 percent, about 20 to about 25 percent, about 25 to about 30 percent, about 30 to about 35 percent, or about 35 to about 40 percent lower than the composite incidence of the clinical endpoint in patients not receiving an effective amount of bempedoic acid and tolvaptan therapy, or receiving an effective amount of bempedoic acid only, or receiving tolvaptan therapy only.

[0132] In some embodiments, patients receiving an effective amount of bempedoic acid and tolvaptan therapy have higher hepatic AMPK activity than patients not receiving an effective amount of bempedoic acid or receiving only tolvaptan therapy. In some embodiments, patients receiving an effective amount of bempedoic acid and tolvaptan therapy have higher hepatic acetyl-coenzyme A carboxylase (ACC) phosphorylation than patients not receiving an effective amount of bempedoic acid or receiving only tolvaptan therapy. In some embodiments, patients receiving an effective amount of bempedoic acid and tolvaptan therapy have higher peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha) activity than patients receiving only tolvaptan therapy.

[0133] In some embodiments, an effective amount of bempedoic acid is administered. Examples of oral dosage forms include, but are not limited to, drenches, tablets, capsules, softgel capsules, cachets, pills, emulsions, lozenges, solutions, suspensions, boluses, powders, elixirs or syrups, pastilles, mouthwashes, granules, or pastes for application to the tongue. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0134] Also provided herein is a method of treating ADPKD in a patient in need thereof, the method comprising administering to the patient a fixed combination of bempedoic acid and tolvaptan, wherein the fixed combination comprises about 30 mg to about 240 mg of bempedoic acid and about 5 mg to about 90 mg of tolvaptan.Also provided herein is a method of treating ADPKD in a patient in need thereof, the method comprising administering to the patient a fixed combination of bempedoic acid and tolvaptan, wherein the fixed combination comprises about 120 mg to about 240 mg of bempedoic acid and about 5 mg to about 90 mg of tolvaptan. Also provided herein is a method of slowing the progression of ADPKD in a patient in need thereof, the method comprising administering to the patient a fixed combination of bempedoic acid and tolvaptan, wherein the fixed combination comprises about 30 mg to about 240 mg of bempedoic acid and about 5 mg to about 90 mg of tolvaptan. Also provided herein is a method of slowing the progression of ADPKD in a patient in need thereof, the method comprising administering to the patient a fixed combination of bempedoic acid and tolvaptan, wherein the fixed combination comprises about 120 mg to about 240 mg of bempedoic acid and about 5 mg to about 90 mg of tolvaptan.Also provided herein is a method of preventing renal failure, reducing total kidney volume and / or slowing the progression of renal dysfunction in a patient having ADPKD, the method comprising administering to the patient a fixed combination of bempedoic acid and tolvaptan, wherein the fixed combination comprises about 30 mg to about 240 mg of bempedoic acid and about 5 mg to about 90 mg of tolvaptan. Provided herein are methods of preventing renal failure, reducing total kidney volume and / or slowing the progression of renal dysfunction in a patient with ADPKD, the methods comprising administering to the patient a fixed combination of bempedoic acid and tolvaptan, wherein the fixed combination comprises about 120 mg to about 240 mg of bempedoic acid and about 5 mg to about 90 mg of tolvaptan.

[0135] In some embodiments, patients receiving a fixed-dose combination have a lower total kidney weight to body weight ratio than patients not receiving a fixed-dose combination, or patients receiving only about 30 mg to about 240 mg of bempedoic acid, or patients receiving only about 5 mg to about 90 mg of tolvaptan. In some embodiments, patients receiving a fixed-dose combination have a lower total kidney weight to body weight ratio than patients not receiving a fixed-dose combination, or patients receiving only about 120 mg to about 240 mg of bempedoic acid, or patients receiving only about 5 mg to about 90 mg of tolvaptan. In some embodiments, patients receiving a fixed-dose combination have a lower blood urea nitrogen level than patients not receiving a fixed-dose combination, or patients receiving only about 30 mg to about 240 mg of bempedoic acid, or patients receiving only about 5 mg to about 90 mg of tolvaptan. In some embodiments, patients receiving the fixed-dose combination have lower blood urea nitrogen levels than patients not receiving the fixed-dose combination, or patients receiving only about 120 mg to about 240 mg of bempedoic acid, or only about 5 mg to about 90 mg of tolvaptan.

[0136] In some embodiments, patients receiving the fixed combination drug have a total kidney to body weight ratio of about 10 to about 140 percent, about 20 to about 140 percent, about 30 to about 140 percent, about 40 to about 140 percent, about 50 to about 140 percent, about 60 to about 140 percent, about 70 to about 140 percent, about 80 to about 140 percent, about 90 to about 140 percent, about 100 to about 140 percent, about 110 to about 140 percent, about 120 to about 140 percent, about 130 to about 140 percent, about 10 to about 80 percent, about 10 to about 70 percent, about 10 to about 60 percent, about 10 to about 50 percent, about 10 to about 40 percent, about 10 to about 30 percent, about 10 to about 20 percent, about 30 to about 70 percent, about 40 from about 70 percent, from about 50 to about 70 percent, from about 60 to about 70 percent, from about 40 to about 60 percent, from about 40 to about 50 percent, from about 10 to about 20 percent, from about 20 to about 30 percent, from about 30 to about 40 percent, from about 40 to about 50 percent, from about 50 to about 60 percent, from about 60 to about 70 percent, from about 70 to about 80 percent, from about 80 to about 90 percent, from about 90 to about 100 percent, from about 100 to about 110 percent, from about 110 to about 120 percent, from about 120 to about 130 percent, or from about 130 to about 140 percent lower than the total kidney weight to body weight ratio in a patient not receiving a fixed dose, receiving only about 30 mg to about 240 mg of bempedoic acid, or receiving only about 5 mg to about 90 mg of tolvaptan.

[0137] In some embodiments, patients receiving the fixed dose have a total kidney to body weight ratio of about 10 to about 140 percent, about 20 to about 140 percent, about 30 to about 140 percent, about 40 to about 140 percent, about 50 to about 140 percent, about 60 to about 140 percent, about 70 to about 140 percent, about 80 to about 140 percent, about 90 to about 140 percent, about 100 to about 140 percent, about 110 to about 140 percent, about 120 to about 140 percent, about 130 to about 140 percent, about 10 to about 80 percent, about 10 to about 70 percent, about 10 to about 60 percent, about 10 to about 50 percent, about 10 to about 40 percent, about 10 to about 30 percent, about 10 to about 20 percent, about 30 to about 70 percent, about 40 to about 50 percent, about 10 to about 60 percent, about 10 to about 70 percent, about 10 to about 80 percent, about 10 to about 80 percent, about 10 to about 90 percent, about 10 to about 14 ... from about 70 percent, from about 50 to about 70 percent, from about 60 to about 70 percent, from about 40 to about 60 percent, from about 40 to about 50 percent, from about 10 to about 20 percent, from about 20 to about 30 percent, from about 30 to about 40 percent, from about 40 to about 50 percent, from about 50 to about 60 percent, from about 60 to about 70 percent, from about 70 to about 80 percent, from about 80 to about 90 percent, from about 90 to about 100 percent, from about 100 to about 110 percent, from about 110 to about 120 percent, from about 120 to about 130 percent, or from about 130 to about 140 percent lower than the total kidney weight to body weight ratio in a patient not receiving a fixed dose, receiving only about 120 mg to about 240 mg of bempedoic acid, or receiving only about 5 mg to about 90 mg of tolvaptan.

[0138] In some embodiments, patients receiving fixed dose combinations may have a BUN level of about 2 to about 15 mg / dL, about 3 to about 15 mg / dL, about 4 to about 15 mg / dL, about 5 to about 15 mg / dL, about 6 to about 15 mg / dL, about 7 to about 15 mg / dL, about 8 to about 15 mg / dL, about 9 to about 15 mg / dL, about 10 to about 15 mg / dL, about 11 to about 15 mg / dL, about 12 to about 15 mg / dL, about 13 to about 15 mg / dL, about 14 to about 15 mg / dL, about 2 to about 14 mg / dL, about 2 to about 13 mg / dL, about 2 to about 12 mg / dL, about 2 to about 11 mg / dL, about 2 to about 10 mg / dL, about 2 to about 9 mg / dL, about 2 to about 8 mg / dL, about 2 to about 15 ... about 2 to about 7 mg / dL, about 2 to about 6 mg / dL, about 2 to about 5 mg / dL, about 2 to about 4 mg / dL, about 2 to about 3 mg / dL, about 3 to about 9 mg / dL, about 4 to about 9 mg / dL, about 5 to about 9 mg / dL, about 6 to about 9 mg / dL, about 7 to about 9 mg / dL, about 8 to about 9 mg / dL, about 3 to about 8 mg / dL, about 3 to about 7 mg / dL, about 3 to about 6 mg / dL, about 3 to about 5 mg / dL or about 3 to about 4 mg / dL, lower than the BUN in a patient not receiving a fixed-dose combination, or receiving only about 30 mg to about 240 mg of bempedoic acid, or receiving only about 5 mg to about 90 mg of tolvaptan.

