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  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present disclosure relates to methods for improving renal function or methods for treating and/or preventing a kidney disease or an associated disorder by administering to a subject in need thereof, a combination of a sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of Formula I or la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.
• SGLT2 sodium-glucose transport protein 2
• eGFR estimated glomerular filtration rate
• T2DM type II diabetes
• CKD a comorbidity and several complications, such as nephropathy (Fowler 2008; Vithian and Hurel 2010; Beckman and Creager 2016; Rangel et al. 2016).
• CKD a comorbidity and several complications, such as nephropathy (Fowler 2008; Vithian and Hurel 2010; Beckman and Creager 2016; Rangel et al. 2016).
• CKD a comorbidity and several complications, such as nephropathy (Fowler 2008; Vithian and Hurel 2010; Beckman and Creager 2016; Rangel et al. 2016).
• CKD a comorbidity and several complications, such as nephropathy (Fowler 2008; Vithian and Hurel 2010; Beckman and Creager 2016; Rangel et al. 2016).
• Up to 40% of US adults with diagnosed T2DM have chronic kidney disease, resulting from diabetic nephropathy, of which over half have moderate to
• SGLT2 inhibitors reduce the secretion of glucose in the urine by inhibition of sodium glucose transport protein 2, and have been shown to reduce the decline of renal function in patients with established cardiovascular disease, diabetes, and chronic kidney disease (Zinman et al. 2015; Neal et al. 2017; Perkovic et al. 2019; Wiviott et al. 2019).
• SGLT2 inhibitors to reduce the decline of eGFR in T2DM patients has been studied in several clinical trials, such as EMPA-REG OUTCOME for empaglifozin (NCT01131676); CANVAS Program and CREDENCE for canaglifozin (NCT01032629, NCT01989754, and NCT02065791); and DECLARE-TIMI 58 (NCT01730534) for dapaglifozin. Although these trials provided some evidence of slowing the decline of renal function, none of them demonstrated any increase in eGFR, or consequently, any improvement of renal function versus baseline (Davidson 2019).
• the DAPA-CKD study evaluated the effects of dapagliflozin in patients with CKD, with or without type 2 diabetes. Although the data from this study represented significant slowing of renal function decline, absolute values for eGFR over the 30 months treatment versus baseline measurements were -7.15 units in the dapagliflozin group and - 9.47 units in the placebo group, thereby indicating that dapagliflozin was capable of slowing the renal function decline when compared to the placebo, but unable to increase eGFR (Heerspink et al. 2020).
• Apabetalone (RVX-208 or RVX000222), a compound of Formula I or la, is a first-in-class Bromodomain and Extra-Terminal (BET)-inhibitor (BETi) that binds selectively to the second bromodomain of BET proteins.
• BET proteins (BRD2, BRD3, BRD4, and BRDT) are epigenetic readers that recognize and bind to acetylated lysines on histones 3 and 4 and on some transcription factors. Histone bound BETs recruit transcription factors and machinery to gene enhancer and promoter sites, facilitating the transcription of proximal genes. Chronic disease profoundly alters the acetylation landscape (Chen et al. 2005; Villagra et al.
• BETonMACE Clinical Phase 3 trial
• NCT02586155 A recently completed clinical Phase 3 trial evaluated the effect on MACE of apabetalone (RVX-208) in type 2 diabetes patients with low HDL cholesterol (below 40mg/dL for males and below 45 mg/dL for females) and a recent ACS (preceding 7-90 days). All patients received high intensity statin treatment.
• BETonMACE was the first clinical trial to chronically dose high-risk cardiovascular disease patients with T2DM with the combination of a BET inhibitor and an SGLT2 inhibitor.
• Example 2 Surprisingly, as detailed in Example 2, we found that patients treated with the combination of RVX-208 and an SGLT2 inhibitor showed pronounced improvement of renal function, as measured by eGFR, compared to treatment with either therapy alone.
• the summary of the results discussed below and in the detailed description of the results in Example 2 demonstrate that RVX-208 or SGLT2 inhibitors by themselves did not improve eGFR in patients with recent ACS and T2DM.
