WO2022006277A1 - Méthodes de traitement de maladies rénales fibrotiques - Google Patents

Méthodes de traitement de maladies rénales fibrotiques Download PDF

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Publication number
WO2022006277A1
WO2022006277A1 PCT/US2021/039898 US2021039898W WO2022006277A1 WO 2022006277 A1 WO2022006277 A1 WO 2022006277A1 US 2021039898 W US2021039898 W US 2021039898W WO 2022006277 A1 WO2022006277 A1 WO 2022006277A1
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level
col3a1
compound
patient
disease
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PCT/US2021/039898
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English (en)
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Prakash Narayan
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Angion Biomedica Corp.
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    • 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
    • A61K31/33—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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • Fibrosis of the kidney can result in progressive loss of renal function, which can lead to end-stage renal failure. Renal failure is fatal without regular dialysis or a kidney transplant. There exists a continuing need for improved treatments for fibrotic diseases of the kidney.
  • the present disclosure provides methods related to treatment of fibrotic disease(s) of the kidney and related diseases, disorders, and conditions and selecting, identifying, and/or characterizing patients likely to benefit from a treatment with Compound 1 :
  • a patient to be treated with a method of the present disclosure has an altered level of one or more gene products or one or more proteins (or fragments thereof) that are part of the mechanism of action of Compound 1 (e.g., down regulated by Compound 1).
  • a patient to be treated with a method of the present disclosure has an elevated level of gene expression (e.g., COL3A1 expression and/or COL1A1 expression).
  • a patient to be treated with a method of the present disclosure has an elevated level of protein expression (e.g., COL3A1 protein and/or COL1A1 protein) or elevated level of a fragment thereof.
  • an elevated level of expression e.g., of COL3A1 and/or COL1 Al
  • a non-italicized name will be used to refer to both the gene and protein product.
  • a level of COL3A1 and/or COL1A1 corresponds to a level of gene expression (e.g., RNA expression, e.g., mRNA expression).
  • a level of COL3A1 and/or COL1 Al corresponds to a level of collagen protein expression.
  • collagen protein expression includes expression of a protein in any form, including, a procollagen polypeptide (e.g., type III procollagen or type I procollagen), a collagen protein (e.g., type III collagen or type I collagen), a preprocollagen polypeptide, an amino-terminal procollagen polypeptide (e.g., pN-type III collagen (“PIIINP”) or pN-type I collagen (“PINP”)), collagen fibril, collagen fiber, and/or any fragment or degradation product thereof.
  • a procollagen polypeptide e.g., type III procollagen or type I procollagen
  • collagen protein e.g., type III collagen or type I collagen
  • preprocollagen polypeptide e.g., an amino-terminal procollagen polypeptide (e.g., pN-type III collagen (“PIIINP”) or pN-type I collagen (“PINP”)), collagen fibril, collagen fiber, and/or any fragment or degradation product thereof.
  • PIIINP pN
  • the present disclosure provides a method for treating a patient diagnosed with, suspected of having, or at risk for a fibrotic disease of the kidney, the method comprising (i) obtaining or determining a level of COL3A1 expression and/or COL1 Al expression in a biological sample from the patient; and (ii) comparing the level of COL3 Al expression and/or COL1 Al expression with that of a threshold level (e.g., those of a healthy subject control or a mean or median of a population of healthy subject controls), wherein if the expression level of COL3A1 and/or COL1 Al is different from the threshold level (e.g., above the threshold level or below the threshold level), administering to the patient an effective amount of Compound 1, or a pharmaceutical composition thereof.
  • obtaining a level of expression of a biomarker may comprise obtaining knowledge of a level that has been determined previously (e.g., obtaining said level from a report, database, etc. containing the value of
  • the present disclosure provides a method for treating a patient diagnosed with, suspected of having, or at risk for a fibrotic disease of the kidney, the method comprising (i) obtaining or determining a level of COL3A1 expression and/or COL1 A1 expression in a biological sample from the patient; and (ii) comparing the level of COL3 A1 expression and/or COL1 A1 expression with that of a threshold level (e.g., those of a healthy subject control or a mean or median of a population of healthy subject controls), wherein if the expression level of COL3A1 and/or COL1 A1 is above the threshold level, administering to the patient an effective amount of Compound 1, or a pharmaceutical composition thereof.
  • a threshold level e.g., those of a healthy subject control or a mean or median of a population of healthy subject controls
  • the present disclosure provides a method for treating a patient diagnosed with, suspected of having, or at risk for a fibrotic disease of the kidney, the method comprising administering an effective amount of Compound 1, or a pharmaceutical composition thereof, to a patient who has been determined to have an altered (e.g., elevated or reduced) level of COL3A1 and/or COL1A1.
  • the present disclosure provides a method for treating a patient diagnosed with, suspected of having, or at risk for a fibrotic disease of the kidney, the method comprising administering an effective amount of Compound 1, or a pharmaceutical composition thereof, to a patient who has been determined to have an elevated level of COL3A1 and/or COL1A1.
  • an elevated level of COL3A1 and/or COL1A1 comprises a level that is above a corresponding threshold level.
  • a reduced level of COL3A1 and/or COL1 A1 comprises a level that is below a corresponding threshold level.
  • the level of COL3A1 and/or COL1 A1 was obtained from or previously determined from a biological sample from the patient.
  • the method further comprises obtaining or determining a level of COL3A1 and/or COL1 A1 in a biological sample from the patient.
  • a method for treating a patient diagnosed with, suspected of having, or at risk for a fibrotic disease of the kidney in a patient characterized by an elevated level of COL3A1 and/or COL1 A1 comprising administering an effective amount of Compound 1, or a pharmaceutical composition thereof, to the patient.
  • an elevated level of COL3A1 and/or COL1 A1 comprises a level that is above a corresponding threshold level.
  • the level of COL3A1 and/or COL1 A1 was obtained from or previously determined from a biological sample from the patient.
  • the method further comprises obtaining or determining a level of COL3A1 and/or COL1 A1 in a biological sample from the patient.
  • a threshold expression level corresponds to a predetermined mean or median level of COL3A1 and/or COL1A1 of a population of healthy subjects (e.g., healthy human subjects). In some embodiments, a threshold expression level corresponds to a predetermined normal range of COL3A1 and/or COL1A1 of a population of healthy subjects (e.g., healthy human subjects).
  • the expression level of COL3 A1 is at least 20% higher than the corresponding threshold expression level. In some embodiments, the expression level of COL1 A1 is at least 20% higher than the corresponding threshold expression level. In some embodiments, the expression levels of both COL3A1 and COL1 A1 are at least 20% higher than the respective corresponding threshold expression levels.
  • the expression level of COL3 A1 is at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% higher than the corresponding threshold expression level. In some embodiments, the expression level of COL1 A1 is at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% higher than the corresponding threshold expression level. In some embodiments, the expression levels of both COL3A1 and COL1 A1 are at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% higher than the respective corresponding threshold expression levels.
  • the biological sample (e.g., from which an expression level of a biomarker is obtained or has been determined) is a renal biopsy sample, a urine sample, or a blood sample.
  • an expression level of a protein biomarker e.g., a propeptide, protein, prepropeptide, amino-terminal propeptide, fibril or fiber, e.g., of COL3A1 and/or of COL1 Al
  • a protein biomarker e.g., a propeptide, protein, prepropeptide, amino-terminal propeptide, fibril or fiber, e.g., of COL3A1 and/or of COL1 Al
  • an expression level of a genetic biomarker e.g., a gene product, e.g., RNA, e.g., mRNA, e.g., mRNA encoding COL3A1 and/or COL1A1
  • a genetic biomarker e.g., a gene product, e.g., RNA, e.g., mRNA, e.g., mRNA encoding COL3A1 and/or COL1A1
  • a genetic biomarker e.g., a gene product, e.g., RNA, e.g., mRNA, e.g., mRNA encoding COL3A1 and/or COL1A1
  • RNA e.g., mRNA, e.g., mRNA encoding COL3A1 and/or COL1A1
  • an expression level of a biomarker is obtained from or determined in a renal biopsy sample from
  • an expression level of a biomarker (e.g., COL3A1 and/or COL1 Al) in a renal biopsy sample is a gene biomarker (e.g., RNA, e.g., mRNA) and/or a protein biomarker.
  • the biological sample is a renal biopsy sample and the expression level of COL3 Al is an mRNA level and/or the expression level of COL1 Al is an mRNA level.
  • an expression level of a biomarker is obtained from or determined in a urine sample from a patient.
  • the biological sample is a urine sample and the expression level of COL3 Al is a level of COL3 Al protein or fragments thereof and/or the expression level of COL1 Al is a level of COL1 Al protein or fragments thereof.
  • an expression level of a biomarker is obtained from or determined in a blood sample from a patient.
  • the biological sample is a blood sample and the expression level of COL3 Al is a level of COL3 Al protein or fragments thereof and/or the expression level of COL1 Al is a level of COL1 Al protein or fragments thereof.
  • provided methods are useful in treating a kidney disease that is or comprises: focal segmental glomerulosclerosis (FSGS), steroid resistant nephrotic syndrome (SRNS), proteinuria, lupus nephritis, minimal change disease, an anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, anti-globular basement membrane (anti-GBM) nephropathy, IgA nephropathy, membranous glomerulonephritis (MG), autosomal dominant polycystic kidney disease (ADPKD), or chronic kidney disease.
  • FSGS focal segmental glomerulosclerosis
  • SRNS steroid resistant nephrotic syndrome
  • proteinuria lupus nephritis
  • minimal change disease an anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis
  • anti-GBM anti-globular basement membrane
  • IgA nephropathy IgA ne
  • provided methods are useful in treating a kidney disease that is or comprises an anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.