[0139] In some embodiments, patients receiving fixed dose combinations may have a BUN level of about 2 to about 15 mg / dL, about 3 to about 15 mg / dL, about 4 to about 15 mg / dL, about 5 to about 15 mg / dL, about 6 to about 15 mg / dL, about 7 to about 15 mg / dL, about 8 to about 15 mg / dL, about 9 to about 15 mg / dL, about 10 to about 15 mg / dL, about 11 to about 15 mg / dL, about 12 to about 15 mg / dL, about 13 to about 15 mg / dL, about 14 to about 15 mg / dL, about 2 to about 14 mg / dL, about 2 to about 13 mg / dL, about 2 to about 12 mg / dL, about 2 to about 11 mg / dL, about 2 to about 10 mg / dL, about 2 to about 9 mg / dL, about 2 to about 8 mg / dL, about 2 to about 9 mg / dL, about 2 to about 10 ... g / dL, about 2 to about 7 mg / dL, about 2 to about 6 mg / dL, about 2 to about 5 mg / dL, about 2 to about 4 mg / dL, about 2 to about 3 mg / dL, about 3 to about 9 mg / dL, about 4 to about 9 mg / dL, about 5 to about 9 mg / dL, about 6 to about 9 mg / dL, about 7 to about 9 mg / dL, about 8 to about 9 mg / dL, about 3 to about 8 mg / dL, about 3 to about 7 mg / dL, about 3 to about 6 mg / dL, about 3 to about 5 mg / dL or about 3 to about 4 mg / dL, lower than the BUN in a patient not receiving a fixed-dose combination, or receiving only about 120 mg to about 240 mg of bempedoic acid, or receiving only about 5 mg to about 90 mg of tolvaptan.

[0140] In some embodiments, patients receiving the fixed-dose combination have a decline in eGFR of about 0.5 to about 5 mL / min / 1.73 m 2 / year, approx. 1 to approx. 5mL / min / 1.73m 2 / year, approx. 1.5 to approx. 5mL / min / 1.73m 2 / year, approx. 2 to approx. 5mL / min / 1.73m 2 / year, approx. 2.5 to approx. 5mL / min / 1.73m 2 / year, approx. 3 to 5 mL / min / 1.73 m 2 / year, approx. 3.5 to approx. 5mL / min / 1.73m 2 / year, approx. 4 to 5 mL / min / 1.73 m 2 / year, approx. 4.5 to approx. 5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 4.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 4mL / min / 1.73m 2 / year, approx. 0.5 to approx. 3.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 3mL / min / 1.73m 2 / year, approx. 0.5 to approx. 2.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 2mL / min / 1.73m 2 / year, approx. 0.5 to approx. 1.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 1 mL / min / 1.73 m 2 / year, approx. 1.7 to approx. 3.4mL / min / 1.73m 2 / year, approx. 1.9 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.1 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.3 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.5 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.7 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.9 to approx. 3.4mL / min / 1.73m 2 / year, approx. 3.1 to approx. 3.4 mL / min / 1.73 m 2 / year, approx. 3.3 to 3.4 mL / min / 1.73 m 2 / year, approx. 1.7 to approx. 1.9 mL / min / 1.73 m 2 / year, approx. 1.9 to approx. 2.1 mL / min / 1.73 m 2 / year, approx. 2.1 to approx. 2.3 mL / min / 1.73 m 2 / year, approx. 2.3 to approx. 2.5mL / min / 1.73m 2 / year, approx. 2.5 to approx. 2.7 mL / min / 1.73 m 2 / year, approx. 2.7 to approx. 2.9 mL / min / 1.73 m 2 / year, approx. 2.9 to approx. 3.1 mL / min / 1.73 m 2 / year, approx. 3.1 to approx. 3.3 mL / min / 1.73 m 2 / year or about 3.3 to 3.4 mL / min / 1.73 m 2 / year lower than patients receiving no fixed-dose combination therapy, or receiving about 30 mg to about 240 mg of bempedoic acid alone, or about 5 mg to about 90 mg of tolvaptan alone.

[0141] In some embodiments, patients receiving the fixed-dose combination therapy experience a decrease in eGFR of about 0.5 to about 5 mL / min / 1.73 m 2 / year, approx. 1 to approx. 5mL / min / 1.73m 2 / year, approx. 1.5 to approx. 5mL / min / 1.73m 2 / year, approx. 2 to approx. 5mL / min / 1.73m 2 / year, approx. 2.5 to approx. 5mL / min / 1.73m 2 / year, approx. 3 to 5 mL / min / 1.73 m 2 / year, approx. 3.5 to approx. 5mL / min / 1.73m 2 / year, approx. 4 to 5 mL / min / 1.73 m 2 / year, approx. 4.5 to approx. 5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 4.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 4mL / min / 1.73m 2 / year, approx. 0.5 to approx. 3.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 3mL / min / 1.73m 2 / year, approx. 0.5 to approx. 2.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 2mL / min / 1.73m 2 / year, approx. 0.5 to approx. 1.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 1 mL / min / 1.73 m 2 / year, approx. 1.7 to approx. 3.4mL / min / 1.73m 2 / year, approx. 1.9 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.1 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.3 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.5 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.7 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.9 to approx. 3.4mL / min / 1.73m 2 / year, approx. 3.1 to approx. 3.4 mL / min / 1.73 m 2 / year, approx. 3.3 to 3.4 mL / min / 1.73 m 2 / year, approx. 1.7 to approx. 1.9 mL / min / 1.73 m 2 / year, approx. 1.9 to approx. 2.1 mL / min / 1.73 m 2 / year, approx. 2.1 to approx. 2.3 mL / min / 1.73 m 2 / year, approx. 2.3 to approx. 2.5mL / min / 1.73m 2 / year, approx. 2.5 to approx. 2.7 mL / min / 1.73 m 2 / year, approx. 2.7 to approx. 2.9 mL / min / 1.73 m 2 / year, approx. 2.9 to approx. 3.1 mL / min / 1.73 m 2 / year, approx. 3.1 to approx. 3.3 mL / min / 1.73 m 2 / year or about 3.3 to 3.4 mL / min / 1.73 m 2 / year lower than patients receiving no fixed-dose combination therapy, or receiving about 120 mg to about 240 mg of bempedoic acid alone, or about 5 mg to about 90 mg of tolvaptan alone.

[0142] In some embodiments, patients receiving the fixed combination drug have a risk of experiencing a decrease in total kidney volume increase of about 0 to about 7 percent / year, about 0.5 to about 7 percent / year, about 1 to about 7 percent / year, about 1.5 to about 7 percent / year, about 2 to about 7 percent / year, about 2.5 to about 7 percent / year, about 3 to about 7 percent / year, about 3.5 to about 7 percent / year, about 4 to about 7 percent / year, about 4.5 to about 7 percent / year, about 5 to about 7 percent / year, about 6 to about 7 percent / year, about 7 to about 7 percent / year, about 8 to about 7 percent / year, about 9 to about 7 percent / year, about 10 to about 7 percent / year, about 11 to about 7 percent / year, about 12 to about 7 percent / year, about 13 to about 7 percent / year, about 14 to about 7 percent / year, about 15 to about 7 percent / year, about 16 to about 7 percent / year, about 17 to about 7 percent / year, about 18 to about 7 percent / year, about 19 to about 7 percent / year, about 20 to about 21 percent / year, about 22 to about 23 percent / year, about 23 to about 24 percent / year, about 24 to about 25 percent / year, about 25 to about 26 percent / year, about 26 to about 27 percent / year, about 27 to about 28 percent / year, about 28 to about 29 percent / year, about 29 to about 30 percent / year, about 29 to about 31 percent / year, about 29 to about 32 percent / year, about 29 to about 33 percent / year, about 29 to about 34 percent / year, about 29 to about 35 percent / year, about 29 to about 36 percent / / year, about 5.5 to about 7 percent / year, about 6 to about 7 percent / year, about 6.5 to about 7 percent / year, about 0 to about 6.5 percent / year, about 0 to about 6 percent / year, about 0 to about 5.5 percent / year, about 0 to about 5 percent / year, about 0 to about 4.5 percent / year, about 0 to about 4 percent / year, about 0 to about 3.5 percent / year, about 0 to about 3 percent / year, about 0 to about 2.5 percent / year, about 0 to about 2 percent / year, about 0 to about 1.5 percent / year, about 0 to about 1 percent / year, about 0 to about 0.5 percent / year, about 1 to about 5 percent / year, about 1.5 to about 5 percent / year, about 2 to about 5 percent / year, about 2.5 to about 5 percent / year, about 3 to about 5 percent / year, about 3.5 to about 5 percent / year, about 4 to about 5 percent / year, about 4.5 to about 5 percent / year, about 1 to about 1.5 percent / year, about 1.5 to about 2 percent / year, about 2 to about 2.5 percent / year, about 2.5 to about 3 percent / year, about 3 to about 3.5 percent / year, about 3.5 to about 4 percent / year, about 4 to about 4.5 percent / year, or about 4.5 to about 5 percent / year less than the percent increase in total kidney volume per year in patients not receiving a fixed-dose combination, or receiving only about 30 mg to about 240 mg of bempedoic acid, or receiving only about 5 mg to about 90 mg of tolvaptan.