• apabetalone was combined with a SGLT2 inhibitor, an unexpected and statistically significant increase of eGFR was observed, and this improvement exceeded the additive effects of RVX-208 and the SGLT2 inhibitor individually.
• RVX-208 in combination with SGLT2 inhibitors increased eGFR from a median of 114 mL/min at baseline to a median of 120 mL/min at last visit on treatment (LVT).
• the SGLT2 inhibitor monotherapy had a median eGFR of 109 mL/min at baseline and a median eGFR of 110 mL/min at LVT (z.e., a modest increase in median eGFR).
• the RVX-208 monotherapy group had a median eGFR of 97 mL/min at baseline and a median eGFR of 96 mL/min at LVT (z.e., no increase in median eGFR).
• the technical solution provided by the present disclosure includes methods of treating and/or preventing, including slowing the progression of, a kidney disease or an associated disorder or methods for improving renal function, as measured by an increase in estimated glomerular filtration rate (eGFR), comprising administering to a subject in need thereof, a combination of a sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of Formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.
• SGLT2 sodium-glucose transport protein 2
• Ri and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen;
• R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen;
• R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;
• Re is selected from amino, amide, alkyl, hydrogen, hydroxyl, piperazinyl, and alkoxy;
• W is selected from C and N, wherein: if W is N, then p is 0 or 1, and if W is C, then p is 1; and for W-(R 4 ) P , W is C, p is 1 and R 4 is H, or W is N and p is 0.
• RVX-208 is a representative example of a compound of Formula I.
• the kidney disease or an associated disorder treated and/or prevented by a method of the disclosure is selected from a kidney disease associated with reduced eGFR (z.e., ⁇ 60 mL/min/1.73 m 2 ⁇ 10%).
• the kidney disease associated with reduced eGFR is also associated with diabetes (type 2 diabetes or T2DM) and a diabetes-related disease or disorder associated with reduced eGFR.
• the kidney disease associated with reduced eGFR is chronic kidney disease (including chronic kidney disease that is a comorbidity of type 2 diabetes).
• the kidney disease associated with reduced eGFR is nephropathy (including diabetic nephropathy).
• the treating and/or preventing of the kidney disease or an associated disorder in a method of the disclosure reduces the decline of renal function, as assessed by increasing eGFR slope, for example, in a subject with T2DM or CKD.
• the treating and/or preventing of the kidney disease or an associated disorder in a method of the disclosure improves renal function, as defined by increasing eGFR slope, for example, in a subject with T2DM or CKD.
• the kidney disease or an associated disorder is treated and/or prevented by a method of the disclosure in a subject with T2DM or CKD.
• the compound of Formula I or la is administered simultaneously with a SGLT2 inhibitor. In some embodiments, the compound of Formula I is administered sequentially with the SGLT2 inhibitor. In some embodiments, the compound of Formula I is administered with the SGLT2 inhibitor as a single composition. In some embodiments, the compound of Formula I and the SGLT2 inhibitor are administered as separate compositions.
• the compound of Formula la is selected from
• Ri and R3 are each independently selected from alkoxy, alkyl, and hydrogen;
• R2 is selected from alkoxy, alkyl, and hydrogen
• R5 and R7 are each independently selected from alkyl, alkoxy, and hydrogen;
• Re is selected from alkyl, hydroxyl, and alkoxy
• W is selected from C and N, wherein: if W is N, then p is 0 or 1, and if W is C, then p is 1; and for W-(R 4 ) P , W is C, p is 1 and R 4 is H, or W is N and p is 0.
• the compound of Formula I or la is 2-(4-(2- hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208 or RVX000222) or a pharmaceutically acceptable salt thereof.
• the daily dose of a compound of Formula I or la, or 2- (4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one, or a pharmaceutically acceptable salt of any of the foregoing is between 100-300 mg, e.g., 200 mg.
• the compound of Formula I or la is given once a day. In some embodiments, it is given twice a day.
