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WO2010042201A1 - Méthodes de traitement de la glomérulosclérose segmentaire focale - Google Patents

Méthodes de traitement de la glomérulosclérose segmentaire focale Download PDF

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WO2010042201A1
WO2010042201A1 PCT/US2009/005528 US2009005528W WO2010042201A1 WO 2010042201 A1 WO2010042201 A1 WO 2010042201A1 US 2009005528 W US2009005528 W US 2009005528W WO 2010042201 A1 WO2010042201 A1 WO 2010042201A1
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fsgs
subject
agent
ctgf
present
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Howard Trachtman
K. Lea Sewell
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Fibrogen Inc
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Fibrogen Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to methods and agents useful for treating focal segmental glomerulosclerosis (FSGS).
  • FSGS focal segmental glomerulosclerosis
  • FSGS Focal segmental glomerulosclerosis
  • FSGS is a type of glomerular disease that reduces kidney function by affecting the glomeruli.
  • FSGS is characterized by the presence of a scarring lesion in a portion (segment) of some (focal) but not all glomeruli.
  • Five recognized subtypes of FSGS have been described, each of which is determined by histological examination of kidney biopsy.
  • the five subtypes of FSGS include: collapsing, tip, cellular, perihilar and not otherwise specified (NOS). Identification of the FSGS subtype is useful for identifying potential differences in clinical presentation, outcome, and pathogenesis of the disease.
  • FSGS can be idiopathic (primary; unknown cause) or secondary (with identified underlying cause). Secondary forms of FSGS are generally considered to result from maladaptive responses that occur due to the loss of functioning nephrons or increased glomerular pressure.
  • FSGS is associated with poor outcome.
  • FSGS generally progress to end stage renal disease (ESRD) in 5 to 20 years following diagnosis or disease onset. More aggressive forms of FSGS can proceed to ESRD in 2 to 3 years. Additionally, greater than 20% of the dialysis population suffers from FSGS. (See Daskalakis et al (2006) Cell MoI Life Sci. 63:2506-11.)
  • CTGF connective tissue growth factor
  • the present invention provides methods for treating focal segmental glomerulosclerosis FSGS in a subject, the methods comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF, thereby treating FSGS in the subject.
  • the present invention also provides an agent that inhibits CTGF for use in a method for treating focal segmental glomerulosclerosis (FSGS).
  • FSGS focal segmental glomerulosclerosis
  • Also provided by the present invention are methods and agents for delaying the onset of or preventing, reducing, or eliminating a symptom of focal segmental glomerulosclerosis (FSGS) in a subject, the methods comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the symptom is proteinuria or elevated urinary protein concentration.
  • the symptom is hypoalbuminemia or low serum albumin levels.
  • the symptom is hypoi ⁇ ltration or reduced estimated glomerular filtration rate (eGFR).
  • the symptom is decreased creatinine clearance.
  • the present invention also provides an agent that inhibits CTGF for use in a method for delaying the onset of or reducing a symptom of focal segmental glomerulosclerosis (FSGS).
  • the present invention provides methods for reducing proteinuria in a subject having focal segmental glomerulosclerosis (FSGS), the methods comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the present invention provides methods for reducing albuminuria in a subject having focal segmental glomerulosclerosis (FSGS), wherein the methods comprise administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the present invention provides methods for increasing serum albumin levels in a subject having focal segmental glomerulosclerosis (FSGS), the methods comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • FGS focal segmental glomerulosclerosis
  • the present invention provides methods for reducing urine protein concentration in a subject having focal segmental glomerulosclerosis (FSGS), the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the present invention provides methods for reducing 24 hour urinary protein excretion in a subject having focal segmental glomerulosclerosis (FSGS), the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • Methods for reducing glomerulosclerosis in a subject having focal segmental glomerulosclerosis are provided by the present invention, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the present invention provides methods for reducing tubulointersitial fibrosis in a subject having focal segmental glomerulosclerosis (FSGS), the methods comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the present invention provides methods for reducing creatinine clearance in a subject having focal segmental glomerulosclerosis (FSGS), the methods comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • FGS focal segmental glomerulosclerosis
  • Methods for increasing or normalizing estimated glomerular filtration rate (eGFR) in a subject having focal segmental glomerulosclerosis (FSGS) comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the present invention provides methods for preventing, reducing, eliminating or delaying the onset of end stage renal disease in a subject having focal segmental glomerulosclerosis (FSGS), the methods comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • FGS focal segmental glomerulosclerosis
  • the subject of the methods may be a tissue, a kidney, an organ, an organism, or a mammalian subject.
  • the subject is a human subject.
  • the subject of the present methods is identified as a subject having FSGS.
  • the subject is identified as a subject having FSGS by the presence of scarring (sclerosis) in a portion (segment) of some (focal), but not all, glomeruli, identified from a biopsy of renal tissue.
  • the subject is identified as a subject having primary (i.e. idiopathic) or secondary FSGS.
  • the agent that inhibits CTGF used in the methods of the present invention may, for example, be a polypeptide, polynucleotide, or small molecule.
  • the agent that inhibits CTGF may be an antibody that binds to CTGF, or a fragment thereof; an antisense molecule; an siRNA; or a small molecule chemical compound.
  • the agent that inhibits CTGF is a monoclonal antibody or a fragment thereof, wherein the monoclonal antibody or fragment thereof specifically bind to CTGF.
  • the agent that inhibits CTGF is a monoclonal antibody directed against CTGF, or a fragment thereof.
  • the agent that inhibits CTGF is CLN-I, described in International Publication No.