[0143] In some embodiments, patients receiving the fixed combination drug experience an increase in total kidney volume of about 0 to about 7 percent / year, about 0.5 to about 7 percent / year, about 1 to about 7 percent / year, about 1.5 to about 7 percent / year, about 2 to about 7 percent / year, about 2.5 to about 7 percent / year, about 3 to about 7 percent / year, about 3.5 to about 7 percent / year, about 4 to about 7 percent / year, about 4.5 to about 7 percent / year, about 5 to about 7 percent / year, about 6 to about 7 percent / year, about 7 to about 7 percent / year, about 8 to about 7 percent / year, about 9 to about 7 percent / year, about 10 to about 7 percent / year, about 11 to about 7 percent / year, about 12 to about 7 percent / year, about 13 to about 7 percent / year, about 14 to about 7 percent / year, about 15 to about 7 percent / year, about 16 to about 7 percent / year, about 17 to about 7 percent / year, about 18 to about 7 percent / year, about 19 to about 7 percent / year, about 20 to about 7 percent / year, about 21 to about 7 percent / year, about 22 to about 7 percent / year, about 23 to about 7 percent / year, about 24 to about 7 percent / year, about 25 to about 7 percent / year, about 26 to about 7 percent / year, about 27 to about 7 percent / year, about 28 to about 7 percent / year, about 29 ... per year, about 5.5 to about 7 percent per year, about 6 to about 7 percent per year, about 6.5 to about 7 percent per year, about 0 to about 6.5 percent per year, about 0 to about 6 percent per year, about 0 to about 5.5 percent per year, about 0 to about 5 percent per year, about 0 to about 4.5 percent per year, about 0 to about 4 percent per year, about 0 to about 3.5 percent per year, about 0 to about 3 percent per year, about 0 to about 2.5 percent per year, about 0 to about 2 percent / year, about 0 to about 1.5 percent / year, about 0 to about 1 percent / year, about 0 to about 0.5 percent / year, about 1 to about 5 percent / year, about 1.5 to about 5 percent / year, about 2 to about 5 percent / year, about 2.5 to about 5 percent / year, about 3 to about 5 percent / year, about 3.5 to about 5 percent / year, about 4 to about 5 percent / year, about 4.5 to about 5 percent / year, about 1 to about 1.5 percent / year, about 1.5 to about 2 percent / year, about 2 to about 2.5 percent / year, about 2.5 to about 3 percent / year, about 3 to about 3.5 percent / year, about 3.5 to about 4 percent / year, about 4 to about 4.5 percent / year, or about 4.5 to about 5 percent / year less than the increase in total kidney volume in patients not receiving a fixed-dose combination, or receiving only about 120 mg to about 240 mg of bempedoic acid, or receiving only about 5 mg to about 90 mg of tolvaptan.

[0144] In some embodiments, patients receiving the fixed-dose combination have a reduced incidence of a composite of a clinical endpoint selected from worsening renal function, renal pain, hypertension, and albuminuria of about 5 to about 50 percent, about 10 to about 50 percent, about 15 to about 50 percent, about 20 to about 50 percent, about 25 to about 50 percent, about 30 to about 50 percent, about 35 to about 50 percent, about 40 to about 50 percent, about 45 to about 50 percent, about 5 to about 45 percent, about 5 to about 40 percent, about 5 to about 35 percent, about 5 to about 30 percent, about 5 to about 25 percent, about 5 to about 20 percent, cents lower, about 5 to about 15 percent, about 5 to about 10 percent, about 15 to about 40 percent, about 20 to about 40 percent, about 25 to about 40 percent, about 30 to about 40 percent, about 35 to about 40 percent, about 15 to about 20 percent, about 20 to about 25 percent, about 25 to about 30 percent, about 30 to about 35 percent, or about 35 to about 40 percent lower than the composite incidence of the clinical endpoint in patients not receiving a fixed-dose combination, or in patients receiving only about 30 mg to about 240 mg of bempedoic acid, or in patients receiving only about 5 mg to about 90 mg of tolvaptan.

[0145] In some embodiments, patients receiving the fixed-dose combination have a reduced incidence of a composite of a clinical endpoint selected from worsening renal function, renal pain, hypertension, and albuminuria of about 5 to about 50 percent, about 10 to about 50 percent, about 15 to about 50 percent, about 20 to about 50 percent, about 25 to about 50 percent, about 30 to about 50 percent, about 35 to about 50 percent, about 40 to about 50 percent, about 45 to about 50 percent, about 5 to about 45 percent, about 5 to about 40 percent, about 5 to about 35 percent, about 5 to about 30 percent, about 5 to about 25 percent, about 5 to about 20 percent, cents lower, about 5 to about 15 percent, about 5 to about 10 percent, about 15 to about 40 percent, about 20 to about 40 percent, about 25 to about 40 percent, about 30 to about 40 percent, about 35 to about 40 percent, about 15 to about 20 percent, about 20 to about 25 percent, about 25 to about 30 percent, about 30 to about 35 percent, or about 35 to about 40 percent lower than the composite incidence of the clinical endpoint in patients not receiving a fixed-dose combination, or in patients receiving only about 120 mg to about 240 mg of bempedoic acid, or in patients receiving only about 5 mg to about 90 mg of tolvaptan.

[0146] In some embodiments, patients receiving a fixed-dose combination have higher hepatic AMPK activity than patients not receiving a fixed-dose combination or patients receiving only about 5 mg to about 90 mg of tolvaptan. In some embodiments, patients receiving a fixed-dose combination have a higher degree of hepatic ACC phosphorylation than patients not receiving a fixed-dose combination or patients receiving only about 5 mg to about 90 mg of tolvaptan. In some embodiments, patients receiving a fixed-dose combination have higher peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha) activity than patients receiving only about 5 mg to about 90 mg of tolvaptan.

[0147] In some embodiments, the fixed dose is administered orally.Examples of oral dosage forms include, but are not limited to, drenches, tablets, capsules, softgel capsules, cachets, pills, emulsions, lozenges, solutions, suspensions, boluses, powders, elixirs or syrups, pastilles, mouthwashes, granules, or pastes for application to the tongue.In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0148] In some embodiments, the fixed dose contains about 180 mg of bempedoic acid. In some embodiments, the fixed dose contains about 5 mg, about 10 mg, about 15 mg, about 30 mg, about 45 mg, about 60 mg, or about 90 mg of tolvaptan.

[0149] Also provided herein is a method of treating ADPKD in a patient in need thereof, comprising administering to the patient an effective amount of bempedoic acid and tolvaptan.Also provided herein is a method of slowing the progression of ADPKD in a patient in need thereof, comprising administering to the patient an effective amount of bempedoic acid and tolvaptan.Also provided herein is a method of preventing renal failure, reducing total kidney volume, and / or slowing the progression of renal dysfunction in a patient having ADPKD in need thereof, comprising administering to the patient an effective amount of bempedoic acid and tolvaptan.

[0150] In some embodiments, the effective amount of bempedoic acid and tolvaptan comprises about 30 mg to about 240 mg of bempedoic acid. In some embodiments, the effective amount of bempedoic acid and tolvaptan comprises about 120 mg to about 240 mg of bempedoic acid. In certain embodiments, the effective amount of bempedoic acid and tolvaptan comprises about 180 mg of bempedoic acid. In some embodiments, the effective amount of bempedoic acid and tolvaptan comprises about 5 mg, about 10 mg, about 15 mg, about 30 mg, about 45 mg, about 60 mg, or about 90 mg of tolvaptan.

[0151] In some embodiments, patients receiving effective amounts of bempedoic acid and tolvaptan have a lower total kidney weight to body weight ratio than patients receiving a placebo, or patients receiving only bempedoic acid, or patients receiving only tolvaptan. In some embodiments, patients receiving effective amounts of bempedoic acid and tolvaptan have a lower blood urea nitrogen level than patients receiving a placebo, or patients receiving only bempedoic acid, or patients receiving only tolvaptan.