  • ANCA-associated glomerulonephritis is selected from Wegener’s granulomatosis, microscopic polyangiitis (MPA), or renal limited vasculitis.
  • provided methods are useful in treating a kidney disease that is or comprises focal and segmental glomerulosclerosis (FSGS).
  • FSGS focal and segmental glomerulosclerosis
  • provided methods are useful in treating a kidney disease that is or comprises primary proteinuric kidney disease. In some embodiments, provided methods are useful in treating a kidney disease that is or comprises primary glomerular disease. [0022] In some embodiments, a patient with a fibrotic disease of the kidney exhibits increased renal COL3 A1 expression that is correlated with urine protein to creatinine ratio. In some embodiments, a patient with a fibrotic disease of the kidney exhibits COL3 A1 expression that is inversely correlated with eGFR.
  • a patient has FSGS and also exhibits (i) increased renal COL3 A1 expression that is correlated with urine protein to creatinine ratio and/or (ii) COL3 A1 expression that is inversely correlated with eGFR.
  • the kidney fibrotic disease is stabilized (i.e., does not worsen) and/or is ameliorated (i.e., one or more symptoms improve) in a patient treated with Compound 1.
  • treatment of a patient with Compound 1 reduces a level of one or more biomarkers (e.g., COL1 A1 and/or COL3A1).
  • administering to the patient: (i) reduces the expression of renal COL3A1 , (ii) reduces the expression of renal COL1A1 , (iii) reduces renal COL3A1 accumulation, (iv) reduces renal COL1A1 accumulation, or (v) any combination thereof.
  • a patient to be treated with a method of the present disclosure exhibits proteinuria.
  • the present disclosure provides a method comprising: (i) receiving a report listing the expression level of one or more biomarkers (e.g., COL3A1 and/or COL1 Al) for a patient with a fibrotic kidney disease; (ii) receiving a request for reimbursement for the biomarker screening and/or a particular therapeutic regimen; (iii) approving payment and/or reimbursement for Compound 1 therapy if the report indicates the level of biomarker is above a threshold level, wherein Compound 1 is described by the formula:
  • biomarkers e.g., COL3A1 and/or COL1 Al
  • a threshold expression level corresponds to a predetermined mean or median level of COL3A1 and/or COL1A1 of a population of healthy subjects. In some embodiments, a threshold expression level corresponds to a predetermined normal range of COL3A1 and/or COL1A1 of a population of healthy subjects.
  • the expression level of COL3 A1 is at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% higher than the corresponding threshold expression level. In some embodiments, the expression level of COL1 A1 is at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% higher than the corresponding threshold expression level. In some embodiments, the expression levels of both COL3A1 and COL1 A1 are at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% higher than the respective corresponding threshold expression levels.
  • the biological sample (e.g., from which an expression level of a biomarker is or has been determined) is a renal biopsy sample, a urine sample or a blood sample.
  • the biological sample is a renal biopsy sample and the expression level of COL3 A1 is an mRNA level and/or the expression level of COL1 A1 is an mRNA level.
  • the biological sample is a urine sample and the expression level of COL3 A1 is a level of COL3 A1 protein or fragments thereof and/or the expression level of COL1 A1 is a level of COL1 A1 protein or fragments thereof.
  • provided methods are useful in treating a kidney disease that is or comprises: focal segmental glomerulosclerosis (FSGS), steroid resistant nephrotic syndrome (SRNS), proteinuria, lupus nephritis, minimal change disease, an anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, anti-globular basement membrane (anti-GBM) nephropathy, IgA nephropathy, membranous glomerulonephritis (MG), autosomal dominant polycystic kidney disease (ADPKD), collagen type III glomerulopathy, nail-patella syndrome, or chronic kidney disease.
  • FSGS focal segmental glomerulosclerosis
  • SRNS steroid resistant nephrotic syndrome
  • proteinuria lupus nephritis
  • minimal change disease an anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis
  • anti-GBM anti-globular basement membrane
  • a kidney disease that is or comprises focal and segmental glomerulosclerosis (FSGS).
  • a patient has FSGS and an elevated level of COL3A1 and/or COL1 A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • a patient has FSGS and also exhibits (i) increased renal COL3 A1 expression that is correlated with urine protein to creatinine ratio and/or (ii) COL3 A1 expression that is inversely correlated with eGFR.
  • provided methods are useful in treating a kidney disease that is or comprises primary proteinuric kidney disease (PPKD).
  • PPKD primary proteinuric kidney disease
  • a patient has PPKD and an elevated level of COL3A1 and/or COL1 A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • provided methods are useful in treating a kidney disease that is or comprises primary glomerular disease (PGD).
  • PGD primary glomerular disease
  • a patient has PGD and an elevated level of COL3A1 and/or COL1 A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • a biological sample from the patient e.g., renal biopsy sample, urine sample, blood sample, etc.
  • provided methods are useful in treating a kidney disease that is or comprises steroid resistant nephrotic syndrome (SRNS).
  • SRNS steroid resistant nephrotic syndrome
  • a patient has SRNS and an elevated level of COL3A1 and/or COL1 A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • provided methods are useful in treating a kidney disease that is or comprises proteinuria.
  • a patient has proteinuria and an elevated level of COL3A1 and/or COL1 A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • a biological sample from the patient e.g., renal biopsy sample, urine sample, blood sample, etc.
  • provided methods are useful in treating a kidney disease that is or comprises lupus nephritis.
  • a patient has lupus nephritis and an elevated level of COL3A1 and/or COL1A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • a biological sample from the patient e.g., renal biopsy sample, urine sample, blood sample, etc.
  • provided methods are useful in treating a kidney disease that is or comprises minimal change disease.
  • a patient has minimal change disease and an elevated level of COL3A1 and/or COL1 A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • a biological sample e.g., renal biopsy sample, urine sample, blood sample, etc.
  • provided methods are useful in treating a kidney disease that is or comprises ANCA-associated glomerulonephritis.
  • a patient has ANCA-associated glomerulonephritis and an elevated level of COL3A1 and/or COL1A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • a biological sample from the patient e.g., renal biopsy sample, urine sample, blood sample, etc.
  • provided methods are useful in treating a kidney disease that is or comprises anti-GBM nephropathy.
  • a patient has anti-GBM nephropathy and an elevated level of COL3A1 and/or COL1 A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • a biological sample from the patient e.g., renal biopsy sample, urine sample, blood sample, etc.
  • provided methods are useful in treating a kidney disease that is or comprises IgA nephropathy.
  • a patient has IgA nephropathy and an elevated level of COL3A1 and/or COL1A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • a biological sample from the patient e.g., renal biopsy sample, urine sample, blood sample, etc.
  • provided methods are useful in treating a kidney disease that is or comprises membranous glomerulonephritis (MG).
  • MG membranous glomerulonephritis
  • a patient has MG and an elevated level of COL3A1 and/or COL1 A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • provided methods are useful in treating a kidney disease that is or comprises autosomal dominant polycystic kidney disease (ADPKD).
  • a patient has ADPKD and an elevated level of COL3A1 and/or COL1 A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • provided methods are useful in treating a kidney disease that is or comprises chronic kidney disease.
  • a patient has chronic kidney disease and an elevated level of COL3A1 and/or COL1 A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • COL3A1 and/or COL1 A1 e.g., mRNA and/or protein
  • provided methods are useful in treating a kidney disease that is or comprises collagen type III glomerulopathy.
  • a patient has collagen type III glomerulopathy and an elevated level of COL3A1 and/or COL1 A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • a biological sample from the patient e.g., renal biopsy sample, urine sample, blood sample, etc.
  • provided methods are useful in treating a kidney disease that is or comprises nail-patella syndrome.
  • a patient has nail-patella syndrome and an elevated level of COL3A1 and/or COL1 A1 (e.g., mRNA and/or protein), for example, as determined in or obtained from a biological sample from the patient (e.g., renal biopsy sample, urine sample, blood sample, etc.).
  • COL3A1 and/or COL1 A1 e.g., mRNA and/or protein
  • provided methods recognize when to adjust or discontinue treatment of a patient with Compound 1.
  • the present disclosure provides a method for treating a patient diagnosed with, suspected of having, or at risk for a fibrotic disease of the kidney, the method comprising: (i) obtaining or determining a level of expression of one or more gene products or proteins in a biological sample from the patient, wherein the one or more gene products or proteins are selected from: COL3A1 and COL1A1; (ii) comparing the expression level of the one or more gene products or proteins with that of a corresponding threshold level; and (iii) if the expression level of COL3 A1 and/or the expression level of COL1 A1 is above the threshold expression level, then administering to the patient an effective amount of Compound 1 or a pharmaceutical composition thereof, and if the expression level of COL3A1 and/or the expression level of COL1 A1 is not above the threshold expression level, then the patient is not administered Compound 1.
  • the present disclosure provides a method for treating a patient diagnosed with, suspected of having, or at risk for a fibrotic disease of the kidney, which patient is characterized by an elevated level of a biomarker (e.g., COL3A1 and/or COL1 Al), the method comprising: (i) administering an effective amount of Compound 1 or a pharmaceutical composition thereof, and (ii) monitoring a level of biomarker (e.g., COL3A1 and/or COL1A1) subsequent to administration (e.g., after a duration of a day, a week, two weeks, a month, two months, 3 months, etc.).
  • a biomarker e.g., COL3A1 and/or COL1 Al
  • the level of biomarker e.g., COL3A1 and/or COL1 Al
  • further treatment with Compound 1 is discontinued.