  • the agent that inhibits CTGF is the antibody produced by the cell line deposited with the American Type Culture Collection (ATCC) on 20th May 2004 with Deposit Number PTA-6006, or a fragment thereof.
  • the agent is useful for manufacturing a medicament for treating FSGS, wherein the agent inhibits CTGF.
  • Figure 1 sets forth data showing methods and agents of the present invention reduced proteinuria in a human subject with focal segmental glomerulosclerosis.
  • Figure 2 sets forth data showing methods and agents of the present invention increased serum albumin levels in a human subject with focal segmental glomerulosclerosis.
  • the present invention is based, in part, on the discovery of unexpected benefits of inhibition of CTGF in treatment of FSGS.
  • the present invention sets forth evidence that inhibition of CTGF provides a therapeutic approach to treat or ameliorate specific physiological and pathological aspects of FSGS.
  • the present invention provides data demonstrating that inhibition of CTGF reduced various symptoms of FSGS, such as, for example, reduced proteinuria and increased serum albumin, in a subject with FSGS.
  • the present invention provides methods and agents for delaying the onset of or preventing, reducing, or eliminating one or more symptoms of FSGS, including, for example, proteinuria, hypoalbuminemia, and hematuria, in a subject having FSGS.
  • the subject is an animal, more preferably a mammal, and most preferably a human.
  • the present invention also provides agents for use in the methods described herein.
  • agents inhibit CTGF and may include small molecule compounds; peptides and proteins including antibodies or functionally active fragments thereof; and polynucleotides including small interfering ribonucleic acids (siRNAs), micro-RNAs (miRNAs), ribozymes, and anti-sense sequences.
  • siRNAs small interfering ribonucleic acids
  • miRNAs micro-RNAs
  • ribozymes ribozymes
  • anti-sense sequences See, e.g., Zeng (2003) Proc Natl Acad Sci USA 100:9779-9784; and Kurreck (2003) Eur J Biochem 270:1628-1644.
  • the present invention also provides agents for use in manufacturing a medicament for treating FSGS, wherein the agent inhibits CTGF.
  • the present invention further provides agents for use in methods of treating FSGS, or delaying the onset of or preventing, reducing, or eliminating a symptom of FSGS, wherein the agent inhibits CTGF.
  • the section headings are used herein for organizational purposes only, and are not to be construed as in any way limiting the subject matter described herein.
  • FGS Focal Segmental Glomerulosclerosis
  • FSGS FSGS vascular endothelial sclerosis
  • a portion a portion of some (focal), but not all, glomeruli, identified from a biopsy of renal tissue.
  • Clinical hallmarks of FSGS include proteinuria, nephrotic syndrome, and frequently the progressive loss of renal function, often resulting in ESRD. (Akash (2007) Saudi J Kidney Dis Transpl. 18 226-30.)
  • FSGS Most instances of FSGS are of unknown cause, referred to as idiopathic or "primary FSGS.” Additionally, FSGS which is secondary to another disease state or injury is referred to as “secondary FSGS.” FSGS has been further classified based on its etiology. Table 1 below sets forth an etiological classification system of FSGS as reported by Deegens et al. ((2008) Neth J Med. 66:3-12), the contents of which are incorporated herein by reference in their entirety. The present invention provides methods and agents that are effective for treating primary or secondary FSGS by inhibiting CTGF.
  • Methods of the present invention are effective at treating FSGS of any etiology, wherein the methods comprise the administration of an agent that inhibits CTGF to a subject having FSGS.
  • Treatment of FSGS of any etiology described below in Table 1 is specifically contemplated by the present invention.
  • Morphological variants of FSGS which are determined by microscopic assessment of kidney biopsy from FSGS subjects, provide another classification system.
  • this classification system there are five morphological variants: collapsing, tip, cellular, perihilar, and not otherwise specified (NOS).
  • This classification system can be applied to both primary (i.e., idiopathic) and secondary FSGS and may be useful for identifying potential differences in clinical presentation, outcome, and pathogenesis.
  • the present invention provides methods and agents that are effective for treating any morphological variant of FSGS (e.g., collapsing, tip, cellular, perihilar, or not otherwise specified (NOS)), wherein the methods and agents are effective at inhibiting CTGF.
  • NOS not otherwise specified
  • Collapsing variant FSGS (also known as collapsing glomerulopathy) is characterized by at least one glomerulus with implosive tuft collapse and overlying visceral epithelial cell hypertrophy and hyperplasia.
  • Most examples of collapsing variant FSGS are idiopathic or HIV-associated.
  • Kidney Int D'Agati et al. (1989) Kidney Int.
  • Tip variant FSGS is characterized by the presence of at least one segmental lesion involving the tip domain (i.e. the most peripheral portion of the glomerular tuft next to the origin of the proximal tubule) with either ECM adhesion or confluence of podocytes with parietal or tubular epithelial cells at the tubular lumen or neck.
  • Tip variant FSGS is more common in Caucasian adults, tends to present with abrupt onset of full nephrotic syndrome, and has the most favorable clinical outcome, and is associated with less tubulointerstitial injury, more steroid responsivity, and the best preservation of renal function. (See, e.g., Thomas et al. (2006) Kidney Int. 69:920-926.) Most cases of tip variant FSGS are idiopathic.
  • Perihilar variant FSGS is defined as perihilar hyalinosis and sclerosis involving the majority of glomeruli with segmental lesions. (D'Agati et al. (2004) Am J Kidney Dis. 43:368-382.) Although this pattern may occur in primary FSGS, it is particularly common in the many secondary forms of FSGS mediated by adaptive structural-functional responses, where it is usually accompanied by glomerular hypertrophy (glomerulomegaly) .