[0152] In some embodiments, patients receiving effective amounts of bempedoic acid and tolvaptan have a total kidney weight to body weight ratio of about 10 to about 140 percent, about 20 to about 140 percent, about 30 to about 140 percent, about 40 to about 140 percent, about 50 to about 140 percent, about 60 to about 140 percent, about 70 to about 140 percent, about 80 to about 140 percent, about 90 to about 140 percent, about 100 to about 140 percent, about 110 to about 140 percent, about 120 to about 140 percent, about 130 to about 140 percent, about 10 to about 80 percent, about 10 to about 70 percent, about 10 to about 60 percent, about 10 to about 50 percent, about 10 to about 40 percent, about 10 to about 30 percent, about 10 to about 20 percent, about 30 to about 70 percent , about 40 to about 70 percent, about 50 to about 70 percent, about 60 to about 70 percent, about 40 to about 60 percent, about 40 to about 50 percent, about 10 to about 20 percent, about 20 to about 30 percent, about 30 to about 40 percent, about 40 to about 50 percent, about 50 percent to about 60 percent, about 60 percent to about 70 percent, about 70 percent to about 80 percent, about 80 percent to about 90 percent, about 90 to about 100 percent, about 100 to about 110 percent, about 110 to about 120 percent, about 120 to about 130 percent, or about 130 percent to about 140 percent lower than the total kidney weight to body weight ratio of patients receiving a placebo, patients receiving only bempedoic acid, or patients receiving only tolvaptan.

[0153] In some embodiments, patients receiving effective amounts of bempedoic acid and tolvaptan may have a BUN level of about 2 to about 15 mg / dL, about 3 to about 15 mg / dL, about 4 to about 15 mg / dL, about 5 to about 15 mg / dL, about 6 to about 15 mg / dL, about 7 to about 15 mg / dL, about 8 to about 15 mg / dL, about 9 to about 15 mg / dL, about 10 to about 15 mg / dL, about 11 to about 15 mg / dL, about 12 to about 15 mg / dL, about 13 to about 15 mg / dL, about 14 to about 15 mg / dL, about 2 to about 14 mg / dL, about 2 to about 13 mg / dL, about 2 to about 12 mg / dL, about 2 to about 11 mg / dL, about 2 to about 10 mg / dL, , about 2 to about 9 mg / dL, about 2 to about 8 mg / dL, about 2 to about 7 mg / dL, about 2 to about 6 mg / dL, about 2 to about 5 mg / dL, about 2 to about 4 mg / dL, about 2 to about 3 mg / dL, about 3 to about 9 mg / dL, about 4 to about 9 mg / dL, about 5 to about 9 mg / dL, about 6 to about 9 mg / dL, about 7 to about 9 mg / dL, about 8 to about 9 mg / dL, about 3 to about 8 mg / dL, about 3 to about 7 mg / dL, about 3 to about 6 mg / dL, about 3 to about 5 mg / dL or about 3 to about 4 mg / dL, lower than the BUN levels of patients receiving a placebo, patients receiving only bempedoic acid, or patients receiving only tolvaptan.

[0154] In some embodiments, patients receiving effective amounts of bempedoic acid and tolvaptan experience a decrease in eGFR of about 0.5 to about 5 mL / min / 1.73 m 2 / year, approx. 1 to approx. 5mL / min / 1.73m 2 / year, approx. 1.5 to approx. 5mL / min / 1.73m 2 / year, approx. 2 to approx. 5mL / min / 1.73m 2 / year, approx. 2.5 to approx. 5mL / min / 1.73m 2 / year, approx. 3 to 5 mL / min / 1.73 m 2 / year, approx. 3.5 to approx. 5mL / min / 1.73m 2 / year, about 4 to 5mL / min / 1.73m 2 / year, approx. 4.5 to approx. 5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 4.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 4mL / min / 1.73m 2 / year, approx. 0.5 to approx. 3.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 3mL / min / 1.73m 2 / year, approx. 0.5 to approx. 2.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 2mL / min / 1.73m 2 / year, approx. 0.5 to approx. 1.5mL / min / 1.73m 2 / year, about 0.5 to about 1mL / min / 1.73m 2 / year, approx. 1.7 to approx. 3.4mL / min / 1.73m 2 / year, approx. 1.9 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.1 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.3 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.5 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.7 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.9 to approx. 3.4mL / min / 1.73m 2 / year, approx. 3.1 to approx. 3.4 mL / min / 1.73 m 2 / year, approx. 3.3 to 3.4 mL / min / 1.73 m 2 / year, approx. 1.7 to approx. 1.9 mL / min / 1.73 m 2 / year, approx. 1.9 to approx. 2.1 mL / min / 1.73 m 2 / year, approx. 2.1 to approx. 2.3 mL / min / 1.73 m 2 / year, approx. 2.3 to approx. 2.5mL / min / 1.73m 2 / year, approx. 2.5 to approx. 2.7 mL / min / 1.73 m 2 / year, approx. 2.7 to approx. 2.9 mL / min / 1.73 m 2 / year, approx. 2.9 to approx. 3.1 mL / min / 1.73 m 2 / year, approx. 3.1 to approx. 3.3 mL / min / 1.73 m 2 / year or about 3.3 to 3.4 mL / min / 1.73 m 2 / year was lower than the decline in eGFR in patients receiving placebo, bempedoic acid alone, or tolvaptan alone.

[0155] In some embodiments, patients receiving effective amounts of bempedoic acid and tolvaptan experience a decrease in total kidney volume increase of about 0 to about 7 percent / year, about 0.5 to about 7 percent / year, about 1 to about 7 percent / year, about 1.5 to about 7 percent / year, about 2 to about 7 percent / year, about 2.5 to about 7 percent / year, about 3 to about 7 percent / year, about 3.5 to about 7 percent / year, about 4 to about 7 percent / year, about 4.5 to about 7 percent / year, about 5 to about 5 percent / year, about 6 to about 5 percent / year, about 7 to about 5 percent / year, about 8 to about 5 percent / year, about 9 to about 5 percent / year, about 10 to about 5 percent / year, about 11 to about 5 percent / year, about 12 to about 5 percent / year, about 13 to about 5 percent / year, about 14 to about 5 percent / year, about 15 to about 5 percent / year, about 16 to about 5 percent / year, about 17 to about 5 percent / year, about 18 to about 5 percent / year, about 19 to about 5 percent / year, about 20 to about 20 percent / year, about 21 to about 21 percent / year, about 22 to about 22 percent / year, about 23 to about 23 percent / year, about 24 to about 24 percent / year, about 25 to about 25 percent / year, about 26 to about 26 percent / year, about 27 to about 27 percent / year, about 28 to about 28 percent / year, about 29 to about 29 percent / year, about 30 to about 30 percent / year, about 31 to about 31 percent / year, about 32 to about 32 percent / year, about 33 to about 33 percent / year, about 34 to per year, about 5 to about 7 percent per year, about 5.5 to about 7 percent per year, about 6 to about 7 percent per year, about 6.5 to about 7 percent per year, about 0 to about 6.5 percent per year, about 0 to about 6 percent per year, about 0 to about 5.5 percent per year, about 0 to about 5 percent per year, about 0 to about 4.5 percent per year, about 0 to about 4 percent per year, about 0 to about 3.5 percent per year, about 0 to about 3 percent per year, about 0 to about 2.5 percent per year 10 cents / year, about 0 to about 2 percent / year, about 0 to about 1.5 percent / year, about 0 to about 1 percent / year, about 0 to about 0.5 percent / year, about 1 to about 5 percent / year, about 1.5 to about 5 percent / year, about 2 to about 5 percent / year, about 2.5 to about 5 percent / year, about 3 to about 5 percent / year, about 3.5 to about 5 percent / year, about 4 to about 5 percent / year, about 4.5 to about 5 percent / year, about 1 to about 1. 5 percent / year, about 1.5 to about 2 percent / year, about 2 to about 2.5 percent / year, about 2.5 to about 3 percent / year, about 3 to about 3.5 percent / year, about 3.5 to about 4 percent / year, about 4 to about 4.5 percent / year, or about 4.5 to about 5 percent / year less than the percent increase in total kidney volume per year in patients receiving a placebo, patients receiving only bempedoic acid, or patients receiving only tolvaptan.

[0156] In some embodiments, patients receiving an effective amount of bempedoic acid and tolvaptan experience an increased or decreased incidence of a composite of a clinical endpoint selected from worsening renal function, renal pain, hypertension, and albuminuria, including from about 5 to about 50 percent, from about 10 to about 50 percent, from about 15 to about 50 percent, from about 20 to about 50 percent, from about 25 to about 50 percent, from about 30 to about 50 percent, from about 35 to about 50 percent, from about 40 to about 50 percent, from about 45 to about 50 percent, from about 5 to about 45 percent, from about 5 to about 40 percent, from about 5 to about 35 percent, from about 5 to about 30 percent, from about 5 to about 25 percent, about 5 to about 20 percent, about 5 to about 15 percent, about 5 to about 10 percent, about 15 to about 40 percent, about 20 to about 40 percent, about 25 to about 40 percent, about 30 to about 40 percent, about 35 to about 40 percent, about 15 to about 20 percent, about 20 to about 25 percent, about 25 to about 30 percent, about 30 to about 35 percent, or about 35 to about 40 percent lower than the composite incidence of the clinical endpoint in patients receiving a placebo, patients receiving only bempedoic acid, or patients receiving only tolvaptan.