• the SGLT2 inhibitor is empagliflozin, canagliflozin, dapagliflozin, remogliflozin, ipragliflozin, bexagliflozin, ertugliflozin, sotagliflozin, luseogliflozin, tofogliflozin, or HM41322.
• the SGLT2 inhibitor is empagliflozin, canagliflozin, or dapagliflozin.
• the SGLT2 inhibitor is dapagliflozin.
• the daily dose of dapagliflozin is between 5-10 mg.
• the daily dose of dapagliflozin is 5 mg or 10 mg.
• Figure 1 depicts a comparison of the change of eGFR from baseline to LVT in patients administered RVX-208 with SGLT2 inhibitors versus patients administered placebo with SGLT2 inhibitors.
• Figure 2 depicts a comparison of the change of eGFR from baseline to LVT in patients administered RVX-208 with SGLT2 inhibitors versus patients administered RVX-208 without SGLT2 inhibitors.
• Figure 3 depicts a drug interaction matrix, comparing the median change of eGFR from baseline to LVT in patients administered RVX-208 with or without SGLT2 inhibitors.
• Figure 4 depicts a drug interaction matrix, comparing the mean change of eGFR from baseline to LVT in patients administered RVX-208 with or without SGLT2 inhibitors.
• Figure 5 depicts a comparison of the rate of change of eGFR (eGFR slope) from baseline to LVT in patients administered RVX-208 with SGLT2 inhibitors versus patients administered placebo with SGLT2 inhibitors.
• Figure 6 depicts a comparison of the rate of change of eGFR (eGFR slope) from baseline to LVT in patients administered RVX-208 with SGLT2 inhibitors versus patients administered RVX-208 without SGLT2 inhibitors.
• alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C2-Cs) alkenyl.
• alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2 propyl 2-butenyl, and 4-(2-methyl-3-butene)- pentenyl.
• alkoxy refers to an alkyl group attached to an oxygen (O-alkyl).
• Alkoxy also include, but are not limited to, an alkenyl group attached to an oxygen (“alkenyloxy”) or an alkynyl group attached to an oxygen (“alkynyloxy”) groups.
• alkenyloxy an alkenyl group attached to an oxygen
• alkynyloxy an alkynyl group attached to an oxygen
• Exemplary alkoxy groups include, but are not limited to, groups with an alkyl, alkenyl or alkynyl group of 1-8 carbon atoms, referred to herein as (Ci-Cs) alkoxy.
• Exemplary alkoxy groups include, but are not limited to, methoxy and ethoxy.
• alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-8 carbon atoms, referred to herein as (Ci- Cs) alkyl.
• Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3 methyl- 1 -butyl, 2-methyl- 3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3 methyl- 1 -pentyl, 4-methyl-l -pentyl, 2- methyl-2-pentyl, 3-methyl-2-pentyl, 4 methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l- butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
• amide refers to the form NRaC(O)(Rb) or C(O)NRbRc, wherein Ra, Rb, and Rc are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
• the amide can be attached to another group through the carbon, the nitrogen, Rb, or Rc.
• the amide also may be cyclic, for example, Rb and Rc, may be joined to form a 3- to 8-membered ring, such as a 5- or 6- membered ring.
• amide encompasses groups such as sulfonamide, urea, ureido, carbamate, carbamic acid, and cyclic versions thereof.
• amide also encompasses an amide group attached to a carboxy group, e.g., amide-COOH or salts such as amide-COONa, an amino group attached to a carboxy group (e.g., amino-COOH or salts such as amino-COONa).
• amine or “amino” as used herein refers to the form NRaRe or N(Rd)Re, wherein Rd and Re are independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocycle, and hydrogen.
• the amino can be attached to the parent molecular group through the nitrogen.
• the amino also may be cyclic, for example any two of Rd and Re may be joined together or with the N to form a 3- to 12-membered ring (e.g., morpholino or piperidinyl).
• the term amino also includes the corresponding quaternary ammonium salt of any amino group.
• Exemplary amino groups include, but are not limited to, alkylamino groups, wherein at least one of Rd and Re is an alkyl group.
