WO2014118705A1 - Procédé de traitement des troubles minéraux et osseux de la maladie rénale chronique en utilisant des antagonistes de la sclérostine - Google Patents

Procédé de traitement des troubles minéraux et osseux de la maladie rénale chronique en utilisant des antagonistes de la sclérostine Download PDF

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WO2014118705A1
WO2014118705A1 PCT/IB2014/058619 IB2014058619W WO2014118705A1 WO 2014118705 A1 WO2014118705 A1 WO 2014118705A1 IB 2014058619 W IB2014058619 W IB 2014058619W WO 2014118705 A1 WO2014118705 A1 WO 2014118705A1
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antibody
sclerostin
patient
antigen
seq
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PCT/IB2014/058619
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English (en)
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Michaela Kneissel
Uwe Junker
Ronenn Roubenoff
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Novartis Ag
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the disclosure relates to method for treating Chronic kidney disease (CKD) with evidence of Mineral and Bone Disorder (MBD), including patients having an actual diagnosis of CKD-MBD, e.g., a stage 3-5 CKD patient (e.g., CKD-5D patient) having ROD, such as ABD, by antagonizing Sclerostin expression, secretion, signaling and/or function.
  • CKD Chronic kidney disease
  • MBD Mineral and Bone Disorder
  • Chronic kidney disease refers to heterogeneous disorders affecting the structure and function of the kidney.
  • the definition of CKD, and the management thereof, is based on the presence of kidney damage (i.e., albuminuria) or decreased kidney function (i.e., glomerular filtration rate (GFR) ⁇ 60 mL/min per 1 ⁇ 73 m 2 ) for 3 months or more, irrespective of clinical diagnosis.
  • CKD is classified into five stages on the basis of GFR, with stage five being a GFR of less than 15 mL/min per 1.73 m 2 or dialysis (see, e.g., Levey et al. (2003) Ann. Intern. Med. 139: 137-147).
  • Patients with stage 5 CKD (CKD-5) are treated with kidney replacement, i.e., dialysis (CKD-5D) or transplant (CKD-5T).
  • CKD- MBD CKD-Mineral and Bone Disorder
  • CKD-MBD is a systemic disorder manifested by either one or a combination of: 1) abnormalities of calcium, phosphorus, PTH or vitamin D metabolism; 2) abnormalities in bone turnover, mineralization, volume, linear growth or strength; and 3) vascular or other soft tissue calcification (Moe et al. (2006)).
  • Renal osteodystrophy refers the bone histopathology in patients with CKD-MBD, which is routinely classified into four major subtypes: high-turnover ROD (osteitis fibrosa) (which includes mild hyperparathyroid (HPT)- related bones disease), mixed uremic osteodystrophy, osteomalacia and adynamic bone disease (ABD) (Malluche and Faugere (1990) Kidney Int 38: 193-211; Moe et al. (2006)). ROD is found almost universally in patients with CKD-5, and in the majority of patients with CKD stages 3-5. (Moe et al. KDIGO guideline: Diagnosis of CKD-MBD: biochemical abnormalities Kidney International (2009) 76 (Suppl 113), S22-S49).
  • Fracture rates in patients with CKD are high and increase with declining kidney function. Fracture prevalence varies widely in patients with CKD-5D, ranging from 10 to 50%. Hip fracture prevalence ranges from 2 to 8%, and vertebral fractures from 7 to 33%. Not only is the fracture rate higher among patients with CKD-5D, but outcomes are worse compared with the general population. For example, a recent retrospective study reported that dialysis patients have a 1-year mortality rate of 64% following a hip fracture compared with 15-20% in the general population; furthermore, their hip fractures occur at a younger age than in the general population (16 and 13 years younger among men and women, respectively). (Coco et al. (2006) Am J Kidney Dis 36(6): 1115-1121). Around 20% of CKD-5D patients develop ABD, which features low bone turnover and high fracture risk. (Spasovski et al. (2003) Nephrol. Dial. Transplant. 18: 1159-1166).
  • the KDIGO guidelines do not recommend the routine use of bisphosphonate, teriparatide or raloxifine, especially in light of safety concerns that arise due to the inherent multi -faceted nature of MBD.
  • PTH could present one option to treat at least some types of ROD, e.g., ABD (Cejka and Haas (2011) Seminars in Dialysis 24:431-33).
  • teriparatide carries an increased risk of osteosarcoma, it can lead to abnormal blood calcium and phosphorus in CKD patients, and preexisting hyperparathyroidism could be exacerbated by teriparatide (Cejka and Haas (2011); Moe et al. (2009)).
  • ABD is particularly difficult to treat, as most of the current anti-resorptive drugs (such as bisphosphonate and raloxifene) or anabolic drugs (such as teriparatide) are contraindicated, and other drugs (e.g., calcitonin) have no efficacy against hip fracture, which is highly increased in ABD patients.
  • drugs e.g., bisphosphonate and raloxifene
  • anabolic drugs such as teriparatide
  • other drugs e.g., calcitonin
  • Sclerostin is a potent negative regulator of bone formation. Increasing evidence suggests that sclerostin exerts its action in adult bone by antagonizing Wnt signaling by binding to Wnt co-receptors, thus preventing signaling activation by Wnt ligands. In adult bone, sclerostin is expressed in osteocytes, which are derived from osteoblasts residing within the mineralized bone matrix.
  • the SO ST gene is a direct target gene of parathyroid hormone (PTH) and SOST expression is suppressed in adult bone following intermittent administration of a bone anabolic dose of PTH(l-34) (Keller and Kneissel (2005) Bone 37(2): 148-58.), suggesting that part of the bone anabolic effect of PTH might be mediated via SOST repression.
  • PTH parathyroid hormone
  • Cejka et al. show that serum sclerostin is higher in patients with CKD-5D than in healthy control patients, and that high serum sclerostin associates with decreased bone turnover and osteoblast number, indicating low bone growth (Cejka et al.