[0157] In some embodiments, patients receiving effective amounts of bempedoic acid and tolvaptan have a higher hepatic AMPK activity than patients receiving a placebo or tolvaptan alone. In some embodiments, patients receiving effective amounts of bempedoic acid and tolvaptan have a higher degree of hepatic ACC phosphorylation than patients receiving a placebo or tolvaptan alone. In some embodiments, patients receiving effective amounts of bempedoic acid and tolvaptan have a higher degree of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha) activity than patients receiving tolvaptan alone.

[0158] In some embodiments, an effective amount of bempedoic acid and an effective amount of tolvaptan are administered orally. Examples of oral dosage forms include, but are not limited to, drenches, tablets, capsules, softgel capsules, cachets, pills, emulsions, lozenges, solutions, suspensions, boluses, powders, elixirs or syrups, pastilles, mouthwashes, granules, or pastes for application to the tongue. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0159] Also provided herein is a method of treating ADPKD in a patient in need thereof, comprising administering to the patient an effective amount of bempedoic acid. Also provided herein is a method of slowing the progression of ADPKD in a patient in need thereof, comprising administering to the patient an effective amount of bempedoic acid. Also provided herein is a method of preventing renal failure, reducing total kidney volume, and / or slowing the progression of renal insufficiency in a patient having ADPKD in need thereof, comprising administering to the patient an effective amount of bempedoic acid.

[0160] In some embodiments, the effective amount of bempedoic acid is about 30 mg to about 240 mg. In some embodiments, the effective amount of bempedoic acid is about 120 mg to about 240 mg. In certain embodiments, the effective amount of bempedoic acid is about 180 mg.

[0161] In some embodiments, patients receiving an effective amount of bempedoic acid have a lower total kidney weight to body weight ratio than patients receiving a placebo or have a total kidney weight to body weight ratio that is equal to or lower than patients receiving tolvaptan therapy. In some embodiments, patients receiving an effective amount of bempedoic acid have a lower blood urea nitrogen level than patients receiving a placebo or have a blood urea nitrogen level that is equal to or lower than patients receiving tolvaptan therapy.

[0162] In some embodiments, a patient receiving an effective amount of bempedoic acid has a total kidney weight to body weight ratio of about 10 to about 140 percent, about 20 to about 140 percent, about 30 to about 140 percent, about 40 to about 140 percent, about 50 to about 140 percent, about 60 to about 140 percent, about 70 to about 140 percent, about 80 to about 140 percent, about 90 to about 140 percent, about 100 to about 140 percent, about 110 to about 140 percent, about 120 to about 140 percent, about 130 to about 140 percent, about 10 to about 80 percent, about 10 to about 70 percent, about 10 to about 60 percent, about 10 to about 50 percent, about 10 to about 40 percent, about 10 to about 30 percent, about 10 to about 20 percent, about 30 to about 70 percent, or about 40 to about 70 percent. or about 50 to about 70 percent, about 60 to about 70 percent, about 40 to about 60 percent, about 40 to about 50 percent, about 10 to about 20 percent, about 20 to about 30 percent, about 30 to about 40 percent, about 40 to about 50 percent, about 50 percent to about 60 percent, about 60 percent to about 70 percent, about 70 percent to about 80 percent, about 80 percent to about 90 percent, about 90 to about 100 percent, about 100 to about 110 percent, about 110 to about 120 percent, about 120 to about 130 percent, or about 130 percent to about 140 percent lower than the total kidney weight to body weight ratio of patients receiving a placebo, or equal to or lower than the total kidney weight to body weight ratio of patients receiving tolvaptan therapy.

[0163] In some embodiments, a patient receiving an effective amount of bempedoic acid may have a BUN level of about 2 to about 15 mg / dL, about 3 to about 15 mg / dL, about 4 to about 15 mg / dL, about 5 to about 15 mg / dL, about 6 to about 15 mg / dL, about 7 to about 15 mg / dL, about 8 to about 15 mg / dL, about 9 to about 15 mg / dL, about 10 to about 15 mg / dL, about 11 to about 15 mg / dL, about 12 to about 15 mg / dL, about 13 to about 15 mg / dL, about 14 to about 15 mg / dL, about 2 to about 14 mg / dL, about 2 to about 13 mg / dL, about 2 to about 12 mg / dL, about 2 to about 11 mg / dL, about 2 to about 10 mg / dL, about 2 to about 15 ... from about 2 to about 8 mg / dL, from about 2 to about 7 mg / dL, from about 2 to about 6 mg / dL, from about 2 to about 5 mg / dL, from about 2 to about 4 mg / dL, from about 2 to about 3 mg / dL, from about 3 to about 9 mg / dL, from about 4 to about 9 mg / dL, from about 5 to about 9 mg / dL, from about 6 to about 9 mg / dL, from about 7 to about 9 mg / dL, from about 8 to about 9 mg / dL, from about 3 to about 8 mg / dL, from about 3 to about 7 mg / dL, from about 3 to about 6 mg / dL, from about 3 to about 5 mg / dL or from about 3 to about 4 mg / dL, a lower BUN than patients receiving a placebo, or a BUN that is equal to or lower than the BUN of patients receiving tolvaptan therapy.

[0164] In some embodiments, patients receiving an effective amount of bempedoic acid experience a decrease in eGFR of about 0.5 to about 5 mL / min / 1.73 m 2 / year, approx. 1 to approx. 5mL / min / 1.73m 2 / year, approx. 1.5 to approx. 5mL / min / 1.73m 2 / year, approx. 2 to approx. 5mL / min / 1.73m 2 / year, approx. 2.5 to approx. 5mL / min / 1.73m 2 / year, approx. 3 to 5 mL / min / 1.73 m 2 / year, approx. 3.5 to approx. 5mL / min / 1.73m 2 / year, approx. 4 to 5 mL / min / 1.73 m 2 / year, approx. 4.5 to approx. 5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 4.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 4mL / min / 1.73m 2 / year, approx. 0.5 to approx. 3.5mL / min / 1.73m 2 / year, about 0.5 to about 3mL / min / 1.73m 2 / year, approx. 0.5 to approx. 2.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 2mL / min / 1.73m 2 / year, approx. 0.5 to approx. 1.5mL / min / 1.73m 2 / year, approx. 0.5 to approx. 1 mL / min / 1.73 m 2 / year, approx. 1.7 to approx. 3.4mL / min / 1.73m 2 / year, approx. 1.9 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.1 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.3 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.5 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.7 to approx. 3.4mL / min / 1.73m 2 / year, approx. 2.9 to approx. 3.4mL / min / 1.73m 2 / year, approx. 3.1 to approx. 3.4 mL / min / 1.73 m 2 / year, approx. 3.3 to 3.4 mL / min / 1.73 m 2 / year, approx. 1.7 to approx. 1.9 mL / min / 1.73 m 2 / year, approx. 1.9 to approx. 2.1 mL / min / 1.73 m 2 / year, approx. 2.1 to approx. 2.3 mL / min / 1.73 m 2 / year, approx. 2.3 to approx. 2.5mL / min / 1.73m 2 / year, approx. 2.5 to approx. 2.7 mL / min / 1.73 m 2 / year, approx. 2.7 to approx. 2.9 mL / min / 1.73 m 2 / year, approx. 2.9 to approx. 3.1 mL / min / 1.73 m 2 / year, approx. 3.1 to approx. 3.3 mL / min / 1.73 m 2 / year or about 3.3 to 3.4 mL / min / 1.73 m 2 / year, a lower eGFR decline per year than patients receiving placebo, or a decline in eGFR per year that is equal to or lower than the decline in eGFR per year in patients receiving tolvaptan therapy.