• Rd and Re each may be optionally substituted with hydroxyl, halogen, alkoxy, ester, or amino.
• aryl refers to a mono-, bi-, or other multi carbocyclic, aromatic ring system.
• the aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, and heterocyclyls.
• aryl groups of this present disclosure can be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
• Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
• Exemplary aryl groups also include, but are not limited to, a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "(Ce) aryl.”
• arylalkyl refers to an alkyl group having at least one aryl substituent (e.g., aryl-alkyl).
• exemplary arylalkyl groups include, but are not limited to, arylalkyls having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "(Ce) arylalkyl.”
• carboxylate refers to the form R g OC(O)N(Rh), R g OC(O)N(Rh)Ri, or OC(O)NRhRi, wherein R g , Rh, and Ri are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
• Exemplary carbamates include, but are not limited to, arylcarbamates or heteroaryl carbamates (e.g., wherein at least one of R g , Rh and Ri are independently selected from aryl and heteroaryl, such as pyridine, pyridazine, pyrimidine, and pyrazine).
• carboxy refers to COOH or its corresponding carboxylate salts (e.g., COONa).
• carboxy also includes “carboxy carbonyl,” e.g., a carboxy group attached to a carbonyl group, e.g., C(O)-COOH or salts, such as C(O)-COONa.
• cycloalkoxy refers to a cycloalkyl group attached to an oxygen.
• cycloalkyl refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-12 carbons, or 3-8 carbons, referred to herein as "(C3-Cs)cycloalkyl,” derived from a cycloalkane.
• exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes.
• Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Cycloalkyl groups can be fused to other cycloalkyl saturated or unsaturated, aryl, or heterocyclyl groups.
• dicarboxylic acid refers to a group containing at least two carboxylic acid groups such as saturated and unsaturated hydrocarbon dicarboxylic acids and salts thereof.
• Exemplary dicarboxylic acids include, but are not limited to, alkyl dicarboxylic acids.
• Dicarboxylic acids may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
• Dicarboxylic acids include, but are not limited to, succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(-)-malic acid, (+)/(-) tartaric acid, isophthalic acid, and terephthalic acid.
• Dicarboxylic acids further include carboxylic acid derivatives thereof, such as anhydrides, imides, hydrazides (for example, succinic anhydride and succinimide).
• esters refers to the structure C(O)O-, C(O)ORj, RkC(O)O-Rj, or RkC(O)O-, where O is not bound to hydrogen, and Rj and Rk can independently be selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, and heterocyclyl.
• Rk can be a hydrogen, but Rj cannot be hydrogen.
• the ester may be cyclic, for example, the carbon atom and Rj, the oxygen atom and Rk, or Rj and Rk may be joined to form a 3- to 12-membered ring.
• Exemplary esters include, but are not limited to, alkyl esters wherein at least one of Rj and Rk is alkyl, such as O-C(O) alkyl, C(O)-O-alkyl, and alkyl C(O)-O-alkyl.
• Exemplary esters also include, but are not limited to, aryl or heteroaryl esters, e.g., wherein at least one of Rj and Rk is a heteroaryl group such as pyridine, pyridazine, pyrimidine and pyrazine, such as a nicotinate ester.
• Exemplary esters also include, but are not limited to, reverse esters having the structure RkC(O)O-, where the oxygen is bound to the parent molecule.
• Exemplary reverse esters include, but are not limited to, succinate, D-argininate, L- argininate, L-lysinate, and D-lysinate.
• Esters also include carboxylic acid anhydrides and acid halides.
• halo or halogen as used herein refer to F, Cl, Br, or I.
• haloalkyl refers to an alkyl group substituted with one or more halogen atoms. “Haloalkyls” also encompass alkenyl or alkynyl groups substituted with one or more halogen atoms.
• heteroaryl refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example 1 to 3 heteroatoms, such as nitrogen, oxygen, and sulfur.
• Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Heteroaryls can also be fused to non-aromatic rings.
• heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl.
• Exemplary heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as "(C2-C5) heteroaryl.”