  • Antibody 1 is a fully human high affinity, neutralizing, anti-sclerostin mAb (IgGilambda) which has displayed potent in vitro activity, and bone anabolic efficacy in a number of rodent models of osteoporosis (See, e.g., WO09047356, which is hereby incorporated by reference herein in its entirety). Disclosed herein are the results from study A2101, in which Antibody 1 was well-tolerated and showed significant increases in bone formation biomarkers and BMD after single ascending doses in healthy postmenopausal osteopenic women.
  • study A2204 is designed to evaluate safety and tolerability and bone anabolic response using 18 F-fluroide PET imaging after a single administration of Antibody 1 in patients with CKD-5D on hemodialysis and with evidence of MBD.
  • methods of treating CKD with evidence of MBD in a patient comprising administering to said patient a therapeutically effective amount of at least one anti-sclerostin antibody or antigen-binding fragment thereof, e.g., Antibody 1, 2, 3, 4 or 5, preferably Antibody 1.
  • anti-sclerostin antibodies or antigen-binding fragments thereof e.g., Antibody 1, 2, 3, 4 or 5, preferably Antibody 1, for use in treating CKD with evidence of MBD in a patient in need thereof.
  • anti-sclerostin antibodies or antigen-binding fragments thereof e.g., Antibody 1, 2, 3, 4 or 5, preferably Antibody 1, for the manufacture of a medicament for treating CKD with evidence of MBD, in a patient in need thereof.
  • a patient in need thereof e.g., an ABD patient that is not resistant to PTH
  • administering a therapeutically effective amount of an anti-sclerostin antibody or antigen-binding fragment thereof, e.g., Antibody 1, 2, 3, 4 or 5, preferably Antibody 1, to said patient.
  • an anti-sclerostin antibody or antigen-binding fragment thereof e.g., Antibody 1, 2, 3, 4 or 5, preferably Antibody 1, to said patient.
  • CKD vascular calcification
  • methods of reducing serum phosphate levels in a patient in need thereof comprising administering a therapeutically effective amount of an anti-sclerostin antibody or antigen-binding fragment thereof, e.g., Antibody 1, 2, 3, 4 or 5, preferably Antibody 1, to said patient.
  • an anti-sclerostin antibody or antigen-binding fragment thereof e.g., Antibody 1, 2, 3, 4 or 5, preferably Antibody 1, to said patient.
  • FGF23 can cause imbalance in calcium and phosphate and homeostasis, leading to increased phosphate secretion from kidney and decreased and calcium absorption by the kidney (see, e.g., Shimada et al. (2004) J Bone Miner Res 19:429-35; Yamashita et al. (2004) Eur J. Endocrinol 151 :55-60; White et al (2000) Nat Genet 26:345- 48).
  • High levels of FGF23 are implicated in left ventricular hypertrophy and are associated with increased mortality in long-term hemodialysis patients. (Jean et al. (2009) Nephrol Dial Transplant 24:2792-96; Faul et al. (2011) J Clin Invest.
  • a patient in need thereof e.g., a CKD patient
  • methods of reducing FGF23 levels in a patient in need thereof comprising administering a therapeutically effective amount of an anti- sclerostin antibody or antigen-binding fragment thereof, e.g., Antibody 1, 2, 3, 4 or 5, preferably Antibody 1, to said patient.
  • an anti- sclerostin antibody or antigen-binding fragment thereof e.g., Antibody 1, 2, 3, 4 or 5, preferably Antibody 1
  • FIGURES Figure 1 in osteopenic female volunteers, Antibody 1 shows a clear increase in lumbar spine bone mineral density (BMD) at 20 mg/kg at day 85 (d85) and the end of study (EOS) versus baseline.
  • BMD lumbar spine bone mineral density
  • EOS end of study
  • FIG. 2 Fg/23 expression is decreased in Sost deficient mice.
  • the disclosure provides methods of treating patients having Chronic kidney disease (CKD) with evidence of Mineral and Bone Disorder (MBD), including patients having a diagnosis of CKD-MBD, e.g., a stage 3-5 CKD patient (e.g., CKD-5D patient) having ROD, such as ABD, by inhibiting sclerostin expression, signalling, secretion and/or function using at least one scerlostin antagonist, preferably at least one anti-sclerostin antibody or antigen- binding fragment thereof.
  • CKD-MBD e.g., a stage 3-5 CKD patient (e.g., CKD-5D patient) having ROD, such as ABD
  • scerlostin antagonist preferably at least one anti-sclerostin antibody or antigen- binding fragment thereof.
  • CKD chronic kidney disease
  • MBD mineral and bone disorder
  • methods of treating chronic kidney disease (CKD) with evidence of mineral and bone disorder (MBD) comprising administering to a patient having CKD with evidence of MBD a therapeutically effective amount of an anti-sclerostin antibody or antigen- binding fragment thereof, e.g, Antibody 1, Antibody 2, Antibody 3, Antibody 4 or Antibody 5.
  • methods of reducing serum phosphate levels in a patient in need thereof comprising administering a therapeutically effective amount of an anti-sclerostin antibody or antigen-binding fragment thereof, e.g, Antibody 1, Antibody 2, Antibody 3, Antibody 4 or Antibody 5, to said patient, e.g, a patient having vascular calcification.
  • a therapeutically effective amount of an anti-sclerostin antibody or antigen-binding fragment thereof e.g, Antibody 1, Antibody 2, Antibody 3, Antibody 4 or Antibody 5
  • a patient having left ventricular hypertrophy e.g, a patient having left ventricular hypertrophy.
  • anti-sclerostin antibodies or antigen-binding fragments thereof e.g., Antibody 1, Antibody 2, Antibody 3, Antibody 4 or Antibody 5, for use in treating CKD with evidence of MBD in a patient in need thereof.