[0165] In some embodiments, a patient being administered an effective amount of bempedoic acid has a progression of increase in total kidney volume of about 0 to about 7 percent / year, about 0.5 to about 7 percent / year, about 1 to about 7 percent / year, about 1.5 to about 7 percent / year, about 2 to about 7 percent / year, about 2.5 to about 7 percent / year, about 3 to about 7 percent / year, about 3.5 to about 7 percent / year, about 4 to about 7 percent / year, about 4.5 to about 7 percent / year, about 5 to about 7 percent / year, about 6 to about 7 percent / year, about 7 to about 7 percent / year, about 8 to about 7 percent / year, about 9 to about 7 percent / year, about 10 to about 7 percent / year, about 11 to about 7 percent / year, about 12 to about 7 percent / year, about 13 to about 7 percent / year, about 14 to about 7 percent / year, about 15 to about 7 percent / year, about 16 to about 7 percent / year, about 17 to about 7 percent / year, about 18 to about 7 percent / year, about 19 to about 20 percent / year, about 21 to about 22 percent / year, about 22 to about 23 percent / year, about 23 to about 24 percent / year, about 24 to about 25 percent / year, about 25 to about 26 percent / year, about 26 to about 27 percent / year, about 27 to about 28 percent / year, about 28 to about 29 percent / year, about 29 to about 30 percent / year, about 29 to about 31 percent / year, about 29 to about 32 percent / year, about 29 to about 33 percent / year, about 29 to about 34 percent / year, about 29 to about 35 percent / year, about 29 to 7 percent / year, about 5.5 to about 7 percent / year, about 6 to about 7 percent / year, about 6.5 to about 7 percent / year, about 0 to about 6.5 percent / year, about 0 to about 6 percent / year, about 0 to about 5.5 percent / year, about 0 to about 5 percent / year, about 0 to about 4.5 percent / year, about 0 to about 4 percent / year, about 0 to about 3.5 percent / year, about 0 to about 3 percent / year, about 0 to about 2.5 percent / year, about 0 to about 2 percent / year, 100 to 1500 cents / year, about 0 to about 1.5 percent / year, about 0 to about 1 percent / year, about 0 to about 0.5 percent / year, about 1 to about 5 percent / year, about 1.5 to about 5 percent / year, about 2 to about 5 percent / year, about 2.5 to about 5 percent / year, about 3 to about 5 percent / year, about 3.5 to about 5 percent / year, about 4 to about 5 percent / year, about 4.5 to about 5 percent / year, about 1 to about 1.5 percent / year, about 1.5 to about 2 percent pts / year, about 2 to about 2.5 percent / year, about 2.5 to about 3 percent / year, about 3 to about 3.5 percent / year, about 3.5 to about 4 percent / year, about 4 to about 4.5 percent / year, or about 4.5 to about 5 percent / year, less than the percent increase in total kidney volume / year in patients receiving placebo, or the percent increase in total kidney volume / year is equal to or less than the percent increase in total kidney volume / year in patients receiving tolvaptan alone.

[0166] In some embodiments, patients receiving an effective amount of bempedoic acid have a composite incidence of a clinical endpoint selected from worsening renal function, renal pain, hypertension, and albuminuria that is about 5 to about 50 percent, about 10 to about 50 percent, about 15 to about 50 percent, about 20 to about 50 percent, about 25 to about 50 percent, about 30 to about 50 percent, about 35 to about 50 percent, about 40 to about 50 percent, about 45 to about 50 percent, about 5 to about 45 percent, about 5 to about 40 percent, about 5 to about 35 percent, about 5 to about 30 percent, about 5 to about 25 percent, about 5 to about 20 percent, or about 5 to about 15 percent, about 5 to about 10 percent, about 15 to about 40 percent, about 20 to about 40 percent, about 25 to about 40 percent, about 30 to about 40 percent, about 35 to about 40 percent, about 15 to about 20 percent, about 20 to about 25 percent, about 25 to about 30 percent, about 30 to about 35 percent, or about 35 to about 40 percent lower than the composite incidence of the clinical endpoint in patients receiving a placebo, or an equivalent or lower incidence of a clinical endpoint selected from worsening renal function, renal pain, hypertension, and albuminuria compared to patients receiving tolvaptan therapy.

[0167] In some embodiments, the effective amount of bempedoic acid is administered orally.Examples of oral dosage forms include, but are not limited to, drench, tablet, capsule, softgel capsule, cachet, pill, emulsion, lozenge, solution, suspension, bolus, powder, elixir or syrup, pastille, mouthwash, granule or paste for applying to tongue.In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0168] Also provided herein are methods of treating dyslipidemia in a patient in need thereof, generally comprising administering to the patient an effective amount of tolvaptan and an effective amount of bempedoic acid. In some embodiments, the methods reduce LDL-C in the patient's blood or serum. In some embodiments, the methods reduce the patient's systolic and / or diastolic blood pressure. In some embodiments, the methods reduce hsCRP in the patient's blood or serum. In some embodiments, the methods reduce the patient's body weight. In some embodiments, the methods reduce the risk of atherosclerotic cardiovascular disease in the patient.

[0169] In some embodiments, tolvaptan is administered orally. In some embodiments, bempedoic acid and tolvaptan are formulated as an oral dosage form. Examples of oral dosage forms include, but are not limited to, drenches, tablets, capsules, softgel capsules, cachets, pills, emulsions, lozenges, solutions, suspensions, boluses, powders, elixirs or syrups, pastilles, mouthwashes, granules, or pastes for application to the tongue. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0170] In some embodiments, the methods disclosed herein reduce the level of apoB in the patient's blood or serum below the levels of patients not receiving a combination of tolvaptan and bempedoic acid. In some embodiments, the methods disclosed herein reduce the level of non-high density lipoprotein cholesterol in the patient's blood or serum below the levels of patients not receiving a combination of tolvaptan and bempedoic acid. In some embodiments, the methods disclosed herein reduce the level of triglycerides in the patient's blood or serum below the levels of patients not receiving a combination of tolvaptan and bempedoic acid. In some embodiments, the methods disclosed herein reduce the number of LDL particles in the patient's blood or serum below that of patients not receiving a combination of tolvaptan and bempedoic acid. In some embodiments, the methods disclosed herein reduce the size of VLDL particles in the patient's blood or serum below the sizes of patients not receiving a combination of tolvaptan and bempedoic acid. In some embodiments, the methods disclosed herein reduce the number of VLDL particles in the patient's blood or serum below that of patients not receiving a combination of tolvaptan and bempedoic acid. In some embodiments, the methods disclosed herein increase the level of apoA1 in the patient's blood or serum compared to the level in a patient not receiving a combination of tolvaptan and bempedoic acid. In some embodiments, the methods disclosed herein do not alter the level of apoA1 in the patient's blood or serum compared to the level of apoA1 in the patient not receiving a combination of tolvaptan and bempedoic acid. In some embodiments, the methods disclosed herein decrease the level of apoA1 in the patient's blood or serum compared to the level in a patient not receiving a combination of tolvaptan and bempedoic acid.

[0171] In certain embodiments, the methods disclosed herein include administering the combined therapeutic agents (e.g., bempedoic acid and tolvaptan) to a patient in a single dosage form. In certain embodiments, the methods disclosed herein include administering the therapeutic agents (e.g., bempedoic acid and tolvaptan) to a patient in separate dosage forms.

[0172] In some embodiments, the patient is a human. EXAMPLES

[0173] Below are examples of specific embodiments for carrying out the present disclosure. These examples are provided for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way.

[0174] Terms not directly defined herein shall be understood to have the meanings generally associated with them as understood in the art of the present disclosure. Certain terms are discussed herein to provide additional guidance to those skilled in the art in describing the compositions, devices, methods, etc. of the aspects of the present disclosure and how to make or use them. It will be understood that the same thing can be said in more than one way. As a result, alternative language and synonyms may be used for any one or more of the terms discussed herein. No importance is placed on whether a term is or is not detailed herein. Some synonyms or alternative methods, materials, etc. are provided. The description of one or a few synonyms or equivalents does not exclude the use of other synonyms or equivalents unless expressly stated. The use of examples, including examples of terms, is for illustrative purposes only and does not limit the scope and meaning of the aspects disclosed herein.

[0175] Example 1: Immunoblot assay of FATP2 and ACLY protein expression in various mouse tissues and kidney cell lines This example describes immunoblot assays evaluating the expression of FATP2 and ACLY proteins in mouse liver, lung, kidney, spleen, muscle tissue, and mouse epithelial cells derived from proximal tubules and inner medullary collecting ducts.

[0176] FATP2 (ACSVL1; SLC27A2) protein expression was observed in immunoblots of homogenates of different mouse tissues and kidney cell lines. Immunoblots of various mouse tissues (Figure 1A, left) revealed the expression of two distinct FATP2 isoforms. The short splice variant (FATP2b, ∼55 kDa), which lacks the protein domain required for the conversion of bempedoic acid to its active metabolite, bempedoic acid-CoA, was expressed in all tissues tested. However, the long-chain form (FATP2a, ∼70 kDa) was significantly expressed only in liver and kidney tissues, and the conversion of the ETC-1002 prodrug to its active form was specifically observed only in these tissues. FATP2a and FATP2b isoforms were expressed in immortalized mouse kidney epithelial cells derived from both proximal tubules and inner medullary collecting ducts, with or without knockout of the Pkd1 gene (Figure 1A, right).

[0177] Similar protein expression levels of both isoforms of FATP2 were also observed in both wild-type (WT) and ADPKD mutant (Pkd1RC / RC) mouse kidney tissues ( Fig. 1B ).

[0178] Pkd1 RC / RC ACLY protein correlated with disease severity in a mouse model of ADPKD that lacked ACLY. ACLY protein expression and activity were increased in Pkd1- / - kidney epithelial cells compared with controls in vitro.