  • Cellular variant FSGS is the least common FSGS variant and the least understood.
  • cellular lesions show segmental endocapillary hypercellularity, which often includes foam cells, associated with variable glomerular epithelial cell proliferation.
  • the cellular lesion presumably represents an early stage in the evolution of segmental sclerosis.
  • the majority of cellular variant FSGS cases are idiopathic. (Stokes et al. (2006) Kidney Int. 70:1783-1792.)
  • FSGS not otherwise specified applies to the identification in a renal biopsy of a pathology that does not meet defining criteria for any other FSGS variant.
  • FSGS NOS is the most common histologic subtype of FSGS. (Thomas et al. (2006) Kidney Int. 69:920-926.) Repeat biopsies have shown that other variants may evolve into FSGS (NOS) over time. Etiologies for FSGS NOS are diverse and include primary, genetic, and other secondary forms.
  • the present invention shows that methods and agents of the present invention reduced proteinuria in a human subject with FSGS. (See, e.g., Example 2.) Therefore, the present invention provides methods and agents useful for treating FSGS in a subject.
  • the present invention also demonstrates that inhibition of CTGF (e.g., by administration of an antibody to CTGF) treats symptoms of FSGS, and in particular, reduces proteinuria and increases serum albumin.
  • the present invention provides methods and agents for treating a variant of FSGS in a subject by inhibiting CTGF.
  • the FSGS variant treated by methods and agents of the present invention is collapsing, tip, cellular, perihilar, or not otherwise specified (NOS).
  • Focal segmental glomerulosclerosis is a considerable cause of end stage renal disease (ESRD), accounting for the presence of ESRD in up to 20% of dialysis patients.
  • ESRD end stage renal disease
  • Progression of FSGS to ESRD can occur in 5 to 20 years following FSGS diagnosis or disease onset. Patients with rapidly progressing FSGS may proceed to ESRD in 2 to 3 years. The accelerated disease course of these patients is associated with "massive" proteinuria (>10g/24h). This rapidly progressing population also exhibits the highest rates of recurrent FSGS in post-transplant grafts (>50%).
  • Proteinuria is considered the most important risk factor for predicting kidney failure and ESRD in FSGS patients.
  • FSGS a 50% reduction in proteinuria during the first six months of treatment was found to be associated with a 45% reduction in risk of disease progression to ESRD.
  • the present invention shows that inhibition of CTGF reduced proteinuria in a human subject with FSGS. (See, e.g., Example 2.)
  • methods and agents of the present invention are therefore useful for reducing the onset of ESRD in a subject having FSGS.
  • edema a condition in which body tissues retain excess fluid.
  • edema is due, at least in part, to hypoalbuminemia (i.e. low serum albumin levels).
  • hypoalbuminemia i.e. low serum albumin levels.
  • Decreased serum albumin levels result in a decrease in serum oncotic pressure which in turn is associated with increased edema.
  • the present invention shows that inhibition of CTGF increased serum albumin levels in a human subject with FSGS.
  • the present invention provides methods and agents useful for preventing, reducing, eliminating, or delaying the onset of a symptom of FSGS in a subject by inhibiting CTGF.
  • the present invention relates, in part, to the discovery that inhibition of CTGF in a subject is effective at treating focal segmental glomerulosclerosis (FSGS).
  • FSGS focal segmental glomerulosclerosis
  • the present invention provides methods for preventing, reducing, eliminating, or delaying the onset of one or more symptoms of FSGS in a subject having FSGS, wherein the method comprises administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • Patients with FSGS present with various symptoms including proteinuria, nephrotic syndrome, hypoalbuminemia (i.e. low serum albumin levels), elevated serum creatinine levels, decreased creatinine clearance, edema, hematuria (i.e.
  • hypercoagulability i.e., increased tendency to form blood clots
  • hyperlipidemia i.e., high cholesterol
  • hypofiltration e.g., reduced eGFR
  • FSGS Patients with FSGS exhibit proteinuria.
  • Methods and agents of the present invention reduced proteinuria in a human subject with FSGS. (See, e.g., Example 2.) Additionally, methods and agents of the present invention reduced proteinuria in an animal model of FSGS. (See, e.g., Example 1.) Therefore, the present invention provides methods and agents useful for treating FSGS in a subject.
  • the present invention demonstrates that inhibition of CTGF (e.g., by administration of an antibody to CTGF) treats symptoms of FSGS, and in particular, reduces proteinuria.
  • Methods and agents of the present invention were effective at reducing proteinuria in a human subject with primary or idiopathic FSGS.
  • the present invention provides methods and agents for treating or preventing primary FSGS in a subject by inhibiting CTGF.
  • the present invention provides methods and agents for treating or preventing secondary FSGS in a subject by inhibiting CTGF.
  • the present invention provides methods and agents for delaying disease progression of FSGS in a subject by inhibiting CTGF.
  • the present invention provides methods and agents for eliminating or delaying the onset of ESRD in a subject having FSGS by inhibiting CTGF.
  • hypoalbuminemia i.e. low serum albumin levels.
  • Hypoalbuminemia is characterized as having serum albumin levels below 3.5g/dL.
  • hypoalbuminemia results from extravascular protein loss and increased degradation due to nephrotic syndrome.
  • albumin is filtered by the glomerulus and catabolized by the renal tubules into amino acids that are recycled.
  • Serum albumin level is an important prognostic indicator in patients with FSGS.
  • serum albumin levels correlate with an increased risk of mortality and morbidity.