  • anti-sclerostin antibodies or antigen-binding fragments thereof e.g, Antibody 1, Antibody 2, Antibody 3, Antibody 4 or Antibody 5, for use in reducing serum phosphate levels in a patient in need thereof, e.g, a patient having vascular calcification.
  • anti- sclerostin antibodies or antigen-binding fragments thereof e.g, Antibody 1, Antibody 2, Antibody 3, Antibody 4 or Antibody 5, for use in increasing serum PTH levels in a patient in need thereof, e.g, a patient having ABD.
  • anti-sclerostin antibodies or antigen-binding fragments thereof e.g, Antibody 1, Antibody 2, Antibody 3, Antibody 4 or Antibody 5, for use in reducing FGF23 levels in a patient in need thereof, e.g, a patient having left ventricular hypertrophy.
  • anti-sclerostin antibodies or antigen-binding fragments thereof e.g, Antibody 1, Antibody 2, Antibody 3, Antibody 4 or Antibody 5, for the manufacture of a medicament for treating CKD with evidence of MBD in a patient in need thereof.
  • anti-sclerostin antibodies or antigen-binding fragments thereof e.g, Antibody 1, Antibody 2, Antibody 3, Antibody 4 or Antibody 5, for the manufacture of a medicament for reducing serum phosphate levels in a patient in need thereof, e.g, a patient having vascular calcification.
  • CKD Chronic Kidney Disease
  • GFR glomerular filtration rate
  • GFR more than 90 mL/min per 1 ⁇ 73 m 2 (stage 1), 60-89 mL/min per 1 ⁇ 73 m 2 (stage 2), 30-
  • Stage 5 CKD patients that are on dialysis are referred to as having "CKD-5D".
  • the patient has stage 3-5 CKD, most preferably stage 5 CKD.
  • CKD-MBD Chroe et al. (2006), Table 3).
  • CKD chronic kidney disease
  • MBD mineral and bone disorder
  • patient having an actual diagnosis of CKD-MBD e.g., a stage 3-5 CKD patient (e.g., CKD-5D patient) having ROD, such as ABD, or having CKD and being suspected of developing MBD in the future.
  • the patient has chronic kidney disease (CKD) with evidence of mineral and bone disorder (MBD).
  • the patient has CKD-MBD.
  • the patient has has serum calcium, PO 4 , PTH and vitamin D levels within KDIGO guidelines (Moe et al. 2009) for greater than 80% of serum samples over the past three months.
  • ROD Reactive osteodystrophy
  • ROD is routinely classified into four major sub-types: high-turnover ROD (osteitis fibrosa) (which includes mild hyperparathyroid (HPT)-related bones disease), mixed uremic osteodystrophy, osteomalacia and adynamic bone disease (ABD) (Malluche and Faugere (1990); Moe et al.).
  • HPT hyperparathyroid
  • ABS adynamic bone disease
  • the patient has ROD.
  • Adynamic bone disease is a type of ROD characterized by reduced osteblasts and osteoclasts, no accumulation of osteoid and markedly low bone turnover.
  • ABD is characterized by a low-bone turnover without osteoid accumulation, i.e. with a thin osteoid seam.
  • the rate of collagen synthesis by osteoblasts and the subsequent mineralization of bone collagen are subnormal in ABD. The latter distinguishes ABD from osteomalacia, where a mineralization defect exceeds the defects in bone formation, resulting in a relative osteoid excess.
  • ABD can be diagnosed by a skilled clinician using, e.g., bone biopsy and histomorphometric analysis, 18 F-fluoride PET-CT imaging, or serum intact PTH (iPTH) levels per country-specific and/or local kidney disease clinical practice guidelines (e.g., ⁇ 100 pg/ml [11.0 pmol/L] as per KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease (2003) Am J Kidney Disease 42:S 1-S139) (Brandenburg and Floege (2008) NDT Plus 3: 135-47), etc.
  • iPTH serum intact PTH
  • bALP bone-specific alkaline phosphatase
  • measurements of bone-specific alkaline phosphatase can also be used to evaluate bone disease (such as ABD) because markedly high or low values predict underlying bone turnover (Sardiwal et al. (2012) Kidney Int. 82(1): 100-105.
  • ABD may be evidenced by elevated bALP.
  • ABD is currently the most common finding in dialysis patients and estimated to be present in approximately 40-50% (Salusky (2001) J. Am Soc Nephrol 12: 1978-85).
  • the patient has ABD.
  • the ABD is evidenced by bone biopsy and histomorphometric analysis, 18 F- fluoride PET-CT imaging, or serum intact PTH (iPTH) levels of less than the iPTH levels considered indicative of ABD for a particular country-specific and/or local kidney disease clinical practice guideline (e.g., less than 100 pg/ml).
  • iPTH serum intact PTH
  • Dialysis is a process for removing waste and excess water from the blood, and is used primarily to replace lost kidney function in people with CKD and renal failure.
  • dialysis hemodialysis, periotoneal dialysis, and hemofiltration
  • hemodiafiltration which combines aspects of hemodialysis and hemofiltration
  • intestinal dialysis which employs dietary supplement, e.g., soluble fiber, polyethylene glycol, mannitol, etc.
  • Hemodialysis can be further distinguished by membrane pore size ("high flux” vs "low flux”) and how the dialysis fluid is prepared (on-line, i.e., continuous mixing and immediate use, vs batchwise preparation).
  • the patient is on hemodialysis, peritoneal dialysis, hemofiltration, or hemodiafiltration.
  • the patient is on high-flux hemodialysis, on-line hemodialysis or both high -flux and on-line hemodialysis.
  • the patient is on hemodialysis, hemofiltration or hemodiafiltration 3 times per week for at least 3 months.
  • Kt/Vurea is a number used to quantify hemodialysis and peritoneal dialysis treatment adequacy: K - dialyzer clearance of urea; t - dialysis time; V urea - volume of distribution of urea, approximately equal to patient's total body water.