  • the level of biomarker e.g., COL3A1 and/or COL1A1
  • the dose of Compound 1 administered to the patient is increased.
  • the level of biomarker e.g., COL3A1 and/or COL1 Al
  • treatment with Compound 1 is continued (e.g., subsequent doses are administered).
  • FIG. 1 provides levels of various inflammation and fibrosis related markers with exposure to escalating levels of Compound 1.
  • FIG. 2 provides a cartoon schematic of varying relationships between genomic responses and kidney disease outcomes.
  • FIG. 3 provides proteinuria of PAN treated model rats treated with Compound 1.
  • FIG. 4 provides fold change in expression for COL1 Al and COL3A1 mRNA in a rat
  • FIG. 5 depicts correlation between COL3 Al expression and renal dysfunction in both murine model and human patients.
  • FIG. 6 depicts a Compound 1 interactome built using in vitro activity data.
  • FIG. 7 provides urine protein levels in PAN treated model rats.
  • FIG. 8A provides COL3 Al mRNA levels in PAN-treated model rats.
  • FIG. 8B provides an association of COL3 Al mRNA levels and urine protein values.
  • FIG. 9A depicts a glomerular COL3 Al interactome.
  • FIG. 9B depicts a tubular COL3 A1 interactome.
  • administering typically refers to administration of a composition to a subject to achieve delivery of an active agent to a site of interest (e.g., a target site which may, in some embodiments, be a site of disease or damage, and/or a site of responsive processes, cells, tissues, etc.)
  • a site of interest e.g., a target site which may, in some embodiments, be a site of disease or damage, and/or a site of responsive processes, cells, tissues, etc.
  • a site of interest e.g., a target site which may, in some embodiments, be a site of disease or damage, and/or a site of responsive processes, cells, tissues, etc.
  • a site of interest e.g., a target site which may, in some embodiments, be a site of disease or damage, and/or a site of responsive processes, cells, tissues, etc.
  • one or more particular routes of administration may be feasible and/or useful in the practice of the present invention.
  • administration may be parenteral
  • the term “comparable” refers to two or more agents, entities, situations, sets of conditions, circumstances, individuals, or populations, etc. that may not be identical to one another but that are sufficiently similar to permit comparison there between so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed.
  • comparable agents, entities, situations, sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features.
  • dosage form may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic agent) for administration to a subject.
  • an active agent e.g., a therapeutic agent
  • each such unit contains a predetermined quantity of active agent.
  • such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen).
  • the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.
  • salt form refers to a form of a relevant compound as a salt appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and/or lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in ./. Pharmaceutical Sciences , 66: 1-19 (1977).
  • the term “reference” describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, individual, population, sample, sequence or value of interest is compared with a reference or control agent, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and/or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and/or comparison to a particular possible reference or control.
  • risk of a disease, disorder, and/or condition refers to a likelihood that a particular individual will develop the disease, disorder, and/or condition. In some embodiments, risk is expressed as a percentage. In some embodiments, risk is from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 up to 100%. In some embodiments risk is expressed as a risk relative to a risk associated with a reference sample or group of reference samples. In some embodiments, a reference sample or group of reference samples have a known risk of a disease, disorder, condition and/or event. In some embodiments a reference sample or group of reference samples are from individuals comparable to a particular individual. In some embodiments, relative risk is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more.
  • the term “subject” refers an organism, typically a mammal (e.g., a human). In some embodiments, a subject is suffering from a relevant disease, disorder or condition. In some embodiments, a human subject is an adult, adolescent, or pediatric subject.
  • a subject is at risk of (e.g., susceptible to), e.g., at elevated risk of relative to an appropriate control individual or population thereof, a disease, disorder, or condition.
  • a subject displays one or more symptoms or characteristics of a disease, disorder or condition.
  • a subject does not display any symptom or characteristic of a disease, disorder, or condition.
  • a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition.
  • a subject is an individual to whom diagnosis and/or therapy and/or prophylaxis is and/or has been administered.
  • the terms “subject” and “patient” are used interchangeably herein.
  • the term “treat” refers to any administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition.
  • such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition.
  • such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
  • treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition.
  • the present disclosure recognizes a problem with current treatments for fibrotic diseases of the kidney and related diseases, disorders, and conditions, namely that there is a lack of specific therapies to treat these diseases.
  • FSGS Current treatments for FSGS include corticosteroids, calcineurin inhibitors, mycophenolate mofetil, adrenocorticotropic hormone (ACTH) and rituximab, which are applied in a trial and error manner, and are effective in at most 25-40% of patients.
  • ACTH adrenocorticotropic hormone
  • rituximab adrenocorticotropic hormone
  • the present disclosure provides specific treatments for patients with fibrotic kidney diseases and related diseases, disorders, and conditions, such as FSGS, based on the genomic mechanism of the disease in those patients.
  • the present disclosure encompasses the recognition that one or more biomarkers can distinguish patients with fibrotic kidney diseases and related diseases, disorders, and conditions that are likely to benefit from therapy with Compound 1.
  • Compound 1 i.e., methyl (Z)-3-(((4-(N-methyl-2-(4-methylpiperazin-l-yl)acetamido)phenyl) amino)(phenyl)methylene)-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridine-6-carboxylate, is in a pharmacological class of tyrosine kinase inhibitors (TKI).
  • TKI tyrosine kinase inhibitors
  • Compound 1 is an orally bioavailable small molecule dual kinase inhibitor of platelet-derived growth factor receptors (PDGFR) and vascular endothelial growth factor receptors (VEGFR2). Compound 1 is useful in methods provided herein.
  • Compound 1 is provided and/or utilized (e.g., for inclusion in a composition and/or for delivery to a subject) in accordance with the present disclosure in a form such as a salt form (e.g., a pharmaceutically acceptable salt form).
  • a salt form e.g., a pharmaceutically acceptable salt form
  • pharmaceutically acceptable salt forms are well known in the art.
  • Compound 1 is provided and/or utilized in a hydrochloride salt form, a maleate salt form, a mesylate salt form, or a tosylate salt form.
  • Compound 1 is provided and/or utilized (e.g., for inclusion in, e.g., during one or more steps of manufacturing of, a composition and/or for delivery to a subject) in accordance with the present disclosure in a form such as a solid form.
  • Compound 1 is provided and/or utilized in accordance with the present disclosure in an amorphous solid form, in a crystalline solid form, or in a mixture thereof.
  • a crystalline solid form may be or comprise a solvate, hydrate, or an unsolvated form. The use of any and all such forms are contemplated by the present disclosure.
  • Compound 1 refers to Compound 1 (i.e., methyl (Z)-3-(((4-(N-methyl-2-(4-methylpiperazin-l-yl)acetamido)phenyl)amino)(phenyl) methylene)-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridine-6-carboxylate) in any available form, such as, e.g., a salt form and/or solid form. It will be understood, therefore, that reference to an amount (e.g., in mg) of Compound 1 means the amount of Compound 1 in free base form.
  • Compound 1 may be provided and/or utilized as, e.g., a salt form of Compound 1 such that the amount of the salt (or other form) is an amount that corresponds to the “free base equivalent” of Compound 1.
  • “50 mg Compound 1” means, e.g., approx. 53.4 mg of Compound 1 Hydrochloride anhydrate, approx. 58.4 mg of Compound 1 Hydrochloride trihydrate, and approx. 58.9 mg of Compound 1 Mesylate anhydrate, etc.
  • compositions that comprises and/or delivers Compound 1 as described herein are provided herein.
  • such administering is achieved by administering a composition that delivers Compound 1 (e.g., in some embodiments, a composition that is or comprises Compound 1, or a composition that otherwise delivers Compound 1 - e.g., that is or comprises a prodrug of Compound 1, a complex or other entity that releases Compound 1 upon administration, etc.).
  • a composition that delivers Compound 1 e.g., in some embodiments, a composition that is or comprises Compound 1, or a composition that otherwise delivers Compound 1 - e.g., that is or comprises a prodrug of Compound 1, a complex or other entity that releases Compound 1 upon administration, etc.
  • the present disclosure is based in part on the discovery that certain biomarkers can distinguish patients who are likely to respond to therapy, for example because the drivers of their kidney disease correspond with the mechanism of action of Compound 1.
  • a patient to be treated with a method of the present disclosure has an altered level of one or more gene products or proteins that are part of the mechanism of action of Compound 1 (e.g., down regulated by Compound 1).
  • a patient to be treated with a method of the present disclosure has an elevated level of COL3A1 expression and/or COL1A1 expression.
  • a level of COL3A1 refers to a gene product (e.g., RNA, e.g., mRNA) or a protein product (e.g., a prepropolypeptide, propolypeptide, amino-terminal propolypeptide, protein, fibril, fiber, or any fragment or degradation product thereof).
  • a level of COL1A1 refers to a gene product (e.g., RNA, e.g., mRNA) or a protein product (e.g., a prepropolypeptide, propolypeptide, amino-terminal propolypeptide, protein, fibril, fiber, or any fragment or degradation product thereof).
  • a gene product e.g., RNA, e.g., mRNA
  • a protein product e.g., a prepropolypeptide, propolypeptide, amino-terminal propolypeptide, protein, fibril, fiber, or any fragment or degradation product thereof.
  • the present disclosure provides a method for treating a patient diagnosed with, suspected of having, or at risk for a fibrotic disease of the kidney, the method comprising: (i) obtaining or determining a level of expression of a biomarker (e.g., COL3 A1 and/or COL1 Al) in a biological sample from the patient; (ii) comparing the level of biomarker expression with that of a threshold level (e.g., a predetermined mean or median level of a population of healthy subjects), wherein if the expression level of the biomarker is above the threshold level, administering to the patient an effective amount of Compound 1, or a pharmaceutical composition thereof.