[0179] Expression of tACLY (total ACLY) and pS455ACLY in mouse epithelial cells derived from the inner medullary collecting duct (IMCD) was examined by immunoblotting (Figure 1C) showing that expression of activated (pS455) ACLY was increased relative to tACLY in Pkd1-null (ID1-3E5) cells compared to wild-type (WT) (IMCD3) cells (densitometric quantification revealed a significant ~50% increase in the pS455-ACLY / t-ACLY ratio in ID1-3E5 cells (p<0.05, unpaired t-test) (Figure 1D)). Total protein staining shows comparable loading between different lanes. Cells were pretreated with a novel small molecule ACLY inhibitor (+ or -, as indicated) prior to lysis and immunoblotting.

[0180] Immunoblotting of mouse epithelial cells from the proximal tubule (PT) showed higher protein expression of total ACLY (tACLY) and activated ACLY (Fig. 1E) as detected with a phospho-specific antibody against Ser455 (pS455ACLY), a known phosphorylation and activation site of AKT. Cells in which Pkd1 expression was knocked out in both alleles showed a significant increase of up to 250% in the pS455-ACLY / t-ACLY ratio in ID1-3E5 cells compared to cells heterozygous for Pkd1 deletion (p<0.05, unpaired t-test) (Fig. 1F)).

[0181] Example 2: Growth inhibition study of ACLY inhibitors bempedoic acid (ETC-1002) and SB-204990 in Pkd1- / - renal epithelial cells in 3D culture This example describes cell proliferation inhibition studies in 3D cultures of renal epithelial cells using either the ACLY inhibitor bempedoic acid or SB-204990, which has the structure of formula (III). JPEG2024521354000003.jpg34170

[0182] ACLY inhibitors alone inhibited cyst growth in 3D cultures of proximal tubule (PT)-derived Pkd1- / - kidney epithelial cells. Cells were cultured in Matrigel for 12 days and treated with 10 μM forskolin + 100 μM IBMX for 11 days, followed by treatment with either vehicle (DMSO; CON), 500 μM metformin, 100 μM ETC-1002 (bempedoic acid), or 30 μM SB-204990 alone or in combination as indicated for the final 3 days (Figure 2A). Summary data revealed that each treatment significantly reduced cyst area relative to controls. Error bars indicate 95% confidence intervals (CI) ( * P < 0.05, ** P < 0.01, *** P < 0.001, indicated comparisons by one-way ANOVA and Tukey's multiple comparison test) (Figure 2B).

[0183] ETC-1002 inhibited cyst growth in inner medullary collecting duct (IMCD)-derived Pkd1- / - renal epithelial cells in 3D culture. Cells were cultured in Matrigel for 6 days and treated for the last 3 days with 10 μM forskolin + 100 μM IBMX ± 500 μM metformin and / or 100 μM ETC-1002 (bempedoic acid), alone or in combination (Figure 2C). Summarized data revealed that each treatment alone significantly reduced cyst area relative to controls. Error bars indicate 95% confidence intervals ( * P<0.05, ** P<0.01, *** P < 0.001 by one-way ANOVA and Tukey's multiple comparison test) (Figure 2D).

[0184] Example 3: Study investigating the effects of bempedoic acid and tolvaptan alone and in combination in an early-onset ADPKD mouse model This example describes the characteristics of an early-onset, rapid-growth ADPKD mouse model, Pkd1 fl / fl; Pax8-rtTA; Tet-O-Cre homozygote, on a C57BL / 6 background.

[0185] Pkd1 deletion and rapidly progressive PKD were induced in Cre+ mice by intraperitoneal administration of doxycycline on postnatal days 10 and 11 (P10 and P11). Mice were treated with various drugs and combinations or vehicle by oral gavage daily from P12-P21 and then sacrificed at age P22 to harvest kidneys for histology, weight measurement, and blood urea nitrogen (BUN) measurements. Treatments included vehicle, tolvaptan 30 mg / kg / d, tolvaptan 100 mg / kg / d, bempedoic acid 30 mg / kg / d, tolvaptan 30 mg / kg / d + bempedoic acid 30 mg / kg / d, and tolvaptan 100 mg / kg / d + bempedoic acid 30 mg / kg / d, as well as an uninduced, untreated group without PKD. Each treatment group consisted of 3-6 mice. Representative H&E (hematoxylin and eosin) staining of kidney sections from Cre+ mice at P22 shows a rapid increase in kidney size over time (vehicle vs. uninduced). Administration of tolvaptan or ETC-1002 (bempedoic acid), respectively, showed a significant decrease in kidney size compared to vehicle controls (Figure 3A).

[0186] Cre+ mice had a dramatic increase in total kidney weight to body weight ratio at the time of euthanasia compared to Cre control mice. Administration of tolvaptan (30 mg / kg / d) or (100 mg / kg / d) each decreased total kidney weight to body weight ratio. Bempedoic acid (30 mg / kg / d) administered alone also significantly decreased total kidney weight to body weight ratio to a similar extent. Total kidney weight to body weight ratio was further decreased when combined with tolvaptan (30 or 100 mg / kg / d), and such combination was lower than either treatment alone (Figure 3B). Bempedoic acid (30 mg / kg / d) decreased total kidney weight to body weight ratio compared to vehicle (6.9 ± 0.4% vs. 11.9 ± 1.2%, P < 0.01, n = 3-6, unpaired t test). Similarly, tolvaptan (100 mg / kg / day) reduced the total kidney weight to body weight ratio compared with vehicle (7.8 ± 1.0%, P < 0.05, n = 6). The addition of bempedoic acid to tolvaptan further reduced the total kidney weight to body weight ratio compared with the tolvaptan alone group (4.9 ± 0.6%, P < 0.05).

[0187] BUN was also dramatically increased in Cre+ mice at the time of euthanasia compared to Cre control mice. Administration of tolvaptan (30 mg / kg / d) or (100 mg / kg / d) each dose-dependently reduced BUN. Bempedoic acid (30 mg / kg / d) also significantly reduced BUN to the same extent as tolvaptan when administered alone, but further reduced BUN when combined with tolvaptan (30 mg / kg / d or 100 mg / kg / d), such that the combination reduced BUN more than either treatment alone (Figure 3C). Bempedoic acid (30 mg / kg / d) reduced BUN compared to vehicle (59 ± 13 vs. 107 ± 14 mg / dL, P < 0.05). Tolvaptan also dose-dependently decreased relative BUN at 30 mg / kg / d (68±8, P<0.05) and 100 mg / kg / d (35±7, P<0.01). The addition of bempedoic acid to 30 mg / kg / d of tolvaptan further decreased BUN significantly (38±7, P<0.05).

[0188] At the end of the study, lysates of kidney samples were prepared in buffer and separated by SDS-PAGE. Separated proteins were electrophoresed onto membranes. Nonspecific binding was blocked and membranes were probed with antibodies against phosphorylated (Thr172)-AMPK, phosphorylated P70S6K, phosphorylated ERK, phosphorylated ACLY, total KIM-1 and total neutrophil gelatinase-associated lipocalin (NGAL). Membranes were incubated with appropriate detection antibodies and relative signal intensities were measured. Protein levels were normalized to total protein levels. Bempedoic acid treatment reduced ACLY activity (Figure 8) and stimulated AMPK activity (Figure 5A / 5B). Bempedoic acid also inhibited mTOR (Figure 6A / 6B), ERK (Figure 7) and NGAL (Figure 9A / 9B) signaling pathways whose expression is upregulated in ADPKD. Finally, bempedoic acid also dramatically reduced the expression of KIM-1, a marker of renal injury, by more than 70% (Figure 4A / 4B), and to a lesser extent, neutrophil gelatinase-associated lipocalin (NGAL) expression. These effects of bempedoic acid occurred both alone and in combination with tolvaptan therapy.

[0189] Lysates of liver samples were prepared in buffer and separated by SDS-PAGE. Separated proteins were electrophoresed onto membranes. Nonspecific binding was blocked and membranes were probed with antibodies against pACLY, pThr172AMPKα, PGC1α, FATP2, pACC and cleaved Cas3. Membranes were incubated with appropriate detection antibodies and relative signal intensity was measured. Target protein levels were normalized to total protein levels. Bempedoic acid, alone and in combination with tolvaptan, inhibited pACLY (an activation marker) (Figure 10A / 10B) and increased the expression of FATP2 (Figure 11A / 11B). Bempedoic acid also increased AMPK activity (Figure 12A / 12B) and promoted phosphorylation of the cone AMPK target ACC in liver tissue (Figure 13A / 13B).

[0190] Example 4: Study examining the effects of bempedoic acid in a slow-onset, late-onset ADPKD mouse model This example describes the characterization of the late onset ADPKD mouse model Pkd1fl / fl;Pax8-rtTA;Tet-On-Cre when treated with bempedoic acid.