  • Kt/Vurea is a dimensionless number.
  • peritoneal dialysis it is dimensionless only by definition. It was developed as a way for measuring the dose of dialysis when they analyzed the data from the National Cooperative Dialysis Study. (Gotch and Sargent (1985). Kidney Int. 28:526-34).
  • a patient is said to be on stable hemodialysis when they present with a monthly Kt/V urea > 1.20 for three consecutive months prior to first dosing.
  • Parathyroid hormone ( ⁇ ) is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids. It is involved in the regulation of vitamin D synthesis, serum calcium and serum phosphate. ⁇ undergoes proteolysis to yield N- terminal fragments and longer lived C-terminal and midregion fragments. PTH can be measured in blood serum in these several forms: intact PTH; N-terminal PTH; mid-molecule PTH, and C-terminal PTH. As used herein, the phrase "intact PTH” or "iPTH” refers to 1-84 PTH as well as amino terminally truncated PTH fragments (i.e, large carboxy -terminal PTH fragmetns).
  • Intact PTH is measured by numerous well-known assays, including, e.g., Elecsys PTH (Roche Diagnostics, Germany); Micro Vue Intact PTH (Quidel Corp., San Diego, CA); DAI Intact-PTH Elisa (Diagnostic Automation Inc., Calabasas, CA), etc.
  • the patient has serum intact PTH (iPTH) levels of less than 100 pg/ml.
  • bone mineral density refers to the amount of mineral matter per square centimeter of bone (usually given in g cm “2 , z-score, t-score) as the term is used in clinical practice. BMD is most frequently measured at the hip or lumbar spine to assess bone formation using x-ray absorptiometry (including dual photon absorptiometry (DPA), dual-energy x-ray absorptiometry (DXA) and peripheral dual-energy x-ray absorptiometry (pDXA)). Information on x-ray absorptiometry may be found in, e.g., Link (2012) Radiology 263:3-17.
  • DPA dual photon absorptiometry
  • DXA dual-energy x-ray absorptiometry
  • pDXA peripheral dual-energy x-ray absorptiometry
  • Volumetric BMD is another measure of bone density, which, unlike x-ray absorptiometry, accounts for a bone's volume.
  • Volumetric (total) BMD can be obtained using quantitative computed tomography (QCT) (e.g, peripheral QCT). Information on QCT may be found in, e.g., Engelke et al (2008) J of Clinical Densitometry: Assessment of Skeletal Health, 11 : 123-162 and Muller et al. (1989) Phus Med Biol. 34:741-9.
  • QCT quantitative computed tomography
  • Percentage change from baseline at month X in bone mineral density (BMD), e.g., at the lumbar spine, can be determined as:
  • the term "improvement” means a meaningful (e.g., statistically meaningful) enhancement in value or quality.
  • an improvement is at least about 0.5% increase above placebo (e.g., at least about 0.5%, at least about 0.75%, at least about 1.0%, at least about 1.25%, at least about 1.5%, at least about 1.75%, etc.).
  • at least about 0.5% increase above placebo is equivalent to about a 1.5% total increase.
  • the patient displays an improvement in lumbar spine bone mineral density (BMD) of at least about 0.5% increase above placebo, as measured by DXA.
  • BMD lumbar spine bone mineral density
  • the patient displays an improvement in volumetric BMD as measured by quantitative computed tomography (QCT).
  • QCT quantitative computed tomography
  • the patient has two evaluable consecutirve vertebral bodies for DXA, i.e., no fractures and no sclerostis.
  • Bone formation may also be assessed using Positron Emission Tomography with 18 F- fluoride ( 18 NaF-PET) imaging. More specifically, renal failure produces bone disorders characterized by reduced bone formation and/or impaired mineralization, such as ABD. Bone biopsy with double tetracycline labeling is considered a gold standard for the direct histomorphometric assessment of bone metabolic activity, but it is invasive and complex. Bone turnover markers (BTMs) in serum or urine can provide rapid response in changes in metabolic activity across the whole skeleton, but cannot provide insight into changes that occur at specific sites such as hip or spine.
  • BTMs Bone turnover markers
  • 18 NaF-PET is a non-invasive imaging technique that has been developed to measure site-specific bone formation rates, and which can be used to "diagnose" ABD (Frost et al. (201 1) J Bone Miner Res. 26: 1002-11; Messa et al (1993) J Clin Endocrinol Metab. 77:949-55).
  • uses and kits following treatment with the anti-sclerostin antibody or antigen binding fragment thereof, the patient displays an improvement in hip and lumbar spine bone formation as measured by 18 F-fluoride PET-CT imaging.
  • a patient having CKD with evidence of MBD including patients having an actual diagnosis of CKD-MBD, e.g., a stage 3-5 CKD patient (e.g., CKD-5D patient) having ROD, such as ABD, or having CKD and being suspected of developing MBD in the future would be considered in need of treatment with the disclosed sclerostin antagonists (e.g., anti-sclerostin antibodies and antigen-binding fragments thereof).
  • sclerostin antagonists e.g., anti-sclerostin antibodies and antigen-binding fragments thereof.
  • treatment refers to both prophylactic or preventative treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting MBD or suspected to have contracted MBD as well as patients who are ill or have been diagnosed as suffering from MBD, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having CKD with evidence of MBD, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of MBD, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • the treatment may be administered to a subject having CKD with evidence of MBD to regulate bone mineralization, regulate bone volume, regulate bone turnover, improve bone architecture, increase bone mineral density (BMD) (spine and/or hip), reduce fracture, and/or improve volumetric BMD.