  • the present invention provides methods and agents useful for increasing serum albumin levels in a subject having FSGS. Further, the present invention provides methods and agents useful for treating hypoalbuminemia in a subject having FSGS by inhibiting CTGF. Hypoalbuminemia is a symptom of FSGS. Thus, the present invention demonstrates that inhibition of CTGF (e.g., by administration of an antibody to CTGF) treats or prevents symptoms of FSGS, and in particular, hypoalbuminemia. Further, the present invention provides methods and agents useful for preventing, reducing, eliminating, or delaying the onset of a symptom of FSGS in a subject by inhibiting CTGF.
  • CTGF e.g., by administration of an antibody to CTGF
  • Glomerular filtration rate is a measurement of the volume of filtrate made by the kidneys per minute. Measurement of glomerular filtration rate in human subjects has been accepted as the best overall index of kidney function in health and disease. (Smith, Diseases of the kidney and urinary tract, In: Structure and Function in Health and Disease, New York; Oxford Univ. Press, 1951:836-887.) Glomerular filtration rate can be determined by various methods, such as by measuring the urinary clearance of a filtration marker, such as inulin, iothalamate, or iohexol. More commonly, glomerular filtration rate is estimated by determining clearance of creatinine, a protein produced by muscle and released into the blood.
  • a filtration marker such as inulin, iothalamate, or iohexol. More commonly, glomerular filtration rate is estimated by determining clearance of creatinine, a protein produced by muscle and released into the blood.
  • Creatinine clearance (often expressed as ml/min) can be determined by comparing the level of creatinine collected in urine over a given period of time, e.g., 12 or 24 hours, with the creatinine level in blood.
  • a typical creatinine clearance rate is about 97 to 137 ml/min in adult males, and about 88 to 128 ml/min in adult females.
  • creatinine clearance is most often estimated from the serum creatinine concentration. Creatinine clearance is related directly to the urine creatinine excretion and inversely to serum creatinine concentration.
  • Various formulas that provide estimates of creatinine clearance, and therefore estimates of glomerular filtration rate, using parameters such as serum creatinine concentration, age, sex, and body size, have been developed and are standard in the art. (See, e.g., Cockcroft and Gault (1976) Nephron 16:31-41; Levey et al (1999) Annals of Internal Medicine 130:462-470; Rule et al (2004) Ann Intern Med 141 :929-937.)
  • Decreased creatinine clearance is a symptom of FSGS.
  • the present invention provides methods and agents for normalizing or increasing creatinine clearance in a subject having FSGS. Decreased creatinine clearance is associated with glomerular hypofiltration, hypoperfusion, and decreased glomerular filtration rate, and is indicative of altered or impaired renal function in FSGS.
  • the present invention provides methods and agents for normalizing or increasing creatinine clearance in a subject having FSGS by inhibiting CTGF.
  • the present invention provides methods and agents for normalizing glomerular creatinine permeability and restoring glomerular selectivity and function in a subject having FSGS by inhibiting CTGF.
  • methods and agents are provided for treating or preventing glomerular hypofiltration, and hypoperfusion in a subject having FSGS by inhibiting CTGF.
  • One of the best predictors of a favorable clinical outcome in a subject with FSGS is attainment of a complete or partial remission of proteinuria. Less than 15% of patients attaining a remission of proteinuria progress to ESRD. (Chun et al. (2004) J Am Soc Nephrol. 15:2169-77; Korbet et al. (1994) Am J Kidney Dis. 23:773-8; Korbet et al. (2003) Brady R, Wilcox C, editors. Therapy in Nephrology and Hypertension: A companion to Brenner and Rector's The Kidney.
  • Methods and agents of the present invention reduced proteinuria and increased serum albumin levels in a human subject with FSGS. (See, e.g., Example 2.) The reduction (i.e. improvement) in proteinuria was sustained for over 11 months. Therefore, the present invention provides methods and agents useful for partial remission in subjects having FSGS by inhibiting CTGF. Methods for complete remission in subjects having FSGS, wherein the method comprises administering to the subject a therapeutically effective amount of an agent that inhibits CTGF, are also specifically provided by the present invention.
  • FSGS Approximately 50% of patients with idiopathic FSGS will progress to ESRD within 10 years of disease diagnosis. Partial remission in FSGS patients has been shown to considerably slow the rate of decline of renal function and reduce the risk of ESRD. (Troyanov et al. (2005) J Am Soc Nephrol. 16:1061-1068.)
  • CTGF e.g., by administration of an antibody to CTGF
  • the present invention provides methods and agents for preventing, reducing, eliminating, or delaying the onset of ESRD in a subject having FSGS.
  • the present invention provides methods for partial remission in a subject having FSGS, wherein the methods comprise administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the present invention provides methods for preventing, reducing, eliminating or delaying the onset of ESRD in a subject having FSGS, wherein the methods comprise administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the methods of the present invention may be combined with the administration of one or more other therapeutic agents.
  • the methods of the present invention may be combined with the administration of one or more therapeutic agents that may be effective in the treatment of FSGS.
  • agents include immunosuppressive agents (e.g., cyclosporine A, mycophenolate mofetil, sirolimus); corticosteroids (e.g., prednisone); alkylating agents (e.g., cyclophosphamide, chlorambucil); antihypertensives, including diuretics such as bumetanide, chlorothiazide, chlorthalidone, furosemide, hydrochlorothiazide, metolazone, and spironolactone; statins (e.g., HMG-CoA reductase inhibitors); beta blockers (e.g., atenolol, bisoprolol, carvedilol, metoprolol, and propranolol);
  • Plasmapheresis is a blood purification procedure that may be used to treat FSGS.