• heterocycle refers to a saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Heterocycles can be aromatic (heteroaryls) or non-aromatic.
• Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
• substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocycl
• Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles.
• Exemplary heterocycles include, but are not limited to, acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, ox
• hydroxy and “hydroxyl” as used herein refer to -OH.
• hydroxyalkyl refers to a hydroxy attached to an alkyl group.
• hydroxyaryl refers to a hydroxy attached to an aryl group.
• ketone refers to the structure C(O)-Rn (such as acetyl, C(O)CH3) or R n -C(O)-R o .
• the ketone can be attached to another group through Rn or R o .
• Rn and Ro can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or Rn and Ro can be joined to form a 3- to 12 membered ring.
• phenyl refers to a 6-membered carbocyclic aromatic ring.
• the phenyl group can also be fused to a cyclohexane or cyclopentane ring.
• Phenyl can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
• thioalkyl refers to an alkyl group attached to a sulfur (S-alkyl).
• Alkyl, “alkenyl,” “alkynyl”, “alkoxy”, “amino” and “amide” groups can be optionally substituted with or interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carbonyl, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido, and N.
• the substituents may be branched to form a substituted or unsubstituted heterocycle or cycloalkyl.
• a suitable substitution on an optionally substituted substituent refers to a group that does not nullify the synthetic or pharmaceutical utility of the compounds of the present disclosure or the intermediates useful for preparing them.
• suitable substitutions include, but are not limited to: Ci-Cs alkyl, C2-C8 alkenyl or alkynyl; Ce aryl, 5- or 6-membered heteroaryl; C3-C7 cycloalkyl; Ci-Cs alkoxy; Ce aryloxy; CN; OH; oxo; halo, carboxy; amino, such as NH(Ci-Cs alkyl), N(Ci-Cs alkyl)2, NH((Ce)aryl), or N((Ce)aryl)2; formyl; ketones, such as CO(Ci-Cs alkyl), -CO((Ce aryl) esters, such as C02(Ci-Cs alkyl) and C02(Ce
• composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
• compositions refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art.
• the compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
• pharmaceutically acceptable composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
• prodrugs as used herein represents those prodrugs of the compounds of the present disclosure that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of Formula I or la.
• a discussion is provided in Higuchi et al., “Prodrugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergam on Press, 1987, both of which are incorporated herein by reference.
• salts refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
• Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, -toluenesulfonate and pamoate (i.
• Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
• Compounds included in the present compositions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
• Examples of such salts include, but are not limited to, alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
• the free base can be obtained by basifying a solution of the acid salt.
• an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
• Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.
• the compounds of Formula I or la may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers.
• stereoisomers when used herein consists of all geometric isomers, enantiomers, or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof.
• Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
• Individual stereoisomers of compounds for use in the methods of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
• Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
• Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
• Geometric isomers can also exist in the compounds of Formula I or la.
• the present disclosure encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring.
• Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards.
• structures depicting double bonds encompass both the E and Z isomers.
• Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
• the arrangements of substituents around a carbocyclic ring are designated as “cis” or “trans.”
• the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
• Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”
• SGLT2 inhibitor refers a substance, such as a small molecule organic chemistry compound ( ⁇ 1 kDa) or a large biomolecule such as a peptide (e.g., a soluble peptide), protein (e.g., an antibody), nucleic acid (e.g., siRNA) or a conjugate combining any two or more of the foregoing, that possesses the activity of inhibiting sodium-glucose transport protein 2 (SGLT2).
• a small molecule organic chemistry compound ⁇ 1 kDa
• a large biomolecule such as a peptide (e.g., a soluble peptide), protein (e.g., an antibody), nucleic acid (e.g., siRNA) or a conjugate combining any two or more of the foregoing, that possesses the activity of inhibiting sodium-glucose transport protein 2 (SGLT2).
• Non-limiting examples of SGLT2 inhibitors include empagliflozin, canagliflozin, dapagliflozin, remogliflozin, ipragliflozin, HM41322, bexagliflozin, ertugliflozin, sotagliflozin, luseogliflozin, tofogliflozin, or a pharmaceutically acceptable salt of any of the foregoing.