  • a biomarker e.g., COL3 A1 and/or COL1 Al
  • a threshold level e.g., a predetermined mean or median level of a population of healthy subjects
  • the present disclosure provides a method for treating a patient diagnosed with, suspected of having, or at risk for a fibrotic disease of the kidney, the method comprising administering an effective amount of Compound 1, or a pharmaceutical composition thereof, to a patient who has been determined to have an elevated level of a biomarker (e.g., COL3A1 and/or COL1 Al).
  • a biomarker e.g., COL3A1 and/or COL1 Al
  • an elevated level of a biomarker comprises a level that is above that of a corresponding threshold level.
  • the level of biomarker e.g., COL3A1 and/or COL1 Al
  • the method further comprises obtaining or determining a level of a biomarker (e.g., COL3A1 and/or COL1 Al) in a biological sample from the patient.
  • a method for treating a patient diagnosed with, suspected of having, or at risk for a fibrotic disease of the kidney in a patient characterized by an elevated level of a biomarker e.g., COL3A1 and/or COL1A1
  • the method comprising administering an effective amount of Compound 1, or a pharmaceutical composition thereof, to the patient.
  • an elevated level of a biomarker comprises a level that is above a corresponding threshold level.
  • the level of biomarker e.g., COL3A1 and/or COL1 Al
  • the method further comprises obtaining or determining a level of a biomarker (e.g., COL3A1 and/or COL1 Al) in a biological sample from the patient.
  • a biomarker e.g., COL3A1 and/or COL1 Al
  • the biological sample is a renal biopsy sample, a urine sample or a blood sample.
  • the biological sample is a renal biopsy sample and the expression level of COL3 A1 is an mRNA level and/or the expression level of COL1 A1 is an mRNA level.
  • Methods for measuring and/or determining levels of a biomarker (e.g., mRNA level) in renal biopsy samples are known in the art, for example, Genovese et ah, Biomark Insights. 2016 May 22; 11 :77-84.
  • the biological sample is a urine sample and the expression level of COL3 A1 is a level of COL3 A1 protein or fragments thereof and/or the expression level of COL1 A1 is a level of COL1 A1 protein or fragments thereof.
  • the biological sample is a blood sample and the expression level of COL3 A1 is a level of COL3 A1 protein or fragments thereof and/or the expression level of COL1A1 is a level of COL1 A1 protein or fragments thereof.
  • a biomarker e.g., a level of collagen protein and/or fragment thereof
  • urine and/or blood samples are known in the art, for example, Soylemezoglu et al., Nephrol Dial Transplant. 1997 Sep;12(9):1883-9.
  • the present disclosure provides methods of administering Compound 1 to a subject or population of subjects described herein, according to a regimen established to achieve one or more desirable outcomes.
  • the kidney fibrotic disease is stabilized (i.e., does not worsen) and/or is ameliorated (i.e., one or more symptoms improve) in a patient treated with Compound 1.
  • treatment of a patient with Compound 1 reduces a level of one or more biomarkers (e.g., COL1 Al and/or COL3A1).
  • treatment of a patient with Compound 1 reduces proteinuria.
  • a regimen has been established to achieve one or more desirable outcomes, relative to that observed for a comparable reference population that has not received Compound 1 (e.g., that has received a placebo).
  • a placebo as used herein is a dosage form that matches that of an active study compound, but does not deliver the active study compound (e.g., Compound 1).
  • a placebo can be a capsule that visually matches an active study drug and is composed of the same capsule shell but is filled with a pharmaceutical excipient (and lacking the active study drug), e.g., silicified microcrystalline cellulose.
  • a reference composition may be or may have been administered at the same intervals and/or in the same amounts as a composition providing Compound 1.
  • a regimen has been established to achieve one or more desirable outcomes, relative to that observed for a comparable reference population that does not have an altered level of a biomarker (e.g., an elevated level of COL3A1 and/or COL1 Al).
  • a patient who expresses a biomarker treated with Compound 1 has an improved outcome (e.g., improved stability and/or amelioration of the fibrotic kidney disease) relative to a patient with the same disease that does not express an elevated level of the biomarker.
  • treatment of a patient with Compound 1 reduces a level of one or more biomarkers (e.g., COL1 Al and/or COL3A1).
  • treatment of a patient with Compound 1 reduces proteinuria.
  • composition providing Compound 1 is administered according to a regimen established to achieve a particular effect, e.g., at a particular time point.
  • composition providing Compound 1 is administered according to a regimen established to achieve a particular effect.
  • a provided method includes: (i) receiving a report listing the expression level of one or more biomarkers (e.g., COL3 Al and/or COL1 Al) for a patient with a fibrotic kidney disease; (ii) receiving a request for reimbursement of the screening and/or of a particular therapeutic regimen; and (iii) approving payment and/or reimbursement for Compound 1 therapy if the report indicates the level of biomarker is above a threshold level.
  • biomarkers e.g., COL3 Al and/or COL1 Al
  • provided methods are useful for treating renal diseases, disorders, and conditions. In some embodiments, provided methods are useful for reducing fibrosis of the kidney in a subject in need thereof. In some embodiments, provided methods are useful for treating a kidney disease, disorder, or condition characterized by or otherwise associated with fibrosis.
  • the present disclosure encompasses the recognition that treating fibrosis (e.g., using provided methods) instead of the underlying etiology may allow for broadly applicable antifibrotic kidney therapies.
  • kidney diseases, disorders, and conditions in which fibrosis is the sole or a predominant component may be suitable for treating kidney diseases, disorders, and conditions in which fibrosis is the sole or a predominant component, as well as those in which fibrosis is a secondary component (e.g., a symptom and/or result of an underlying disease, disorder, or condition).
  • provided methods are useful for treating acute injuries (e.g., acute organ injuries, such as acute kidney injury), as well as for treating chronic injuries (e.g., chronic kidney injury).
  • provided methods are useful for treating fibrosis associated with an acute injury, such as that incurred from trauma and/or surgery.
  • provided methods are useful for treating damaged and/or ischemic organs, transplants, or grafts, as well as ischemia/reperfusion injury or post-surgical scarring.
  • provided methods are useful for treating renal fibrosis.
  • provided methods are useful for treating renal fibrosis secondary to, or otherwise associated with, an underlying indication.
  • provided methods are useful for treating renal fibrosis associated with renal failure, renal obstruction, renal trauma, renal transplantation, chronic kidney disease, diabetes, hypertension, radiocontrast nephropathy, immune-mediated glomerulonephritides (e.g., lupus nephritis, ANCA-associated glomerulonephritides (e.g., Wegener’s granulomatosis, microscopic polyangiitis, or renal limited vasculitis), anti-GBM nephropathy, IgA nephropathy, membranous glomerulonephritis, or focal and segmental glomerulosclerosis), non-immune-mediated glomerulonephritides (e.g., autosomal dominant polycystic kidney disease, collagen type
  • provided methods are useful for treating nephrotic syndrome and/or diseases, disorders, or conditions associated with nephrotic syndrome (e.g., focal and segmental glomerulosclerosis, minimal change disease, and membranous nephropathy).
  • nephrotic syndrome e.g., focal and segmental glomerulosclerosis, minimal change disease, and membranous nephropathy.
  • provided methods are useful for treating a fibrotic disease of the kidney that is or comprises: focal segmental glomerulosclerosis (FSGS), steroid resistant nephrotic syndrome (SRNS), proteinuria, lupus nephritis, minimal change disease, an anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, anti-globular basement membrane (anti-GBM) nephropathy, IgA nephropathy, membranous glomerulonephritis (MG), autosomal dominant polycystic kidney disease (ADPKD), or chronic kidney disease.
  • FSGS focal segmental glomerulosclerosis
  • SRNS steroid resistant nephrotic syndrome
  • proteinuria lupus nephritis
  • minimal change disease an anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis
  • anti-GBM anti-globular basement membrane
  • IgA nephropathy I
  • provided methods are useful for treating a fibrotic disease of the kidney that is or comprises an anti neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.
  • ANCA-associated glomerulonephritis is selected from Wegener’s granulomatosis, microscopic polyangiitis (MPA), or renal limited vasculitis.
  • provided methods are useful for treating focal and segmental glomerulosclerosis.
  • provided methods are useful for treating polycystic kidney disease (e.g., autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease).
  • provided methods are useful for treating primary proteinuric kidney disease (PPKD).
  • PPKD primary proteinuric kidney disease
  • PGDs primary glomerular diseases
  • PGDs are among the leading causes of chronic kidney disease and end-stage kidney disease in the world. PGDs predominantly affect younger patients, significantly reducing their quality of life, productivity, and longevity.
  • FSGS, membranous nephropathy (MN), and IgA nephropathy are among the three most common primary glomerular diseases in adults. Accordingly, in some embodiments, provided methods are useful for treating FSGS. In some embodiments, provided methods are useful for treating MN. In some embodiments, provided methods are useful for treating IgA nephropathy.
  • CNIs calcineurin inhibitors
  • provided methods are useful for treating patients with proteinuria (e.g., persistent proteinuria). It is well established that higher rates of urinary protein excretion are associated with worse prognosis, and therapies that reduce proteinuria are desirable for improving renal outcomes. Patients with persistent proteinuria (e.g., who continue to have >
  • ESKD end-stage kidney disease
  • eGFR estimated glomerular filtration rate
  • Patients with persistent proteinuria also develop further complications of chronic kidney disease (CKD) such as dyslipidemia, cardiovascular disease, abnormalities in mineral-bone metabolism, and hypertension, resulting in significant increases in morbidity and mortality and utilization of health care resources.