[0191] Late Pkd1 knockout and slowly progressive PKD were induced in Cre+ mice by intraperitoneal administration of doxycycline (50 mg / kg / day) on postnatal days 27-29 (P27-P29) and again on P43 and P57. Mice were then sacrificed on P28, P60, and P120, and the total kidney weight to body weight ratio was measured. This ratio was dramatically increased in male control mice on P60 and in both male and female control mice on P120, compared to Cre- control mice on P28. Treatment with bempedoic acid (30 mg / kg / d, mixed in the diet, starting on P30 and continuing until P60 or P120) significantly reduced the total kidney weight to body weight ratio at P60 in male mice, and this trend was also observed at P120 in both male and female mice (Figure 9).

[0192] Incorporation by Reference The entire disclosure of each patent document and scientific article referenced herein is incorporated by reference for all purposes.

[0193] Equivalent The present disclosure may be embodied in other specific forms without departing from its spirit or essential characteristics. Therefore, the above-described embodiments should be considered in all respects as illustrative rather than limiting the disclosure described herein. The scope of the present disclosure is indicated by the appended claims rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. A fixed-dose drug or pharmaceutical composition comprising bempedoic acid and tolvaptan.

2. 2. The fixed dose or pharmaceutical composition of claim 1, wherein the fixed dose or pharmaceutical composition contains from about 30 mg to about 240 mg of bempedoic acid.

3. 3. The fixed dose or pharmaceutical composition of claim 1 or 2, wherein the fixed dose or pharmaceutical composition comprises from about 5 mg to about 120 mg of tolvaptan, from about 5 mg to about 90 mg of tolvaptan, or from about 5 mg to about 60 mg of tolvaptan.

4. 3. The fixed dose or pharmaceutical composition of claim 1 or 2, wherein the fixed dose or pharmaceutical composition comprises about 5 mg, about 10 mg, about 15 mg, about 30 mg, about 45 mg, about 60 mg or about 90 mg of tolvaptan.

5. 3. The fixed dose or pharmaceutical composition of claim 1 or 2, wherein the fixed dose or pharmaceutical composition comprises about 180 mg of bempedoic acid.

6. 3. The fixed dose or pharmaceutical composition of claim 1 or 2, further comprising one or more pharma- ceutically acceptable excipients.

7. 3. The fixed dose or pharmaceutical composition of claim 1 or 2, wherein the fixed dose or pharmaceutical composition is formulated for oral administration.

8. 8. The fixed dose or pharmaceutical composition of claim 7, wherein the fixed dose or pharmaceutical composition is formulated as an oral solid dosage form selected from the group consisting of tablets, capsules, softgel capsules, pills, solutions and suspensions.

9. 3. The fixed dose or pharmaceutical composition of claim 1 or 2, wherein the fixed dose or pharmaceutical composition provides an immediate release of bempedoic acid.

10. 3. The fixed dose or pharmaceutical composition of claim 1 or 2, wherein the fixed dose or pharmaceutical composition provides a sustained release of bempedoic acid.

11. 1. A fixed-dose drug or pharmaceutical composition for treating or slowing the progression of autosomal dominant polycystic kidney disease (ADPKD) in a patient receiving tolvaptan therapy or for preventing renal failure in a patient with ADPKD receiving tolvaptan therapy, comprising: A fixed-dose or pharmaceutical composition comprising an effective amount of bempedoic acid.

12. 12. A fixed dose or pharmaceutical composition according to claim 11, wherein the effective amount of bempedoic acid is from 30 mg to 240 mg or 180 mg.

13. 2. A patient receiving effective amounts of bempedoic acid and tolvaptan therapy via a fixed dose combination or pharmaceutical composition, have a smaller annual decline in estimated glomerular filtration rate than patients not receiving effective doses of bempedoic acid and tolvaptan therapy, or patients receiving effective doses of bempedoic acid alone, or patients receiving tolvaptan therapy alone; have a smaller annual increase in total kidney volume than patients not receiving effective doses of bempedoic acid and tolvaptan therapy, or patients receiving effective doses of bempedoic acid alone, or patients receiving tolvaptan therapy alone; a lower incidence of a composite of clinical endpoints selected from worsening renal function, renal pain, hypertension, and albuminuria than patients not receiving effective amounts of bempedoic acid and tolvaptan therapy, or patients receiving effective amounts of bempedoic acid alone, or patients receiving tolvaptan therapy alone; hepatic AMPK activity is higher than in patients not receiving an effective amount of bempedoic acid or receiving tolvaptan therapy alone; have a greater degree of hepatic acetyl-Coenzyme A carboxylase (ACC) phosphorylation than patients not receiving an effective amount of bempedoic acid or receiving tolvaptan therapy alone; and / or 13. The fixed dose drug or pharmaceutical composition of claim 11 or 12, which has higher peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α) activity than patients receiving tolvaptan therapy alone.

14. 1. A fixed dose drug or pharmaceutical composition for treating or slowing the progression of autosomal dominant polycystic kidney disease (ADPKD) or preventing renal failure in patients with ADPKD in a patient in need thereof, comprising: The fixed dose or pharmaceutical composition according to claim 1 or 2.

15. A patient receiving a fixed dose or pharmaceutical composition, have a smaller annual decline in estimated glomerular filtration rate than patients not receiving the fixed dose or pharmaceutical composition, patients receiving about 30 mg to about 240 mg of bempedoic acid alone, or patients receiving about 5 mg to about 90 mg of tolvaptan alone; have a lower annual increase in total kidney volume than patients not receiving the fixed dose or pharmaceutical composition, patients receiving about 30 mg to about 240 mg of bempedoic acid alone, or patients receiving about 5 mg to about 90 mg of tolvaptan alone; a lower incidence of a composite of clinical endpoints selected from worsening renal function, renal pain, hypertension, and albuminuria than patients not receiving the fixed-dose combination drug or pharmaceutical composition, patients receiving only about 30 mg to about 240 mg of bempedoic acid, or patients receiving only about 5 mg to about 90 mg of tolvaptan. has higher hepatic AMPK activity than patients not receiving the fixed dose or pharmaceutical composition or patients receiving about 5 mg to about 90 mg of tolvaptan alone; have a greater degree of hepatic acetyl-Coenzyme A carboxylase (ACC) phosphorylation than patients not receiving the fixed-dose combination drug or pharmaceutical composition, or patients receiving about 5 mg to about 90 mg of tolvaptan alone; and / or 15. The fixed dose drug or pharmaceutical composition of claim 14, which has greater peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α) activity than a patient receiving about 5 mg to about 90 mg of tolvaptan alone.

16. 1. A fixed-dose drug or pharmaceutical composition for treating or slowing the progression of autosomal dominant polycystic kidney disease (ADPKD) in a patient in need thereof, or for preventing renal failure in a patient having ADPKD, comprising: A fixed-dose or pharmaceutical composition comprising an effective amount of bempedoic acid.

17. 17. The fixed dose or pharmaceutical composition of claim 16, wherein the effective amount of bempedoic acid is from about 30 mg to about 240 mg or about 180 mg.

18. 18. The fixed dose or pharmaceutical composition of claim 16 or 17, further comprising an effective amount of tolvaptan.

19. 20. The fixed dose or pharmaceutical composition of claim 18, wherein the effective amount of tolvaptan comprises about 5 mg, about 10 mg, about 15 mg, about 30 mg, about 45 mg, about 60 mg, or about 90 mg of tolvaptan.

20. 19. A patient receiving a fixed dose or pharmaceutical composition according to claim 16 comprising an effective amount of bempedoic acid or a fixed dose or pharmaceutical composition according to claim 18 comprising effective amounts of bempedoic acid and tolvaptan, have a smaller annual loss in estimated glomerular filtration rate than patients receiving placebo or have a similar or lower total kidney weight to body weight ratio than patients receiving tolvaptan therapy; A smaller annual increase in total kidney volume than patients receiving placebo, or a similar or lower blood urea nitrogen concentration than patients receiving tolvaptan therapy; a lower incidence of a composite of clinical endpoints selected from worsening renal function, renal pain, hypertension, and albuminuria than patients receiving placebo, bempedoic acid alone, or tolvaptan alone; hepatic AMPK activity was higher than in patients receiving placebo or tolvaptan alone; a greater degree of hepatic acetyl-Coenzyme A carboxylase (ACC) phosphorylation than patients receiving placebo or tolvaptan alone; and / or 19. The fixed dose drug or pharmaceutical composition of claim 16 or 18, which has higher peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α) activity than patients receiving tolvaptan alone.

21. A patient receiving an effective amount of bempedoic acid via a fixed dose or pharmaceutical composition, A lower incidence of a composite of clinical endpoints selected from worsening renal function, renal pain, hypertension, and albuminuria than patients receiving a placebo, or 20. The fixed dose drug or pharmaceutical composition of claim 16 or 18, which has a similar or lower incidence of a composite of clinical endpoints selected from worsening renal function, renal pain, hypertension and albuminuria than patients receiving tolvaptan therapy.

22. 17. A fixed dose or pharmaceutical composition according to claim 11, 14 or 16 for human use.

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