• SGLT2 inhibitors are disclosed in W001/027128, W004/013118, W004/080990, EP1852439A1 , WOOl/27128, WO03/099836, W02005/092877, W02006/034489, W02006/064033, W02006/1 17359, W02006/117360, W02007/025943, W02007/028814, W02007/031 548, W02007/093610, WO2007/128749, W02008/049923, W02008/055870, and W02008/055940, each of which is incorporated herein by reference in its entirety.
• treatment refers to an amelioration of a disease or disorder, or at least one discernible symptom thereof.
• treatment refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient.
• treatment or “treating” refers to reducing the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both.
• treatment or “treating” refers to delaying the onset or progression of a disease or disorder. For example, treating a cholesterol disorder may comprise decreasing blood cholesterol levels.
• prevention refers to a reduction of the risk of acquiring a given disease or disorder or a symptom of a given disease or disorder.
• diabetes-related disease or disorder refers to a complication of type 2 diabetes and/or comorbidity of type 2 diabetes, whereby a subject suffering therefrom has an eGFR, as determined by blood or serum creatinine levels, age, body size, and gender, of ⁇ 60 mL/min/1.73 m 2 ⁇ 10% (z.e., 54-66 mL/min/1.73 m 2 ), if or when calculated.
• a diabetes-related disease or disorder as defined herein are diabetic nephropathy, chronic kidney disease that is a comorbidity of type 2 diabetes, and a combination thereof.
• kidney disease or an associated disorder refers to a kidney disease associated with reduced eGFR.
• the kidney disease or associated disorder is also associated with diabetes (type 2 diabetes), or a diabetes-related disease or disorder.
• Non-limiting examples of a kidney disease associated with reduced eGFR include chronic kidney disease, nephropathy (e.g., Cla nephropathy, combination antiretroviral (cART) related-nephropathy, oxalate nephropathy), acute kidney failure or acute kidney injury, Alport syndrome, glomerulopathy (e.g, C3 glomerulopathy, C3 glomerulopathy with monoclonal gammopathy, C4 glomerulopathy), cardiorenal syndrome, Charcot-Mari e-Tooth disease with glomerulopathy, congenital nephrotic syndrome, congestive renal failure, coronavirus (COVID- 19) associated kidney failure and kidney disease, Fabry’s diseases, diabetic kidney disease, glomerular diseases, glycosuria, hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), hypercalcemia, hyperkalemia, hypocalcemia, kidney stones, nephrolithiasis, lupus kidney disease, l
• renal function refers to kidney function as measured by estimated glomerular filtration rate (eGFR) and/or the eGFR slope.
• eGFR estimated glomerular filtration rate
• eGFR slope To improve renal function means to increase the eGFR and/or to increase the eGFR slope.
• the present disclosure provides a method for improving renal function or a method for treating and/or preventing, including slowing the progression of, a kidney-related disease or an associated disorder, as measured by an increase in estimated glomerular filtration rate (eGFR), wherein the method comprises administering to a subject in need thereof, a combination of a sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of Formula I:
• SGLT2 sodium-glucose transport protein 2
• Ri and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen;
• R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen;
• R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;
• Re is selected from amino, amide, alkyl, hydrogen, hydroxyl, piperazinyl, and alkoxy;
• W is selected from C and N, wherein: if W is N, then p is 0 or 1, and if W is C, then p is 1; and for W-(R 4 ) P , W is C, p is 1 and R 4 is H, or W is N and p is 0.
• the compound of Formula I is a compound of Formula la:
• Ri and R3 are each independently selected from alkoxy, alkyl, and hydrogen;
• R2 is selected from alkoxy, alkyl, and hydrogen
• R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;
• Re is selected from alkyl, hydroxyl, and alkoxy
• W is selected from C and N, wherein: if W is N, then p is 0 or 1, and if W is C, then p is 1; and for W-(R 4 ) P , W is C, p is 1 and R 4 is H, or W is N and p is 0.