  • CKD chronic kidney disease
  • RAAS renin-angiotensin-aldosterone system
  • ARB angiotensin-receptor blockers
  • RAAS blockers reduce proteinuria and improve clinical outcomes in proteinuric renal diseases regardless of the etiology.
  • Other standard of care recommendations include aggressive blood pressure control ( ⁇ 130/80), and HMG-CoA reductase inhibitors (e.g., statins) in patients with hyperlipidemia.
  • statins HMG-CoA reductase inhibitors
  • the inhibitors of the mineralocorticoid receptor and sodium glucose co-transporter-2 (SGLT-2) are increasingly being used in these patients as well.
  • provided methods are useful for treating primary glomerular diseases (e.g., FSGS, membranous nephropathy, or IgA nephropathy) and persistent proteinuria.
  • primary glomerular diseases e.g., FSGS, membranous nephropathy, or IgA nephropathy
  • persistent proteinuria e.g., FSGS, membranous nephropathy, or IgA nephropathy
  • PDGFRP Platelet- derived growth factor receptor beta
  • a kidney disease to be treated by methods of the present disclosure is nephrotic syndrome (NS).
  • NS is a group of rare renal diseases, including focal and segmental glomerulosclerosis (FSGS), minimal change disease (MCD), and membranous nephropathy.
  • FSGS focal and segmental glomerulosclerosis
  • MCD minimal change disease
  • membranous nephropathy is a rare renal disease that attacks the kidney’s filtering units (glomeruli) causing serious scarring which leads to permanent kidney damage and even failure (Fogo, A.B. Nat. Rev. Nephrol. 2015 Feb;l l(2):76-87, PMCID:PMC4772430). It will be appreciated that there are at least three types of FSGS.
  • Primary FSGS is FSGS that has no known cause (also referred to as idiopathic FSGS). Secondary FSGS is caused by one or more factors such as infection, drug toxicity, diseases such as diabetes or sickle cell disease, obesity, or other kidney diseases. Genetic FSGS (also called familial FSGS) is caused by one or more genetic mutations. Primary FSGS is idiopathic in nature. Manifestations of this disease include hypoalbuminemia and edema, lipid abnormalities and nephrotic range proteinuria. More than 5400 patients are diagnosed with FSGS every year (O’Shaughnessy, M.M., et al. Nephrol. Dial. Transplant 2018 Apr l;33(4):661-9).
  • a kidney disease to be treated by methods of the present disclosure is minimal change disease (MCD).
  • MCD is a kidney disease in which large amounts of protein are lost in the urine. It is one of the most common causes of the nephrotic syndrome worldwide. In children, MCD is usually primary (or idiopathic), but in adults, the disease is usually secondary. Secondary causes for MCD include allergic reactions, use of certain painkillers such as non-steroidal anti-inflammatory drugs (NSAIDs), tumors, or viral infections.
  • a kidney disease to be treated by methods of the present disclosure is membranous glomerulonephritis (MG or MGN), also known as membranous nephropathy (MN).
  • MG is a slowly progressive renal disease caused by immune complex formation in the glomerulus.
  • Immune complexes are formed by binding of antibodies to antigens in the glomerular basement membrane.
  • the antigens may be part of the basement membrane, or deposited from elsewhere by the systemic circulation.
  • a kidney disease to be treated by methods of the present disclosure is anti -neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.
  • ANCA-associated glomerulonephritis is a rapidly progressive renal disease and includes, e.g., Wegener's granulomatosis, microscopic polyangiitis, and renal limited vasculitis.
  • Wegener's granulomatosis is an organ- and/or life-threatening autoimmune disease of unknown etiology.
  • the classical clinical triad consists of necrotizing granulomatous inflammation of the upper and/or lower respiratory tract, necrotizing glomerulonephritis, and an autoimmune necrotizing systemic vasculitis affecting predominantly small vessels.
  • the detection of anti-neutrophil cytoplasmic antibodies directed against proteinase 3 (PR3-ANCA) is a highly specific indicator for Wegener's granulomatosis.
  • Microscopic polyangiitis is a disorder that causes blood vessel inflammation (vasculitis), which can lead to organ damage.
  • the kidneys, lungs, nerves, skin, and joints are the most commonly affected areas of the body.
  • MPA is diagnosed in people of all ages, all ethnicities, and both genders. The cause of this disorder is unknown.
  • Renal limited vasculitis is a type of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis that presents with only a renal manifestation; no other organs, including lungs, are involved.
  • ANCA anti
  • a kidney disease to be treated by methods of the present disclosure is lupus nephritis.
  • Lupus nephritis is inflammation of the kidney that is caused by the autoimmune disease systemic lupus erythematous (SLE). With lupus, the body's immune system targets its own body tissues; lupus nephritis occurs when lupus involves the kidneys.
  • a kidney disease to be treated by methods of the present disclosure is anti-globular basement membrane (anti-GBM) nephropathy.
  • Anti-GBM nephropathy is a disease that occurs as a result of injury to small blood vessels (capillaries) in the kidneys and/or lungs.
  • capillaries small blood vessels
  • autoantibodies are targeted to the basement membrane in capillary blood vessels of the kidneys and lung, where they target and damage GBM.
  • a kidney disease to be treated by methods of the present disclosure is IgA nephropathy, also known as Berger’s disease.
  • IgA nephropathy is a kidney disease that occurs when IgA deposits build up in the kidneys, causing inflammation that damages kidney tissues.
  • IgA nephropathy affects the kidneys by attacking the glomeruli. The buildup of IgA deposits inflames and damages the glomeruli, causing the kidneys to leak blood and protein into the urine. The damage may lead to scarring of the nephrons that progresses slowly over many years. Eventually, IgA nephropathy can lead to end-stage kidney disease.
  • a kidney disease to be treated by methods of the present disclosure is polycystic kidney disease (e.g., autosomal recessive polycystic kidney disease (ARPKD) - congenital hepatic fibrosis (CHF)).
  • ARPKD-CHF is a highly aggressive fibropolycystic disease that is characterized by the formation and expansion of fluid-filled cysts in the kidneys, enlargement of the kidneys and progressive fibrosis of both the kidney and the liver (Hartung, E.A., and Guay -Woodford, L.M. Pediatrics 2014 Sep;134(3):e833-e845; Gunay- Aygun, M., et al. J.
  • ARPKD-CHF congenital hepatic fibrosis
  • Caroli’s disease manifests as cystic dilatation of the intrahepatic ducts, often accompanies ARPKD-CHF (Sung, J.M., et al. Clin. Nephrol. 1992 Dec;38(6):324-8).
  • a subject is suffering from, susceptible to, or at risk of Caroli’s disease.
  • the need for transplantation is often driven by both progressive organ dysfunction and by significant enlargement of the diseased organ(s), and is accompanied by severe pain (www.arpkdchf.org).
  • a kidney disease to be treated by methods of the present disclosure is or includes renal cysts.
  • Aberrant signaling by tyrosine kinases including platelet- derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) and their receptors (R), PDGFR and VEGFR/KDR, respectively, has been implicated in the formation and expansion of renal cysts.
  • PDGF platelet- derived growth factor
  • VEGF vascular endothelial growth factor
  • R receptors
  • a PDGF-driven ciliopathy and/or overexpression of PDGF in the cyst lining and adjacent tubules are thought to, in part, drive renal cystic disease (Torres, V.E., et al. Lancet 2007 Apr 14;369(9569): 1287-301; Park. J.H. et al.
  • a kidney disease to be treated by methods of the present disclosure is collagen type III glomerulopathy.
  • Collagen type III glomerulopathy also known as collagenic or collagenofibrotic glomerulopathy, is characterized by pathological accumulation of collagen type III in glomeruli.
  • Collagen type III glomerulopathy presents either in childhood, often with a family history suggesting autosomal recessive inheritance, or in adults as a sporadic occurrence.
  • Proteinuria is a typical manifestation, with progression to end stage renal disease (ESRD) in approximately 10 years.
  • ESRD end stage renal disease
  • a kidney disease to be treated by methods of the present disclosure is nail-patella syndrome.
  • Nail-patella syndrome is a multi-organ disorder caused by mutations in the LMX1B gene. Nail-patella syndrome manifests with orthopedic and cutaneous deformities, as well as kidney complications due to development of structural lesions of collagen type III within glomerular basement membranes. Although the structural lesions may be asymptomatic, they are usually accompanied by proteinuria.
  • VEGF-driven angiogenesis is also thought to contribute to the growth of renal cysts, and inhibition of VEGFR/KDR signaling is associated with decreased tubule cell proliferation, decreased cystogenesis, and blunted renal enlargement (Bello-Ruess, E., et al. Kidney Int. 2001 Jul;60(l):37-45; Schrijvers, B.F., et al. Kidney Int. 2004 Jun;65(6):2003-17). Nevertheless, the role of VEGF in fibropoly cystic disease is more controversial, with at least some reports suggesting that this growth factor might be associated with disease mitigation (Spirli, C., et al. Gastroenterology 2010 Jan;138(l):360-71).
  • one or more subjects or populations are selected to received Compound 1 as described herein based on one or more markers and/or characteristics such as, for example, one or more risk factors of fibrosis or an associated disease, disorder or condition and/or one or more biomarkers, etc.
  • a subject or population thereof is selected to receive Compound 1 using technologies provided herein (e.g., based on assessment of one or more markers and/or characteristics, such as one or more biomarkers, e.g., COL3A1 and/or COL1 Al).