  • BMD bone mineral density
  • a "therapeutically effective amount” refers to an amount of a sclerostin antagonist (e.g., sclerostin inhibitory polynucleotide, sclerostin inhibitory polypeptide, antagonistic anti-sclerostin antibody or antigen-binding fragments thereof, and antagonistic small molecules, e.g., Antibody 1 as set forth in as disclosed in WO09047356, the contents of which are incorporated by reference herein in its entirety) that is effective, upon single or multiple dose administration to a subject (such as a human patient) at treating, preventing, preventing the onset of, curing, delaying, reducing the severity of, ameliorating at least one symptom of a disorder (e.g., CKD with evidence of MBD) or recurring disorder, or prolonging the survival of the subject beyond that expected in the absence of such treatment.
  • an individual active ingredient e.g., an anti-sclerostin antibody
  • the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • the term "patient” includes any human or nonhuman animal.
  • the term "patient” includes any human or nonhuman animal.
  • nonhuman animal includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.
  • the patient is a human.
  • anti-sclerostin antibodies or antigen- binding fragments thereof e.g., Antibody 1-5 or antigen-binding fragments thereof, preferably Antibody 1 or antigen-binding fragments thereof
  • antigen-binding fragments thereof for the treatment of CKD with evidence of MBD, including patients having an actual diagnosis of CKD-MBD, e.g., a stage 3-5 CKD patient (e.g., CKD-5D patient) having ROD, such as ABD.
  • An antibody is a polypeptide comprising a framework region from an immunoglobulin gene or portion thereof that specifically binds and recognizes an epitope, e.g., an epitope found on sclerostin.
  • antibody as used herein includes whole antibodies and any antigen-binding fragment or single chains thereof.
  • a whole “antibody” is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain is comprised of a heavy chain variable (VH) region and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CHI, CH2 and CH3.
  • Each light chain is comprised of a light chain variable (VL) region and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • the VL and VH regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VL and VH is composed of three CDRs and four FRs arranged from amino- terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the CDRs of the heavy chain are referred to herein as HCDR1, HCDR2 and HCDR3.
  • the CDRs of the light chain are referred to herein as LCDR1, LCDR2, and LCDR3.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an epitope on an antigen.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells
  • antibody includes single domain antibodies, maxibodies, nanobodies, peptibodies (Amgen), minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger & Hudson, Nature Biotechnology, 23, 9, 1126-1136 (2005)).
  • Antigen-binding fragments of antibodies can be grafted into scaffolds based on polypeptides such as Fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies). Details of various types of antibodies and antigen-binding fragments thereof for use in the disclosed methods may be found in WO09047356.
  • antibody Also included within the definition of “antibody” are single-chain antibodies.
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Natl. Acad. Sci. 85:5879-5883).
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term "antigen-binding region" of an antibody.
  • a single-chain antibody may comprise the antibody variable regions alone, or in combination, with all or part of the following polypeptide elements: hinge region, CHI, CH2, and CH3 domains of an antibody molecule.
  • antigen-binding fragments of antibodies are also included within the definition of “antibody”. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • antigen-binding fragment refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., an antigen of sclerostin).
  • Antigen-binding fragments include, e.g., but are not limited to, Fab, Fab' and F(ab') 2 , Fd, single-chain Fvs (scFv), single-chain antibodies, disulphide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain.
  • Examples include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulphide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al, Nature 341 : 544-546, 1989; Muyldermans et al, TIBS 24: 230-235, 2001), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR).
  • CDR complementarity determining region
  • Antibody any combinations of variable regions and hinge region, CHI, CH2, and CH3 domains.
  • Antigen binding fragments can be incorporated into single chain molecules comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen binding regions (Zapata et al, Protein Eng. 8(10): 1057-1062 (1995); and U.S. Pat. No. 5,641,870).
  • Antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for antigen-binding capability in the same manner as are whole antibodies. It will be understood by one skilled in the art that antibodies may undergo a variety of posttranslational modifications.
  • modifications often depends on the host cell line used to express the protein as well as the culture conditions. Such modifications may include variations in glycosylation, methionine oxidation, diketopiperizine formation, aspartate isomerization and asparagine deamidation.
  • a frequent modification is the loss of a carboxy-terminal basic residue (such as lysine or arginine) due to the action of carboxypeptidases (as described in Harris, RJ. Journal of Chromatography 705: 129-134, 1995).
  • Table 1, infra provides antibodies for use in the disclosed used, methods and kits that may retain or relinquish the carboxy-terminal lysine.
  • Antibody constant regions may be of various isotypes.
  • "Isotype” refers to the antibody class (e.g., IgM, IgE, IgG such as IgGi, IgG4 or IgGi) that is provided by the heavy chain constant region genes.
  • the sclerostin antagonist is an anti-sclerostin antibody of the IgGi, IgG 4 or Igd isotype.
  • the terms “monoclonal antibody” as used herein refer to an antibody molecule derived from a preparation of antibody molecules of single molecular composition. Thus, a monoclonal antibody displays a single binding specificity and affinity for a particular epitope.
  • the sclerostin antagonist is a monoclonal anti-sclerostin antibody.
  • Chimeric or humanized antibodies of the present disclosure can be prepared using art- recognized techniques employing the sequences of the antibodies and antibody fragments described herein (e.g., see Table 1).
  • DNA encoding the heavy and light chain immunoglobulins can be obtained from the murine hybridoma of interest and engineered to contain non-murine (e.g., human) immunoglobulin sequences using standard molecular biology techniques.
  • the murine variable regions can be linked to human constant regions using methods known in the art (see e.g., U.S. Patent No. 4,816,567 to Cabilly et al.).
  • the murine CDR regions can be inserted into a human framework using methods known in the art.
  • the sclerostin antagonist is a chimeric or humanized anti-sclerostin antibody
  • human antibody is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region also is derived from such human sequences, e.g., human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis as described in Knappik, et al. (2000. J Mol Biol 296, 57-86).
  • the human antibodies for use in the disclosed methods may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • human antibody is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences, which are instead referred to as “chimeric” antibodies and/or “humanized” humanized antibodies.