• the compound of Formula I or la is 2-(4-(2- hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208 or RVX000222) or a pharmaceutically acceptable salt thereof.
• the method comprises administering to the subject, a daily dose of 100-300 mg of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one or an equivalent amount of a pharmaceutically acceptable salt thereof.
• the method comprises administering to the subject, a daily dose of 200 mg daily of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one or an equivalent amount of a pharmaceutically acceptable salt thereof.
• the SGLT2 inhibitor is selected from empagliflozin, canagliflozin, dapagliflozin, bexagliflozin, ertugliflozin, sotagliflozin, luseogliflozin, tofogliflozin, and HM41322.
• the SGLT2 inhibitor is selected from empagliflozin, canagliflozin, and dapagliflozin.
• the compound of Formula I or la is administered simultaneously with the SGLT2 inhibitor as separate compositions.
• the compound of Formula I or la is administered with the SGLT2 inhibitor as a single composition.
• the subject is a human.
• the subject is a human on statin therapy.
• the subject is a human on high intensity or maximum tolerated statin therapy.
• the high intensity statin treatment or therapy refers to a daily dose of at least 20 mg, or at least 40 mg, or 20-80 mg, or 20-40 mg, or 40-80 mg.
• the maximum tolerated statin treatment or therapy refers to a daily lose of at least 40 mg, or 40 mg- 80 mg, or 80 mg.
• the subject is on rosuvastatin therapy. In one embodiment, the subject is on atorvastatin therapy.
• the subject is a human with type 2 diabetes or chronic kidney disease.
• the subject is a human with low HDL cholesterol (below 40 mg/dL for males and below 45 mg/dL for females) and a recent acute coronary syndrome (ACS) (preceding 7-90 days).
• ACS acute coronary syndrome
• the kidney disease or an associated disorder is a kidney disease associated with reduced eGFR, for example, in a subject with type 2 diabetes or chronic kidney disease.
• the kidney disease associated with reduced eGFR is associated with type 2 diabetes or a diabetes-related disease or disorder.
• the kidney disease associated with reduced eGFR is nephropathy. In one embodiment, the kidney disease associated with reduced eGFR is diabetic nephropathy.
• the kidney disease associated with reduced eGFR is chronic kidney disease.
• the chronic kidney disease that is a comorbidity of type 2 diabetes.
• the method improves renal function by increasing eGFR slope, for example, in a subject with type 2 diabetes or chronic kidney disease.
• the method reduces the decline of renal function by increasing eGFR slope, for example, in a subject with type 2 diabetes or chronic kidney disease.
• the present disclosure provides a method for improving renal function by increasing the estimated glomerular filtration rate (eGFR), the method comprising administering to a subject in need thereof, a combination of a sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of Formula I or Formula la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof as defined above.
• eGFR estimated glomerular filtration rate
• the present disclosure provides a method for increasing estimated glomerular filtration rate (eGFR), the method comprising administering to a subject in need thereof, a combination of a sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of Formula I or Formula la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof as defined above.
• eGFR estimated glomerular filtration rate
• the method for improving renal function or the method for increasing the eGFR treats and/or prevents a kidney disease or associated disorder.
• Exemplary embodiments of the method for improving renal function or the method for increasing the eGFR such as specific compounds of Formula I or la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof; specific daily doses of compounds of Formula I or la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof; specific SGLT2 inhibitors; manner of administration of compounds of Formula I or la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof and the SGLT2 inhibitor (/. ⁇ ., simultaneously, sequentially, as separate compositions, or as a single composition); subject criteria, subject sub-populations; and specific diabetes-related diseases and disorders are as described in any one or more of the exemplary embodiments above.
• Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA.
• Molecular and cellular biology 29(5), 1375-1387. Brown, J. D., Lin, C. Y., Duan, Q., Griffin, G., Federation, A., Paranal, R. M., Bair, S., Newton, G., Lichtman, A., Kung, A., Yang, T., Wang, H., Luscinskas, F. W., Croce, K., Bradner, J. E., & Plutzky, J. (2014).