  • technologies are used to inform or determine one or more features of a therapeutic regimen (e.g., selection of subject(s) to receive a particular therapy (e.g.,
  • Compound 1 therapy and/or dose thereof and/or timing of administration of such therapy).
  • assessment of one or more markers and/or characteristics is performed with respect to the same subject at a plurality of different time points. In some embodiments, assessment of one or more markers and/or characteristics is performed with respect to a particular patient prior to initiation of a particular therapeutic regimen (e.g., a Compound 1 therapeutic regimen) and/or prior to administration of a particular dose of therapy (e.g., Compound 1 therapy) in accordance with such therapeutic regimen.
  • a particular therapeutic regimen e.g., a Compound 1 therapeutic regimen
  • a particular dose of therapy e.g., Compound 1 therapy
  • a subject or population thereof is suffering from or is susceptible to a kidney disease as described herein. In some embodiments, a subject or population thereof is suffering from or is susceptible to fibrotic disease of the kidney as described herein. In some embodiments, a subject or population thereof is suffering from or is susceptible to a disease, disorder, or condition characterized by or otherwise associated with fibrosis of the kidney as described herein.
  • a subject or population thereof is suffering from or is susceptible to an acute kidney injury. In some embodiments, a subject or population thereof is suffering from or is susceptible to a chronic kidney injury. In some embodiments, a subject or population thereof is suffering from a traumatic injury. In some embodiments, a subject or population thereof has undergone, is undergoing, or will undergo an organ transplantation. In some embodiments, a subject or population thereof is suffering from or susceptible to a damaged and/or ischemic organ, transplant, or graft. In some embodiments, a subject or population thereof is suffering from or susceptible to ischemia/reperfusion injury. In some embodiments, a subject or population thereof is suffering from or susceptible to post-surgical scarring.
  • a subject or population thereof is suffering from or is susceptible to renal fibrosis. In some embodiments, a subject or population thereof is suffering from or is susceptible to renal fibrosis secondary to, or otherwise associated with, an underlying indication.
  • a subject or population thereof is suffering from or is susceptible to renal failure, renal obstruction, renal trauma, renal transplantation, chronic kidney disease, diabetes, hypertension, radiocontrast nephropathy, immune-mediated glomerulonephritides (e.g., lupus nephritis, ANCA-associated glomerulonephritides (e.g., Wegener’s granulomatosis, microscopic polyangiitis, or renal limited vasculitis), anti-GBM nephropathy, IgA nephropathy, membranous glomerulonephritis, or focal and segmental glomerulosclerosis), non-immune-mediated glomerulonephritides (e.g., autosomal dominant polycystic kidney disease), minimal change disease, or nephrotic syndrome (e.g., steroid- resistant nephrotic syndrome).
  • immune-mediated glomerulonephritides e.g., lupus nep
  • a subject or population thereof is suffering from or is susceptible to a fibrotic disease of the kidney that is or comprises: focal segmental glomerulosclerosis (FSGS), steroid resistant nephrotic syndrome (SRNS), proteinuria, lupus nephritis, minimal change disease, an anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, anti-globular basement membrane (anti-GBM) nephropathy, IgA nephropathy, membranous glomerulonephritis (MG), autosomal dominant polycystic kidney disease (ADPKD), or chronic kidney disease.
  • FSGS focal segmental glomerulosclerosis
  • SRNS steroid resistant nephrotic syndrome
  • proteinuria lupus nephritis
  • minimal change disease an anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis
  • anti-GBM anti-globular basement membrane
  • a subject or population thereof is suffering from or is susceptible to a fibrotic disease of the kidney that is or comprises an anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.
  • ANCA-associated glomerulonephritis is selected from Wegener’s granulomatosis, microscopic polyangiitis (MPA), or renal limited vasculitis.
  • a subject or population thereof is suffering from or is susceptible to collagen type III glomerulopathy or nail- patella syndrome.
  • a subject or population thereof is suffering from or is susceptible to nephrotic syndrome and/or diseases, disorders, or conditions associated with nephrotic syndrome (e.g., focal and segmental glomerulosclerosis, minimal change disease, and membranous nephropathy).
  • a subject or population thereof is suffering from or is susceptible to focal and segmental glomerulosclerosis (FSGS).
  • FSGS focal and segmental glomerulosclerosis
  • a subject or population thereof is suffering from or is susceptible to collagen type III glomerulopathy.
  • a subject or population thereof is suffering from or is susceptible to nail-patella syndrome.
  • a subject or population thereof is suffering from or is susceptible to polycystic kidney disease (e.g., autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease).
  • a subject or population thereof is suffering from or is susceptible to primary proteinuric kidney disease (e.g., as confirmed from a renal biopsy).
  • a subject or population thereof is suffering from or is susceptible to primary glomerular diseases (e.g., as confirmed from a renal biopsy).
  • a subject or population thereof is suffering from or susceptible to persistent proteinuria.
  • a subject or population thereof is suffering from or susceptible to primary glomerular disease (e.g., as confirmed from a renal biopsy) and persistent proteinuria.
  • a subject or population thereof is suffering from or susceptible to proteinuric chronic kidney disease.
  • a subject or population thereof is suffering from or is susceptible to focal and segmental glomerulosclerosis. In some embodiments, a subject or population thereof is suffering from or is susceptible to membranous nephropathy. In some embodiments, a subject or population thereof is suffering from or susceptible to IgA nephropathy.
  • a subject or population thereof is suffering from or is susceptible to renal fibrosis and has an altered level of one or more biomarkers (e.g., an elevated level of COL3A1 and/or COL1A1).
  • biomarkers e.g., an elevated level of COL3A1 and/or COL1A1.
  • the present disclosure provides certain biomarkers that can distinguish subjects (e.g., subjects suffering from or at risk of renal fibrosis or associated diseases, disorders, and conditions) who are more likely than others to respond to therapy with Compound 1.
  • the present disclosure provides the insight that certain biomarkers can distinguish patients who are likely to respond to therapy, for example because the drivers of their kidney disease correspond with the mechanism of action of Compound 1.
  • an altered level of one or more gene products or proteins that are part of the mechanism of action of Compound 1 e.g., down- or up-regulated by Compound 1).
  • one or more biomarkers comprise an elevated level of COL3 A1 expression and/or COL1A1 expression.
  • a patient with an altered level of one or more biomarkers may have an improved response to treatment with Compound 1 relative to a patient who does not have a level of the biomarker that meets the threshold criteria.
  • one biomarker is used to characterize subjects; in some embodiments, more than one biomarker (e.g., two, three, etc.) is used to characterize subjects.
  • a biomarker is a component of a biological sample that may be detected and/or quantified when present in the biological sample.
  • a level of a biomarker corresponds to a level of gene expression (e.g., RNA expression, e.g., mRNA expression).
  • a level of a biomarker corresponds to a level of collagen protein expression.
  • a biomarker is or includes collagen protein expression in any form, e.g., procollagen polypeptide, collagen protein, preprocollagen polypeptide, amino-terminal procollagen polypeptide, collagen fibril, collagen fiber, and/or any fragment or degradation product of any thereof.
  • a biomarker is differentially present in a sample taken from a subject of one status as compared with another status (e.g., more responsive to Compound 1 therapy vs. less responsive to Compound 1 therapy). In some embodiments, a biomarker is differentially present in a sample taken from the same subject at two or more different time points, i.e., when the status of the subject has changed from one time point to another.
  • a biomarker is detected and/or quantified in a tissue sample (e.g., from a biopsy, such as a kidney biopsy) and/or in a biological fluid (e.g., blood, urine, etc.).
  • a biomarker is a level of mRNA that is detected and/or quantified in a kidney tissue sample, e.g., obtained from a kidney biopsy.
  • a biomarker is detected and/or quantified in a urine sample (e.g., a level of a protein or protein fragment).
  • a biomarker is detected and/or quantified in a blood sample (e.g., a level of a protein or protein fragment).
  • a biomarker may include one or more of a peptide, protein, nucleic acid (e.g., polynucleotide, DNA, RNA, etc.), polysaccharide (e.g., lectins or sugars), lipid, enzyme, small molecule, ligand, receptor, antigen, or antibody.
  • a biomarker comprises a protein.
  • a biomarker comprises a nucleic acid (e.g., mRNA).
  • detection of a threshold level of one or more biomarkers is used to select and/or characterize patients who may be responsive to Compound 1 therapy.
  • levels of one or more biomarkers in a sample from a subject are compared to a threshold level.
  • a biomarker is considered increased if the level is increased relative to a threshold level (e.g., increased by at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%, or more).
  • a threshold level is determined from a population of healthy volunteers (e.g., a mean or median level from a population of healthy volunteers).
  • a method includes an in vitro method for determining a level of a biomarker.
  • in vitro methods for determining a level of a biomarker include, but are not limited to, a chemiluminescence assay, enzymatic assay, enzyme immunoassay, multiplex immunoassay, ELISA, chromatographic immunoassay, electrophoresis assay, radioimmunoassay, colorimetric assay, chromatography/mass spectrometry (e.g., GC/MS, LC/MS, LC/MS/MS, etc.), High Performance Liquid Chromatography (“HPLC”), and/or PCR (e.g., real-time PCR).
  • HPLC High Performance Liquid Chromatography
  • a method for detecting a level of a biomarker includes chromatographic and/or MS methods.
  • Exemplary methods include, but are not limited to, gas chromatography (GC), liquid chromatography/mass spectroscopy (LC-MS), gas chromatography/mass spectroscopy (GC-MS), nuclear magnetic resonance (NMR), magnetic resonance imaging (MRI), Fourier Transform InfraRed (FT-IR), and inductively coupled plasma mass spectrometry (ICP-MS).