  • the sclerostin antagonist is a human antibody.
  • human monoclonal antibody refers to antibodies displaying a single binding specificity and that have variable regions in which both the framework and CDR regions are derived from human sequences.
  • the human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic nonhuman animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell. Such animals are available from the companies Medarex and Kirn.
  • the human monoclonal antibodies are produced by a transgenic mouse having human immunoglobulin genes.
  • the sclerostin antagonist is a human monoclonal antibody.
  • recombinant human antibody includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the human antibody, e.g., from a transfectoma, antibodies isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of all or a portion of a human immunoglobulin gene, sequences to other DNA sequences.
  • Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. In some embodiments of the disclosed methods, pharmaceutical compositions, kits and uses, the sclerostin antagonist is a recombinant human antibody.
  • an antibody that "specifically binds to a sclerostin polypeptide” is intended to refer to an antibody that binds to sclerostin polypeptide with a K D of about 1 x 10 " 8 M or less, about 1 x 10 "9 M or less, or about 1 x 10 "10 M or less.
  • An antibody that "cross- reacts with an antigen other than sclerostin” (or the like) is intended to refer to an antibody that binds to that antigen with a KD of about 0.5 x 10 "8 M or less, about 5 x 10 "9 M or less, or about 2 x 10 "9 M or less.
  • an antibody that "does not cross-react with a particular antigen” is intended to refer to an antibody that binds to a particular antigen with a K D of about 1.5 x 10 "8 M or greater, or a K D of between about 5 x 10 "8 M and about 10 x 10 "8 M, or about 1 x 10 "7 M or greater.
  • Antibodies that do not cross-react with a particular antigen exhibit a lack of significant binding against that particular antigen in standard binding assays.
  • the anti-sclerostin antibody specifically binds sclerostin.
  • the anti-sclerostin antibody specifically binds sclerostin and does not cross react with an antigen other than sclerostin. In certain embodiments of the disclosed methods, pharmaceutical compositions, kits and uses, the anti- sclerostin antibody specifically binds sclerostin and does not cross react with Dan or Gremlin.
  • the anti- sclerostin antibody competes with Antibody 1, 2, 3, 4 or 5 for binding to sclerostin. Competing antibodies typically recognize the same epitope.
  • the anti-sclerostin antibody binds the same epitope as that which is bound by Antibody 1, 2, 3, 4, or 5.
  • Antibodies 1, 2, 3, 4 and 5 are set forth, e.g., in US 7758858, US7381409, US7578999, WO05003158, WO06119062, WO06119107, WO08115732, and US7744874, the contents of which are incorporated by reference herein in their entirety.
  • a cell-based Wnt signaling assay is intended to refer to a cell-based (e.g., HEK293) super top flash (STF) assay. Such assay is described in more details in WO09047356.
  • the antibodies have an IC 50 less than about ⁇ , preferably less than about 100 nM and more preferably less than about 20 nM as measured in a cell-based Wnt signaling assay in HEK293 cell lines in the presence of sclerostin.
  • anti-sclerostin antibodies for use in the disclosed methods, pharmaceutical compositions, kits and uses have the ability to reverse sclerostin inhibition of in vitro bone mineralization. In a related embodiment, they have the ability to reverse sclerostin inhibition of the Wnt-1 mediated signaling pathway. In another related embodiment, they disrupt sclerostin LRP6 binding and can block the inhibitory effect that sclerostin has at high doses on BMP induced Smadl phosphorylation.
  • Sclerostin inhibits Wnt 1 -mediated activation of STF (Supertopflash, reporter readout for canonical Wnt signaling) in HEK293 cells.
  • the antibodies for use in the disclosed methods, pharmaceutical compositions, kits and uses restore the Wnt signaling reporter readout in a highly reproducible manner.
  • the observed inhibitory effect of the antibodies according to the disclosure on sclerostin action in the Wnt signaling reporter assay in non-osteoblastic cells has been shown to translate into induction of bone formation responses due to sclerostin inhibition in vivo. Indeed, in vivo experiments in aged rodents show that the antibodies according to the disclosure promote strong bone anabolism. The bone mass increase reached the effect level of daily intermittent treatment with extremely high anabolic doses of parathyroid hormone (which was used as a positive control).
  • the antibodies for use in the disclosed methods, pharmaceutical compositions, kits and uses have affinities to sclerostin in the low pM range (preferably about 100 pM or less, preferably about 50 pM or less, preferably about 10 pM or less, more preferably about 1 pM or less) and inhibit sclerostin impact on wnt signalling with an IC 50 around about 10 nM.
  • a "BMP2-induced mineralization assay” is intended to refer to an assay the measures restoration of BMP2 induced mineralisation in the presence of sclerostin in a cell-based assay (e.g., in MC3T3 cells). Such assay is described in more details in WO09047356.
  • the antibodies have an IC50 less than about 1 ⁇ , preferably less than about 500 nM and more preferably less than about 200 nM as measured in BMP2- induced mineralization assay in MC3T3 cells in the presence of sclerostin.
  • a "Smadl phosphorylation assay” is intended to refer to an assay the measures restoration of BMP6 induced Smadl phosphorylation in the presence of sclerostin in a cell based assay (e.g., in MC3T3-E1 cells). Such assay is described in more details in WO09047356.
  • the antibodies have an IC50 less than about 1 ⁇ , preferably less than about 500 nM, preferably less than about 200 nM as measured in BMP6 Smadl phosphorylation assay in MC3T3-E1 cell line in the presence of sclerostin
  • an "LPJWsclerostin ELISA” is intended to refer to an ELISA assay used to measure the interaction of sclerostin with LRP-6. Such assay is described in more details in WO09047356.
  • the antibodies have an IC 50 less than about 1 ⁇ , preferably less than about lOOnM, more preferably less than about 10 nM (e.g., about 6 nM), more preferably less than about 5nM, more preferably less than about 3 nM as measured in LPJWsclerostin ELISA.