  • the basic procedure of plasmapheresis includes removal of blood, separation of blood cells from plasma, and return of these blood cells to the patient's circulation, diluted with fresh plasma or a plasma substitute.
  • Use of plasmapheresis in combination with methods and agents of the present invention is specifically provided herein.
  • the methods of the present invention further comprise determining the extent or severity of one or more symptoms of FSGS before, during, and/or after administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • an improvement or a reduction in the extent or severity of a symptom of FSGS (e.g., hypoalbuminemia) following administration of the agent that inhibits CTGF can be determined as follows. A first measurement of serum albumin levels in a subject having FSGS is taken prior to or during a course of treatment with an agent of the invention. A subsequent measurement of serum albumin levels is taken during or after the course of treatment. The first and subsequent measurements are compared and a difference showing maintenance of serum albumin levels in the subject, or an increase in such levels in the subject, is indicative of an improvement or reduction in the extent or severity of the symptom of FSGS.
  • FSGS affects individuals of any age, that is, subjects having FSGS may be adults, children, or the elderly.
  • the present invention shows that methods and agents were effective at treating FSGS in an adolescent subject having FSGS. (See, e.g., Example 2.) Therefore, the present invention provides methods and agents that are effective at treating FSGS in an adolescent subject having FSGS by inhibiting CTGF. Methods useful for treating adult subjects, wherein the methods comprise administering to the adult subject a therapeutically effective amount of an agent that inhibits CTGF, are specifically provided by the present invention.
  • a majority of patients with primary FSGS do not respond to steroid therapy i.e. steroid-resistant FSGS.
  • the present invention shows that CTGF inhibition, by administration of an anti-CTGF antibody, reduced proteinuria in a human subject with steroid-resistant FSGS. (See, e.g., Example 2.) Therefore, methods and agents of the present invention are effective at treating steroid-resistant FSGS in a subject by inhibiting CTGF. Steroid-resistant FSGS patients are at greater risk of progressing to end stage renal disease (ESRD).
  • ESRD end stage renal disease
  • methods and agents of the present invention are useful for preventing, reducing, eliminating, and delaying the onset of end stage renal disease in a subject having steroid-resistant FSGS, wherein the methods comprise administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the present invention provides methods and agents useful for treating FSGS in a subject that has undergone renal transplant by inhibiting CTGF.
  • the methods of the present invention are useful for treating FSGS in a subject that has undergone renal transplant, wherein the methods comprise administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.
  • the present invention relates to methods for treating FSGS in a subject.
  • the subject can be, e.g., a kidney or an organism.
  • the invention is applicable to a variety of different organisms, including, for example, vertebrates, large animals, and primates.
  • the subject is a mammalian subject, and in particular embodiments, the subject is a human subject.
  • applications with humans are clearly foreseen, veterinary applications are also envisaged herein.
  • the present methods of treatment involve administration of a therapeutically effective amount of an agent to a subject, wherein the agent inhibits CTGF, and wherein the subject would benefit from treatment of FSGS.
  • the subject has or is at risk of having FSGS.
  • the subject has or is at risk of having one or more symptoms of FSGS.
  • the subject of the present methods is identified as a subject having FSGS. Identification of a subject having FSGS can occur before, during, or after administration of an agent that inhibits CTGF. Diagnosis of FSGS is described herein.
  • the subject is identified as a subject having FSGS by the presence of scarring (sclerosis) in a portion (segment) of some (focal), but not all, glomeruli, identified from a biopsy of renal tissue.
  • the subject is identified as a subject having idiopathic (i.e. primary) or secondary FSGS.
  • the agent that inhibits CTGF may be a polypeptide, polynucleotide, or small molecule; for example, an antibody that binds to CTGF, an antisense molecule, siRNAs, small molecule chemical compounds, etc.
  • inhibiting CTGF can be accomplished by any of the means well-known in the art for modulating the expression and activity of CTGF.
  • Use of an agent that inhibits CTGF, such as, for example, a human monoclonal antibody directed against CTGF is preferred, although any method or agent inhibiting expression of the gene encoding CTGF, inhibiting production of CTGF, or inhibiting activity of CTGF is provided by the present invention.
  • the present invention involves an agent that inhibits CTGF.
  • CTGF sequences from a large number of species are known in the art and an exemplary CTGF is human CTGF, which has SWISSPROT Accession No. P29729.
  • the agent may decrease one or more of the biological activities of CTGF. Activities associated with CTGF include, but are not limited to, stimulation of cell migration, production of extracellular matrix by a cell in vivo or ex vivo, and/or reduction in fibrosis in a subject.
  • the biological activity is selected from the group consisting of cell growth, differentiation of fibroblasts and/or endothelial cells, and induction of expression of proteins involved in extracellular matrix formation and remodeling including, e.g., collagens including, but not limited to, types I, II, III, and FV; and fibronectin.
  • Assays for CTGF activity are known in the art, for example the cell migration assay described in Example 5 International Publication No. WO 2004/108764, incorporated by reference herein in its entirety.
  • antibodies for use in the methods of the present invention are described, e.g., in U.S. Patent No. 5,408,040; International Publication No. WO 99/07407; International Publication No. WO 99/33878; and International Publication No. WO 00/35936.
  • antibodies for use in the methods of the present invention specifically bind to a region in the N-terminal portion of CTGF; the N- terminal portion may be considered to comprise amino acid residues 1 to 198 of human CTGF (SWISSPROT Accession No. P029729).