  • the present disclosure encompasses the recognition that COL1 A1 and/or COL3A1 are useful biomarkers in the methods provided herein. In some embodiments, the present disclosure provides insight that increased levels of COL1 A1 and/or COL3 A1 expression may be useful in selecting and/or characterizing patients for Compound 1 therapy.
  • COL1 A1 is a biomarker useful in the methods provided herein.
  • COL3 A1 is a biomarker useful in the methods provided herein.
  • an elevated level of COL1A1 and/or COL3A1 corresponds to a level of gene expression (e.g., RNA, e.g., mRNA).
  • an elevated level of COL1A1 and/or COL3A1 corresponds to a level of collagen protein expression.
  • an elevated level of COL1A1 and/or COL3A1 protein is or includes e.g., a corresponding procollagen polypeptide, collagen protein, preprocollagen polypeptide, amino- terminal procollagen polypeptide, collagen fibril, collagen fiber, and/or any fragment or degradation product of any thereof.
  • an increased level of COL1 A1 and/or COL3A1 is above a threshold level (e.g., a predetermined median or mean level). In some embodiments, an increased level of COL1 A1 and/or COL3A1 is more than about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%, or more of a threshold level. In some embodiments, an increased level of COL1 A1 and/or COL3A1 is more than about 0.5, about 1.0, about 1.5, or about 2.0, or more standard deviations above a threshold level.
  • a threshold level e.g., a predetermined median or mean level. In some embodiments, an increased level of COL1 A1 and/or COL3A1 is more than about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%, or more of a threshold level. In some embodiments, an
  • subjects who are selected for Compound 1 therapy based on increased levels of COL1 A1 and/or COL3A1 achieve improved outcomes (e.g., compared to subjects who do not meet one or more selection criteria for Compound 1 therapy).
  • the present disclosure provides methods of treating a disease, disorder, or condition characterized by increased expression of COL1 A1 and/or COL3A1, comprising administering Compound 1 to a subject or population of subjects in need thereof.
  • a disease, disorder, or condition is a renal disease, disorder, or condition (e.g., a renal disease, disorder, or condition associated with fibrosis) as described herein.
  • a renal disease, disorder, or condition is characterized by increased expression of COL1A1 and/or COL3A1.
  • the present disclosure provides methods comprising administering Compound 1 to a subject in need thereof, wherein the subject has been determined to have increased level(s) of COL1A1 and/or COL3A1.
  • a subject has been determined to have increased level(s) of COL1 A1 and/or COL3A1 in a renal biopsy sample and/or a urine sample.
  • the present disclosure provides methods comprising determining level(s) of COL1A1 and/or COL3A1 by: obtaining a biological sample from a subject; performing an assay on the sample to determine level(s) of COL1 A1 and/or COL3A1 in the sample; and comparing the determined level(s) to a threshold level.
  • a sample has increased level(s) of COL1 A1 and/or COL3A1 compared to a threshold level
  • Compound 1 is administered to the subject.
  • if a sample does not have increased level(s) of COL1 A1 and/or COL3A1 compared to a threshold level then Compound 1 is not administered to the subject.
  • the present disclosure provides methods comprising determining level(s) of COL1 A1 and/or COL3A1 in a biological sample from a subject; comparing the determined level(s) to a threshold level; and identifying the subject as in need of therapeutic intervention when the sample is determined to have increased level(s) of COL1 A1 and/or COL3A1 compared to the threshold level.
  • a subject is identified as in need of therapeutic intervention with Compound 1 therapy.
  • a provided method further comprises administering Compound 1 to a subject (e.g., a subject identified as in need of therapeutic intervention).
  • provided technologies are useful for monitoring subjects (e.g., monitoring status of subjects over time and/or monitoring therapy).
  • the present disclosure provides methods comprising determining level(s) of COL1A1 and/or COL3A1 in each of a plurality of biological samples obtained at different time points from a single patient; and comparing the determined level(s) from a first time point with that from at least one later time point.
  • the present disclosure provides methods comprising determining level(s) of COL1 A1 and/or COL3A1 from a biological sample obtained from a subject for whom level(s) of COL1 A1 and/or COL3A1 have previously been obtained at least once; and comparing the determined level(s) with the previously obtained level(s).
  • a first time point and one or more later time points are separated from one another by a reasonably consistent interval.
  • a significant change in the determined level over time indicates a change in the subject’s status.
  • a significant change in a determined level over time is a change (e.g., an increase or a decrease) of at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%, or more compared to a threshold level.
  • a significant change in a determined level over time is a change of more than about 0.5, about 1.0, about 1.5, or about 2.0, or more standard deviations away a threshold level.
  • such methods further comprise administering Compound 1 therapy to a subject (e.g., a subject who has been determined to have moved from a non- responsive to a responsive state).
  • a subject e.g., a subject who has been determined to have moved from a non- responsive to a responsive state.
  • provided methods are useful for monitoring therapy (e.g., efficacy and/or other indicators of response).
  • a sample from a first time point was obtained from a subject prior to administration of Compound 1
  • a sample from a second time point was obtained from a subject after administration of Compound 1.
  • Compound 1 therapy is continued.
  • Compound 1 therapy is discontinued, or dosage amount and/or frequency of Compound 1 therapy is increased.
  • a method includes an in vitro method for determining a level of a biomarker.
  • a method for determining a level of a biomarker can be or include a chemiluminescence assay, enzymatic assay, enzyme immunoassay, multiplex immunoassay, ELISA, chromatographic immunoassay, electrophoresis assay, radioimmunoassay, colorimetric assay, UV spectroscopy, chromatography/mass spectrometry (e.g., GC/MS, LC/MS, LC/MS/MS, etc.), High Performance Liquid Chromatography (“HPLC”), and/or PCR (e.g., quantitative PCR and/or real-time PCR).
  • a chemiluminescence assay e.g., enzymatic assay, enzyme immunoassay, multiplex immunoassay, ELISA, chromatographic immunoassay, electrophoresis assay, radioimmunoassay,
  • a level of a biomarker corresponds to a level of gene expression (e.g., RNA, e.g., mRNA) and is quantified using methods known in the art.
  • a method of determining a level of expression of a biomarker gene can be or include a chemiluminescence assay, UV spectroscopy, hybridization assay (e.g., Fluorescent in Situ Hybridization (FISH), e.g., RNA- FISH), enzymatic assay, enzyme immunoassay (e.g., ELISA), multiplex assay, electrophoresis assay, radioassay, colorimetric assay, chromatography/mass spectrometry (e.g., GC/MS, LC/MS, LC/MS/MS, etc.), High Performance Liquid Chromatography (“HPLC”), and/or PCR (e.g., quantitative PCR and/or real-time PCR).
  • FISH Fluorescent in Situ Hybridization
  • RNA- FISH e.g., RNA- FISH
  • enzymatic assay e.g., enzyme immunoassay (e.g., ELISA), multiplex
  • a level of a biomarker corresponds to a level of protein (e.g., procollagen polypeptide, collagen protein, preprocollagen polypeptide, amino-terminal procollagen polypeptide, collagen fibril, collagen fiber, and/or any fragment or degradation product of any thereof) and is quantified using methods known in the art.
  • protein e.g., procollagen polypeptide, collagen protein, preprocollagen polypeptide, amino-terminal procollagen polypeptide, collagen fibril, collagen fiber, and/or any fragment or degradation product of any thereof
  • a method of determining a level of expression of a biomarker protein can be or include a chemiluminescence assay, enzymatic assay, enzyme immunoassay, multiplex immunoassay, ELISA, chromatographic immunoassay, electrophoresis assay, radioimmunoassay, colorimetric assay, UV spectroscopy, chromatography/mass spectrometry (e.g., GC/MS, LC/MS, LC/MS/MS, etc.), or High Performance Liquid Chromatography (“HPLC”).
  • a chemiluminescence assay e.g., COL1 A1 and/or COL3A1
  • a chemiluminescence assay e.g., enzymatic assay, enzyme immunoassay, multiplex immunoassay, ELISA, chromatographic immunoassay, electrophoresis assay, radioimmunoassay, colorimetric assay, UV spectroscopy,
  • composition providing Compound 1, as described herein can be administered to subjects in accordance with methods provided herein.
  • a composition providing Compound 1 is a composition comprising Compound 1 (in a pharmaceutically acceptable form as described herein), formulated together with one or more pharmaceutically acceptable carriers.
  • a composition providing Compound 1 is or comprises Compound 1 present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • compositions providing Compound 1 may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), capsules, tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
  • oral administration for example, drenches (aqueous or non
  • a composition providing Compound 1 is formulated for oral administration (e.g., in a capsule form). In some embodiments, a composition providing Compound 1 is administered orally.
  • a composition providing Compound 1 is administered as one or more unit dosage forms.
  • a composition providing Compound 1 is administered as one or more solid unit dosage forms (e.g., one or more capsules or tablets).
  • Compound 1 is administered as one or more oral unit dosage forms.
  • a composition providing Compound 1 is an immediate release solid unit dosage forms.
  • a composition providing Compound 1 is a capsule. In some embodiments, a composition providing Compound l is a tablet. [0154] In some embodiments, a composition providing Compound 1 is administered as a single dose. In some embodiments, a composition providing Compound 1 is administered at regular intervals. Administration at an “interval,” as used herein, indicates that the therapeutically effective amount is administered periodically (as distinguished from a one-time dose). In some embodiments, a composition providing Compound 1 is administered bimonthly, monthly, twice monthly, triweekly, biweekly, weekly, twice weekly, thrice weekly, daily, twice daily, or every six hours in accordance with methods provided herein.