  • the antibodies have an IC50 of about 5.8 nM, about 6.0 nM, about 6.5 nM, about 7.0 nM, about 9.6 nM, about 10.6 nM, about 12.1 nM, or about 19.4 nM in a in LPJWsclerostin ELISA.
  • an antibody that "inhibits" one or more sclerostin functional properties e.g., biochemical, immunochemical, cellular, physiological or other biological activities, or the like, as described above, e.g., BMP-2 induced mineralization
  • sclerostin functional properties e.g., biochemical, immunochemical, cellular, physiological or other biological activities, or the like, as described above, e.g., BMP-2 induced mineralization
  • An antibody that inhibits sclerostin activity effects such a statistically significant decrease by at least 10% of the measured parameter, by at least 50%, 80% or 90%, and in certain embodiments an antibody used in the disclosed methods, pharmaceutical compositions, kits and uses may inhibit greater than 95%, 98% or 99% of sclerostin functional activity.
  • K assoc or "K a ", as used herein, is intended to refer to the association rate of a particular antibody-antigen interaction
  • K d i s or "K D ,” as used herein, is intended to refer to the dissociation rate of a particular antibody-antigen interaction
  • KD is intended to refer to the dissociation constant, which is obtained from the ratio of K d to K a (i.e. K d /K a ) and is expressed as a molar concentration (M). KD values for antibodies can be determined using methods well established in the art.
  • a method for determining the K D of an antibody is by using surface plasmon resonance, or using a biosensor system, such as a Biacore ® system, KinExA-based system, Electrochemiluminescene (BioVeris), Solution Equilibrium Titration, Receptor Binding Inhibition Potency Assay, etc.
  • a biosensor system such as a Biacore ® system, KinExA-based system, Electrochemiluminescene (BioVeris), Solution Equilibrium Titration, Receptor Binding Inhibition Potency Assay, etc.
  • affinity refers to the strength of interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable region of the antibody “arm” interacts through weak non-covalent forces with antigen at numerous sites; the more interactions, the stronger the affinity.
  • antibody refers to an informative measure of the overall stability or strength of the antibody-antigen complex. It is controlled by three major factors: antibody affinity; the valence of both the antigen and antibody; and the structural arrangement of the interacting parts. Ultimately these factors define the specificity of the antibody, that is, the likelihood that the particular antibody is binding to a precise antigen epitope.
  • high affinity for an IgG antibody refers to an antibody having a KD of about 10 "8 M or less, about 10 "9 M or less, or about 10 "10 M or less for a target antigen.
  • high affinity binding can vary for other antibody isotypes.
  • “high affinity” binding for an IgM isotype refers to an antibody having a K D of about 10 "7 M or less, or about 10 "8 M or less.
  • the sclerostin antagonist is high affinity anti-sclerostin antibody.
  • antibodies for use in the disclosed methods, pharmaceutical compositions, kits and uses have a K D less than about 10 nM, less than about 1 nM, less than about 100 pM, less than about 50 pM, or less than about 25 pM, e.g., about 15-25 pM, e.g., about 21 pM +/- 4 pM as determined by surface plasmon resonance.
  • antibodies for use in the disclosed methods, pharmaceutical compositions, kits and uses have a KD of about 0.5 to about 10 pM, e.g, about 0.6 pM, about 1 pM, about 3 pM, about 4 pM, or about 6 pM as measured in a KinExA-based determination experiment as set forth in Example
  • antibodies for use in the disclosed methods, pharmaceutical compositions, kits and uses have a K D of about 0.2 to about 2.5 pM, e.g, about 0.3 pM, about 0.6 pM, about 2.2 pM as measured in a KinExA-based determination experiment as set forth in Example 3 of US7744874.
  • sclerostin antagonists e.g., anti-sclerostin antibodies
  • WO09047356 WO2000/32773, WO2006102070, US20080227138, US20100028335, US 20030229041, WO2005003158, WO2009039175 WO2009079471, WO03106657, WO2006119062, WO08115732, WO2005/014650, WO2005/003158, WO2006/119107, WO2008/061013, WO2008/133722, WO2008/115732, US7592429, US7879322, US7744874, the contents of which are incorporated by reference herein in their entirety.
  • any (or several) of the sclerostin antagonists disclosed in these references may be used in the disclosed methods, pharmaceutical compositions, kits and uses.
  • Further anti-sclerostin antibodies that may be used in the disclosed methods and uses include those known as AMG167 and AMG785 (Amgen) (see, e.g., Padhi et al. (2011) J. Bone Miner. Res. 26: 19-26) and those found in Ominsky et al. (2010) J. Bone Min. Res (Epub Dec. 2); Li et al. (2010) J. Bone Miner. Res. 25:2371-80; Li et al. (2009) J. Bone Miner Res. 24:578-88; Ominsky et al. (2010) J.
  • an anti-sclerostin antibody for use in the disclosed methods and uses binds to an epitope of sclerostin described in WO2006/119062, WO2005014650 or WO2005003158 or WO09047356.
  • anti-sclerostin antibodies and antigen-binding fragments thereof for use in the disclosed methods, pharmaceutical compositions, kits and uses are found in WO09047356 (equivalent to US7879322), WO06119107 (equivalent to US7872106 and US 7592429) and WO08115732 (equivalent to US7744874), e.g.:
  • Heavy chain (H) SEQ ID NO:2 (with or without the SEQ ID NO: 114
  • Light chain (L) SEQ ID NO: 3 (with or without 20 SEQ ID NO: 125
  • Table 1 Preferred anti-sclerostin antibodies for use in the disclosed methods, pharmaceutical compositions, kits and uses.
  • the CDR regions in Table 1 are delineated using the Kabat system (Kabat, E. A., et al, 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242).