  • An example of a suitable region in the N-terminal portion of CTGF is from L143 to Vl 54 of human CTGF (SWISSPROT Accession No. P029729).
  • an exemplary antibody for use in the methods of the present invention is described in International Publication No. WO 2004/108764, incorporated by reference herein in its entirety.
  • the exemplary CLN-I antibody is produced by the cell line deposited with the American Type Culture Collection (ATCC) on 20th May 2004 with Deposit Number PTA-6006.
  • ATCC American Type Culture Collection
  • Such antibodies, or fragments thereof, can be administered by various means known to those skilled in the art.
  • antibodies to CTGF can be injected intravenously, intraperitoneally, or subcutaneously.
  • polynucleotides including small interfering ribonucleic acids (siRNAs), micro-RNAs (miRNAs), ribozymes, and anti-sense sequences may be used in the present methods to inhibit expression and/or production of CTGF.
  • siRNAs small interfering ribonucleic acids
  • miRNAs micro-RNAs
  • ribozymes and anti-sense sequences
  • anti-sense constructs that target CTGF expression have been described and utilized to reduce CTGF expression in various cell types. (See, e.g., International Publication No. WO 96/38172; International Publication No. WO 00/27868; International Publication No.
  • Such antisense constructs can be used to reduce expression of CTGF and thereby ameliorate or prevent the pathological processes induced by CTGF.
  • Such constructs can be designed using appropriate vectors and expressional regulators for cell- or tissue- specific expression and constitutive or inducible expression.
  • Such genetic constructs can be formulated and administered according to established procedures within the art.
  • the agent that inhibits CTGF is an antibody to CTGF.
  • the antibody is a monoclonal antibody to CTGF.
  • the antibody is a human or humanized antibody to CTGF.
  • the antibody is CLN-I, as described in International Publication No. WO 2004/108764.
  • the agent is a small molecule.
  • the agent is a nucleic acid.
  • the nucleic acid is selected from the group consisting of a cyclic nucleotide, an oligonucleotide, or a polynuycleotide.
  • the agent is an antisense oligonucleotide or an siRNA.
  • the present invention also provides the use of the present methods in combination with other therapies.
  • the method is used in combination with another therapy, e.g., to further augment therapeutic effect on certain pathological events, etc.
  • the two treatments may be administered at the same time or consecutively, e.g., during a treatment time course or following disease progression and remission.
  • the method is used in combination with another therapeutic method having a similar or different mode of action, e.g., an ACE inhibitor, ARBs, statin, advanced glycation endproduct (AGE) inhibitor, etc.
  • the agents of the present invention can be delivered directly or in pharmaceutical compositions containing excipients, as is well known in the art.
  • Present methods of treatment can comprise administration of an effective amount of an agent of the present invention to a subject having or at risk for having focal segmental glomerulosclerosis (FSGS).
  • FSGS focal segmental glomerulosclerosis
  • the subject is a mammalian subject, and in a most preferred embodiment, the subject is a human subject.
  • an effective amount, e.g., dose, of agent or drug can readily be determined by routine experimentation, as can an effective and convenient route of administration and an appropriate formulation.
  • Various formulations and drug delivery systems are available in the art. (See, e.g., Gennaro, ed. (2000) Remington's Pharmaceutical Sciences, supra; and Hardman, Limbird, and Gilman, eds. (2001) The Pharmacological Basis of Therapeutics, supra.)
  • Suitable routes of administration may, for example, include oral, rectal, topical, nasal, pulmonary, ocular, intestinal, and parenteral administration.
  • Primary routes for parenteral administration include intravenous, intramuscular, and subcutaneous administration.
  • Secondary routes of administration include intraperitoneal, intra-arterial, intra-articular, intracardiac, intracisternal, intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration.
  • the indication to be treated, along with the physical, chemical, and biological properties of the agent, dictate the type of formulation and the route of administration to be used, as well as whether local or systemic delivery would be preferred.
  • Pharmaceutical dosage forms of an agent of the invention may be provided in an instant release, controlled release, sustained release, or target drug-delivery system.
  • Commonly used dosage forms include, for example, solutions and suspensions, (micro-) emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols, and lyophilized formulations.
  • special devices may be required for application or administration of the agent, such as, for example, syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks.
  • Pharmaceutical dosage forms are often composed of the agent, an excipient(s), and a container/closure system.
  • One or multiple excipients also referred to as inactive ingredients, can be added to an agent of the invention to improve or facilitate manufacturing, stability, administration, and safety of the agent, and can provide a means to achieve a desired drug release profile. Therefore, the type of excipient(s) to be added to the agent can depend on various factors, such as, for example, the physical and chemical properties of the agent, the route of administration, and the manufacturing procedure.
  • Pharmaceutically acceptable excipients are available in the art, and include those listed in various pharmacopoeias.
  • compositions of an agent of the present invention may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, levigating, emulsifying, (nano/micro-) encapsulating, entrapping, or lyophilization processes.
  • the agents of the present invention can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.
  • the agent may be formulated in aqueous solution, if necessary using physiologically compatible buffers, including, for example, phosphate, histidine, or citrate for adjustment of the formulation pH, and a tonicity agent, such as, for example, sodium chloride or dextrose.
  • physiologically compatible buffers including, for example, phosphate, histidine, or citrate for adjustment of the formulation pH
  • a tonicity agent such as, for example, sodium chloride or dextrose.
  • semisolid, liquid formulations, or patches may be preferred, possibly containing penetration enhancers.
  • penetration enhancers are generally known in the art.