• NF-KB directs dynamic super enhancer formation in inflammation and atherogenesis.
• Molecular cell 56(2), 219-231. 28. Das, S., Senapati, P., Chen, Z., et al. (2017). Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells. Nat Commun 8, 1467 (2017)
• Apabetalone (RVX-208) was evaluated in a recently completed clinical Phase 3 trial (BETonMACE; NCT02586155) for the effect on MACE in type 2 diabetes patients with low HDL cholesterol (below 40 mg/dL for males and below 45 mg/dL for females) and a recent acute coronary syndrome (ACS) (preceding 7-90 days). All patients received high intensity statin treatment or maximum tolerated statin treatment, which was 20-40 mg daily or a maximum daily dose of 40 mg for rosuvastatin or 40-80 mg daily or a maximum daily dose of 80 mg for atorvastatin.
• SGLT2 inhibitor empagliflozin, dapagliflozin, or canagliflozin
• statin therapy atorvastatin and rosuvastatin
• a total of 150 patients received both RVX-208 and an SGLT2 inhibitor; a total of 148 received an SGLT2 inhibitor, but no RVX-208; a total of 1062 received RVX-208, but no SGLT2 inhibitor; a total of 1058 received neither RVX-208 or an SGLT2 inhibitor.
• eGFR estimated glomerular filtration rate
• Serum creatinine was collected as part of the chemistry panel at the following time points: baseline, week 24, week 52, week 76, week 100, and last visit on treatment (LVT).
• the Cockcroft-Gault formula requires the input of an individual’s age, sex, and weight.
• the last visit on treatment (LVT) timepoint represented the longest study exposure duration for patients receiving RVX-208 or placebo with and without SGLT2 inhibitors and is the focus of this analysis.
• the median time to LVT (and study drug exposure) for patients with a baseline and LVT measurements for eGFR administered an SGLT2 inhibitor was 742 days (2.03 years).
• Figures 1-2 each compare the median change of eGFR from baseline to last visit on treatment (LVT) between two groups of patients, a test group, and a control group, which are described as follows:
• RVX-208 in combination with SGLT2 inhibitors the eGFR from a median of 114 mL/min at baseline to a median of 120 mL/min at last visit on treatment (LVT).
• the mean change from baseline to LVT in this combination therapy group was +2.7 mL/min/1.73 m 2 ( Figure 4); the median change from baseline to LVT was +2.9 mL/min/1.73 m 2 ( Figure 3).
• the SGLT2 inhibitor monotherapy group had a median eGFR of 109 mL/min at baseline and a median eGFR of 110 mL/min at LVT.
• the mean change from baseline to LVT in this group was -0.3 mL/min/1.73 m 2 ( Figure 4); the median change from baseline to LVT was -4.5 mL/min/1.73 m 2 ( Figure 3).
• the RVX-208 monotherapy group had a median eGFR of 97 mL/min at baseline and a median eGFR of 96 mL/min at last visit on treatment (LVT).
• the mean change of eGFR from baseline to LVT in this group was -3.3 mL/min/1.73 m 2 ( Figure 4); the median change from baseline to LVT was -3.2 mL/min/1.73 m 2 ( Figure 3).
• the statistical parameters for the RVX-208 and SGLT2 inhibitor combination therapy are as described above.
• eGFR slope The rate of change of eGFR (eGFR slope) from baseline to LVT in the patient population receiving the combination of an SGLT2 inhibitor in addition to RVX-208, the combination of an SGLT2 inhibitor in addition to placebo, and RVX-208 without an SGLT2 inhibitor was assessed from baseline to LVT.
• Figures 5-6 each compare the median rate of change in eGFR (eGFR slope) from baseline to last visit on treatment (LVT) between the same two groups of patients as described above for Figures 1-2.
• the SGLT2 monotherapy was not able to increase the eGFR slope, with the median eGFR slope from baseline to LVT being -0.006 over a median of 734 days (2.01 years) of study drug exposure.

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