  • a composition providing Compound 1 is administered at regular intervals indefinitely. In some embodiments, a composition providing Compound 1 is administered at regular intervals for a defined period of time.
  • Example 1 Compound 1 Decreases Expression of Certain Fibrosis and Inflammation Related Markers
  • Compound 1 is in a pharmacological class of tyrosine kinase inhibitors (TKI) and has a chemical name of: (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-l-yl)acetamido)phenyl)amino) (phenyl)methylene)-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridine-6-carboxylate.
  • TKI tyrosine kinase inhibitors
  • PDGFR platelet-derived growth factor receptors
  • VEGFR2 vascular endothelial growth factor receptors
  • the present example describes Bio-Map studies of Compound 1 in cell culture systems using DiscoverX technology platform and that were profiled in a KINOMEscan (Ambit/Di scoveRx/Eurofms, CA) biochemical assay.
  • Exemplary culture systems analyzed were: (1) Lung fibroblasts only (MyF) and (2) Renal proximal tubular epithelial cells + lung fibroblasts (REMyF). When activated, these cell systems mimic pathological conditions such as chronic inflammation, fibrosis, and matrix remodeling.
  • Compound 1 treatment decreased levels of several inflammation-related markers including monocyte chemotactic protein (MCP-1), macrophage colony stimulating factor (M-CSF), soluble interleukin (sIL-8), Interferon induced T cell alpha chemoattractant (I-TAC), IL-8, Interferon gamma induced Protein- 10 (IP- 10).
  • MCP-1 monocyte chemotactic protein
  • M-CSF macrophage colony stimulating factor
  • sIL-8 soluble interleukin
  • I-TAC Interferon induced T cell alpha chemoattractant
  • IL-8 Interferon gamma induced Protein- 10
  • Compound 1 treatment also decreased levels of fibrosis-related markers including N-cadherin, a-SMA, Collagen I and III, TIMP-1, plasminogen activator inhibitor (PAI-1), matrix metalloprotease, MMP-1, MMP-9, tissue and urokinase plasminogen activator (tPA and uPA), soluble VEGF and epidermal growth factor (EGFR) as shown in FIG. 1.
  • fibrosis- related markers including N-cadherin, a-SMA, Collagen I and III, TIMP-1, plasminogen activator inhibitor (PAI-1), matrix metalloprotease, MMP-1, MMP-9, tissue and urokinase plasminogen activator (tPA and uPA), soluble VEGF and epidermal growth factor (EGFR) as shown in FIG. 1.
  • the present example demonstrates that Compound 1 induced dose-dependent decrease in expression of a number of different inflammation and fibrosis-related markers.
  • the present example demonstrates that a mixed cell culture comprising renal epithelial cells and activated myofibroblasts treated with Compound 1 (13 mM) reduced expression of COL1 and COL3.
  • the present disclosure encompasses a recognition that in different patients, disease driving pathways may have divergent outcomes or converge on a common disease related outcome. For example, as depicted in FIG. 2, in some instances, different individuals may have distinct genomic responses that all result in a common kidney disease endpoint, while in other instances, different individuals may have a shared genomic response that leads to different kidney disease endpoints. For example, distinct disease-driving pathways in different individuals may lead to a common outcome of a fibrotic kidney disease, such as, e.g., FSGS. As such, different patients may respond to different therapies and interventions for the same disease.
  • the present disclosure provides the insight that identifying and neutralizing the particular disease drivers of a given patient may provide an early and effective way to manage kidney disease endpoints. Specifically, the present example determined the signalosome in various models of Focal and Segmental Glomerulosclerosis (FSGS) to identify biomarkers for treatment with Compound 1.
  • FSGS Focal and Segmental Glomerulosclerosis
  • Exemplary and etiologically distinct murine models of FSGS were used to characterize the kidney transcriptome and proteome that are associated with therapeutic activity of Compound 1.
  • kidneys were harvested.
  • kidney tissue was preserved in RNAlater (Sigma-Aldrich) for glomerular isolation by manual microdissection.
  • RNAlater Sigma-Aldrich
  • glomeruli were isolated by magnetic bead extraction.
  • RNA was extracted from glomerular preparations.
  • RNA extraction, RNA sequencing, data normalization and filtering were then performed. Differential expression analysis was performed using DESeq2 and EdgeR (M. F Love, et ak, (December 5, 2014) Genome Biol. 15: 550; M.
  • Hierarchical cluster dendrograms were generated to determine the ability of overall transcriptional profiles to recapitulate treatment groups. Rat and murine genes were converted to the corresponding human orthologs using the NCBI homolog (Build 64) and Genomatix annotated ortholog databases. Signalosome of rodent models treated with Compound 1 was analyzed and compared with transcriptome of renal dysfunction in human patients to thereby identify biomarkers of patients to be treated with Compound 1.
  • PAN puromycin aminonucleoside
  • rat puromycin aminonucleoside nephropathy (PAN) model of proteinuric kidney disease exhibit proteinuria that is mitigated by treatment with Compound 1, but not with sham.
  • Animals were sacrificed on Day 21 after PAN administration.
  • Mean arterial pressure (MAP) was evaluated prior to sacrifice and was not substantially different between vehicle treated and Compound 1 treated animals (data not shown).
  • MAP Mean arterial pressure
  • Kidneys were harvested and one of the two kidneys were used for analysis of the glomerular transcriptome. The other kidneys were homogenized for determination of COL1 A1 and COL3 A1 expression. Therapeutic intervention with Compound 1 was associated with decreased renal COL1 A1 and COL3A1 expression, shown in FIG. 4.
  • the present disclosure provides the insight that disease-driving networks in animal (e.g., murine) models of kidney disease may prove beneficial in those human patients that share the same transcriptional elements.
  • animal e.g., murine
  • lupus nephritis lupus nephritis
  • 54 proteins e.g., cytokines, TIMP, and metalloproteases
  • COL1A1 and COL3A1 have been identified as disease-associated nodes in human FSGS. See , e.g., Canadas-Garre, M., et al. J. Transl. Med. (2016) 16:292; Grgic, F, et al. Kidney Int. 2014 Dec; 86(6): 1116-1129; Schwab, K., et al. Am. J. Nephrol. 2004;24:438-447; and Grgic, F, et al. Kidney International. Furthermore, increased renal COL3A1 expression is associated with increased renal dysfunction in human FSGS. Additionally, expression of renal COL3A1 was shown to correlate with renal dysfunction in a rat PAN model of FSGS, similarly to the correlation observed in human kidney disease (FIG. 5).
  • Compound 1 interactome network include MAP2K5, MAP3K3, MAPK7, PRKAR1A, PIK3R1, SMPD1, AXL, FYN, PLXND1, CDC42PB, VAT1, RPS6KA2, RBPMS, CAV1, BGN, NPRl, FGFR1, EFEMP2, COL6A1, HEG1, PCGF2, COL6A2, MYH11, PDGFRA, PDGFRB, and KIT.
  • the present disclosure identified biomarkers in rodent models of kidney disease and in human patients that correspond with the Compound 1 mechanism of action.
  • the present disclosure encompasses a recognition that patients with fibrotic kidney diseases who have an altered level of one or more of these biomarkers may benefit from treatment with Compound 1.
  • Example 3 Therapeutic Treatment of Patients Expressing Biomarkers for Compound 1
  • the present example describes treatment of fibrotic disease of the kidney in a patient.
  • a nephropathy patient with suspected or confirmed glomerular disease i.e., suspected of having FSGS or MCD
  • a renal biopsy For example, mRNA is extracted from single glomeruli (see Menon et al., JCI Insight. 2020, 5(6):el33267), and sequenced to quantify levels of certain biomarkers associated with Compound l’s mechanism of action.
  • COL1A1 and COL3A1 expression are quantified.
  • a threshold level is a level that is about 20% or more above a predetermined normal range or mean or median level in a healthy patient. If a subject does not have a level of biomarker above the threshold level, then alternate treatment is determined. In some embodiments, in a patient to be treated with Compound 1, the kidney disease is stabilized and/or ameliorated.
  • Urine protein was determine using the Bradford assay.
  • Renal homogenates were subjected to analysis for COL3A1 and peptidylprolyl isomerase A (housekeeping gene) mRNA.
  • qPCR was performed on a Thermofisher Quant-Studio 3 Real-Time PCR system, each sample was diluted three-fold, and qPCR reaction was performed in triplicate for all tissue samples. Renal slices were stained with periodic acid Schiff for morphometric analysis or with Collagen Type III (Col3al) Antibody (BioCompare) for immunohistochemical analysis.
  • COL3 A1 mRNA level was elevated ⁇ 4-fold in the PAN cohort (FIG. 8A). There was a significant and direct association between the fold-increase in renal COL3 A1 mRNA level and the corresponding urine protein value (FIG. 8B). Immunohistochemical analysis indicated deposition of collagen type III restricted to the glomerular mesangium.
  • the present example demonstrates that an increase in COL3A1 mRNA is directly associated with an increase in urine protein in a rat model of kidney disease.
  • collagen type III deposition is restricted to the glomerulus, which may be indicative of a robust COL3A1 transcriptomic network in that compartment, compared to, e.g., the tubulointerstitium.

Abstract

La présente invention concerne des biomarqueurs et des méthodes utiles pour traiter, cribler et/ou évaluer le traitement de maladies fibrotiques du rein, avec du méthyle (Z)-3-(((4- (N-méthyl-2-(4-méthylpiperazin1l-yl)acétamido)phényl)amino)(phényl)méthylène)-2-oxo-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate.
PCT/US2021/039898 2020-07-01 2021-06-30 Méthodes de traitement de maladies rénales fibrotiques WO2022006277A1 (fr)

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