  • the agents can be formulated in liquid or solid dosage forms and as instant or controlled/sustained release formulations.
  • Suitable dosage forms for oral ingestion by a subject include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions.
  • the agents may also be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • Solid oral dosage forms can be obtained using excipients, which may include, fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, antiadherants, cationic exchange resins, wetting agents, antioxidants, preservatives, coloring, and flavoring agents.
  • excipients can be of synthetic or natural source.
  • excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatine, magnesium carbonate, magnesium/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinyl pyrrolidone, silicates, silicium dioxide, sodium benzoate, sorbitol, starches, stearic acid or a salt thereof, sugars (i.e. dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oils (hydrogenated), and waxes. Ethanol and water may serve as granulation aides.
  • coating of tablets with, for example, a taste-masking film, a stomach acid resistant film, or a release-retarding film is desirable.
  • Natural and synthetic polymers, in combination with colorants, sugars, and organic solvents or water, are often used to coat tablets, resulting in dragees.
  • the agent powder, suspension, or solution thereof can be delivered in a compatible hard or soft shell capsule.
  • the agents of the present invention can be administered topically, such as through a skin patch, a semi-solid or a liquid formulation, for example a gel, a (micro-) emulsion, an ointment, a solution, a (nano/micro)-suspension, or a foam.
  • the penetration of the agent into the skin and underlying tissues can be regulated, for example, using penetration enhancers; the appropriate choice and combination of lipophilic, hydrophilic, and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, emulsif ⁇ ers; by pH adjustment; and use of complexing agents.
  • Other techniques, such as iontophoresis may be used to regulate skin penetration of an agent of the invention. Transdermal or topical administration would be preferred, for example, in situations in which local delivery with minimal systemic exposure is desired.
  • the agents for use according to the present invention are conveniently delivered in the form of a solution, suspension, emulsion, or semisolid aerosol from pressurized packs, or a nebuliser, usually with the use of a propellant, e.g., halogenated carbons dervided from methan and ethan, carbon dioxide, or any other suitable gas.
  • a propellant e.g., halogenated carbons dervided from methan and ethan, carbon dioxide, or any other suitable gas.
  • hydrocarbons like butane, isobutene, and pentane are useful.
  • the appropriate dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin, for use in an inhaler or insufflator may be formulated. These typically contain a powder mix of the agent and a suitable powder base such as lactose or starch.
  • Agents formulated for parenteral administration by injection are usually sterile and, can be presented in unit dosage forms, e.g., in ampoules, syringes, injection pens, or in multi-dose containers, the latter usually containing a preservative.
  • the agents may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents, such as buffers, tonicity agents, viscosity enhancing agents, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives.
  • the vehicle may contain water, a synthetic or vegetable oil, and/or organic co-solvents.
  • the parenteral formulation would be reconstituted or diluted prior to administration.
  • Depot formulations providing controlled or sustained release of an agent of the invention, may include injectable suspensions of nano/micro particles or nano/micro or non-micronized crystals.
  • Polymers such as poly(lactic acid), poly(glycolic acid), or copolymers thereof, can serve as controlled/sustained release matrices, in addition to others well known in the art.
  • Other depot delivery systems may be presented in form of implants and pumps requiring incision.
  • Suitable carriers for intravenous injection for the agents of the invention are well-known in the art and include water-based solutions containing a base, such as, for example, sodium hydroxide, to form an ionized compound, sucrose or sodium chloride as a tonicity agent, for example, the buffer contains phosphate or histidine.
  • a base such as, for example, sodium hydroxide
  • sucrose or sodium chloride as a tonicity agent
  • the buffer contains phosphate or histidine.
  • Co-solvents such as, for example, polyethylene glycols, may be added.
  • These water-based systems are effective at dissolving agents of the invention and produce low toxicity upon systemic administration.
  • the proportions of the components of a solution system may be varied considerably, without destroying solubility and toxicity characteristics.
  • the identity of the components may be varied.
  • low-toxicity surfactants such as polysorbates or poloxamers
  • polyethylene glycol or other co-solvents polyethylene glycol or other co-solvents
  • biocompatible polymers such as polyvinyl pyrrolidone may be added, and other sugars and polyols may substitute for dextrose.
  • a therapeutically effective dose can be estimated initially using a variety of techniques well-known in the art. Initial doses used in animal studies may be based on effective concentrations established in cell culture assays. Dosage ranges appropriate for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays.
  • a therapeutically effective dose or amount of a compound, agent, or drug of the present invention refers to an amount or dose of the compound, agent, or drug that results in amelioration of symptoms or a prolongation of survival in a subject.
  • Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50/ ED50. Agents that exhibit high therapeutic indices are preferred.
  • the effective amount or therapeutically effective amount is the amount of the agent or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician, e.g., improved kidney function, reduced proteinuria, etc.
  • Dosages preferably fall within a range of circulating concentrations that includes the ED50 with little or no toxicity. Dosages may vary within this range depending upon the dosage form employed and/or the route of administration utilized. The exact formulation, route of administration, dosage, and dosage interval should be chosen according to methods known in the art, in view of the specifics of a subject's condition.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety that are sufficient to achieve the desired effects, e.g., improved vascular function, improved cardiac function, etc, i.e., minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each agent but can be estimated from, for example, in vitro data and animal experiments. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • the amount of agent or composition administered may be dependent on a variety of factors, including the sex, age, and weight of the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient.
  • a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass and rubber stoppers such as in vials.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compositions comprising an agent of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Example 1 CTGF Inhibition Ameliorates Symptoms of FSGS in an Animal Model of FSGS
  • PAN puromycin aminonucleoside- induced nephrosis
  • Puromycin aminonucleoside 50 mg/kg (Sigma-Aldrich Co, St. Louis, MO) was injected intravenously into male Sprague-Dawley rats (Charles River Co., Wilmington, MA) weighing 290 to 320 g. Following the development of proteinuria, as determined by increased urinary protein concentration, rats were randomized into three treatment groups on day 21 and treated as follows. Group 1 was treated with anti- CTGF antibody (CLN-I, 3 mg/kg; see International Publication No. WO 2004/108764), Group 2 was treated with anti-CTGF antibody (CLN-I, 10 mg/kg); and Group 3 was treated with an isotype-matched control human IgG (IgG, 10 mg/kg)). Antibodies were administered i.p. at doses of 3 mg/kg or 10 mg/kg (approximate injection volume of 0.5 ml) three times weekly for three weeks.
  • Urine samples were collected at days 14 and 28, and urine protein levels (i.e. urinary protein concentrations) were determined for each sample using a sulfosalicylic method as previously reported (Bradley GM, Benson ES: Examination of the Urine, 15th Ed., Philadelphia, WB Saunders, 1974).
  • Serum and urine samples were collected from the subject at various time points to assess changes in the following parameters: urinary and serum levels of protein, albumin, and creatinine; estimated glomerular filtration rate (eGFR); 24-hour urinary protein, and albumin excretion rate.
  • eGFR estimated glomerular filtration rate
  • agents and methods of the present invention are effective at decreasing proteinuria (i.e. urinary protein-creatinine ratio) in a subject having FSGS.
  • proteinuria is a symptom of FSGS
  • agents and methods of the present invention are effective at reducing a symptom of FSGS.
  • agents and methods of the present invention are effective at increasing serum albumin levels in a subject having FSGS.
  • agents and methods of the present invention are effective at treating FSGS in a subject by inhibiting CTGF.
  • a reduction of proteinuria in FSGS subjects has been shown to reduce ESRD risk. (Deegens et al. (2008) Neth J Med. 66:3-12.) Therefore, these results further suggested that the agents and methods of the present invention would be effective at preventing or delaying the onset of ESRD in a subject with FSGS by inhibiting CTGF.
  • Adolescent subjects (age 12-15) and adult subjects (age 16-64) with steroid-resistant FSGS are enrolled at various medical centers in the United States. Biopsy diagnosis of FSGS is confirmed centrally, and subjects wash out any non-steroid immunosuppressive/ immunomodulatory medications and sulodexide for 28 days prior to initiating study treatment on Day 0. Medications including but not restricted to corticosteroids, anti-hypertensives, and anti-oxidants remain stable throughout the trial.
  • Anti-CTGF antibody is administered intravenously at 5 mg/kg (maximum of 500 mg) every 2 weeks for a total of 4 infusions.
  • Serum and urine samples are collected from the subjects at various time points to assess changes in the following parameters: protein levels; urinary and serum levels of protein, albumin, and creatinine; estimated glomerular filtration rate (eGFR); 24-hour urinary protein; and the albumin excretion rate as well as fasting serum lipids.

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Abstract

La présente invention concerne des méthodes et des agents utiles dans le traitement de la glomérulosclérose segmentaire focale (FSGS).
PCT/US2009/005528 2008-10-07 2009-10-07 Méthodes de traitement de la glomérulosclérose segmentaire focale Ceased WO2010042201A1 (fr)

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US8946172B2 (en) 2008-08-25 2015-02-03 Excaliard Pharmaceuticals, Inc. Method for reducing scarring during wound healing using antisense compounds directed to CTGF
US9173894B2 (en) 2011-02-02 2015-11-03 Excaliard Pharamaceuticals, Inc. Method of treating keloids or hypertrophic scars using antisense compounds targeting connective tissue growth factor (CTGF)
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CN116568332A (zh) * 2020-12-03 2023-08-08 德尔塔4有限公司 氯吡格雷用于治疗局灶性节段性肾小球硬化（fsgs）

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US8252762B2 (en) 2008-08-25 2012-08-28 Excaliard Pharmaceuticals, Inc. Antisense oligonucleotides directed against connective tissue growth factor and uses thereof
US8772260B2 (en) 2008-08-25 2014-07-08 Isis Pharmaceuticals, Inc Methods for inhibiting expression of connective tissue growth factor
US8946172B2 (en) 2008-08-25 2015-02-03 Excaliard Pharmaceuticals, Inc. Method for reducing scarring during wound healing using antisense compounds directed to CTGF
US9096851B2 (en) 2008-08-25 2015-08-04 Excaliard Pharmaceuticals, Inc. Antisense oligonucleotides directed against connective tissue growth factor and uses thereof
US9688987B2 (en) 2008-08-25 2017-06-27 Excaliard Pharmaceuticals, Inc. Antisense oligonucleotides directed against connective tissue growth factor and uses thereof
US9173894B2 (en) 2011-02-02 2015-11-03 Excaliard Pharamaceuticals, Inc. Method of treating keloids or hypertrophic scars using antisense compounds targeting connective tissue growth factor (CTGF)
WO2022117060A1 (fr) * 2020-12-03 2022-06-09 江苏恒瑞医药股份有限公司 Composition pharmaceutique comprenant un anticorps anti-facteur de croissance du tissu conjonctif
CN116568332A (zh) * 2020-12-03 2023-08-08 德尔塔4有限公司 氯吡格雷用于治疗局灶性节段性肾小球硬化（fsgs）

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