  • VH CDR1, 2 and 3 sequences and VL CDR1, 2 and 3 sequences can be "mixed and matched" (i.e., CDRs from different antibodies can be mixed and matched), although each antibody contains a HCDRl, HCDR2 and HCDR3, as well as a LCDRl, LCDR2 and LCDR3 to create other anti-sclerostin antibodies. Sclerostin binding of such "mixed and matched" antibodies can be tested using the binding assays described in WO2009/047356.
  • the HCDRl, HCDR2 and/or HCDR3 sequence from a particular VH sequence should be replaced with a structurally similar CDR sequence(s).
  • the LCDRl, LCDR2 and/or LCDR3 sequence from a particular VL sequence should be replaced with a structurally similar CDR sequence(s).
  • VH and VL sequences can be created by substituting one or more VH and/or VL CDR region sequences with structurally similar sequences from the CDR sequences shown herein (e.g., Table 1) for monoclonal antibodies that may be used in the disclosed methods, pharmaceutical compositions, kits and uses.
  • Anti-sclerostin antibodies disclosed in WO09047356 (the complete contents of which are incorporated herein by reference).
  • the anti-sclerostin antibody for use in the disclosed methods and uses is found in WO09047356 and referred to herein as "Antibody 1" (See Table 1).
  • Antibody 1 has a VH domain with amino acid SEQ ID NO: 4 and a VL domain with amino acid SEQ ID NO:5.
  • Other anti- sclerostin antibodies useful with the present disclosure may include one or more (1, 2, 3, 4, 5 or 6) CDRs from Antibody 1.
  • the CDRs in the heavy chain are SEQ ID NOs: 6-8.
  • the CDRs in the light chain are SEQ ID N0s:9-11.
  • the Antibody 1 VH CDRS may be expressed along with VH framework regions (e.g., VH human framework regions), the Antibody 1 VL CDRS may be expressed along with VL framework regions (e.g., VL human framework regions), the Antibody 1 VH and VL CDRS may be expressed along with VH and VL framework regions (e.g., VH and VL human framework regions) (e.g., human or humanized), and the Antibody 1 heavy and light domains may be expressed as SEQ ID NOs:2 and 3.
  • a stage 3-5 CKD patient e.g., CKD-5D patient
  • ROD such as ABD
  • a therapeutically effective amount of an anti-sclerostin antibody or antigen-binding fragment thereof e.g., Antibody 1, 2, 3, 4 or 5, preferably Antibody 1 to said patient.
  • the sclerostin antagonist is an anti- sclerostin antibody or antigen-binding fragment thereof.
  • the anti- sclerostin antibody or antigen-binding fragment thereof binds to human sclerostin with a K D less than 10 nM as determined by surface plasmon resonance or a biosensor system; has an IC 50 less than 1 ⁇ as measured in a cell-based Wnt signaling assay in HEK293 cell lines in the presence of sclerostin; has an IC 50 less than 1 ⁇ as measured in BMP2-induced mineralization assay in MC3T3 cells in the presence of sclerostin; has an IC50 less than 1 ⁇ as measured in LRP6/sclerostin ELISA; and/or has an IC50 less than 1 ⁇ as measured in BMP6 Smadl phosphorylation assay in MC3T3-E1 cell line in the presence of s
  • the anti-sclerostin antibody or antigen-binding fragment thereof is selected from the group consisting of: an anti-sclerostin antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO:4; an anti-sclerostin antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 5; an anti-sclerostin antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 4 and a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO:5; or an anti-sclerostin antibody or antigen-binding fragment thereof comprising the three Complementarity -Determining Regions (CDRs) of the amino acid sequence set forth as SEQ ID NO:4 and the three CDRs of the amino acid sequence set forth as SEQ ID NO: 5.
  • CDRs Complementarity -
  • the three CDRs of the amino acid sequence set forth as SEQ ID NO:4 are set forth in SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8.
  • the three CDRs of the amino acid sequence set forth as SEQ ID NO: 5 are set forth in SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11.
  • the anti-sclerostin antibody or antigen-binding fragment thereof is selected from the group consisting of: an anti-sclerostin antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 14; an anti-sclerostin antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 15; an anti-sclerostin antibody or antigen- binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 14 and a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 15; or an anti-sclerostin antibody or antigen-binding fragment thereof comprising the three CDRs of the amino acid sequence set forth as SEQ ID NO: 14 and the three CDRs of the amino acid sequence set forth as SEQ ID NO: 15.
  • the three CDRs of the amino acid sequence set forth as SEQ ID NO: 14 are set forth in SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18.
  • the three CDRs of the amino acid sequence set forth as SEQ ID NO: 15 are set forth in SEQ ID NO: 19, SEQ ID NO:20, and SEQ ID NO:21.
  • the anti-sclerostin antibody or antigen-binding fragment thereof is selected from the group consisting of: an anti-sclerostin antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO:24; an anti-sclerostin antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 25; an anti-sclerostin antibody or antigen- binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO:24 and a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO:25; or an anti-sclerostin antibody or antigen-binding fragment thereof comprising the three CDRs of the amino acid sequence set forth as SEQ ID NO:24 and the three CDRs of the amino acid sequence set forth as SEQ ID NO:25.
  • the three CDRs of the amino acid sequence set forth as SEQ ID NO:24 are set forth in SEQ ID NO:26, SEQ ID NO:27, and SEQ ID NO:28.
  • the three CDRs of the amino acid sequence set forth as SEQ ID NO: 25 are set forth in SEQ ID NO:29, SEQ ID NO:30, and SEQ ID NO:31.
  • the anti-sclerostin antibody or antigen-binding fragment thereof is selected from the group consisting of: an anti-sclerostin antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO:34; an anti-sclerostin antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 35; an anti-sclerostin antibody or antigen- binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO:34 and a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO:35; or an anti-sclerostin antibody or antigen-binding fragment thereof comprising the three CDRs of the amino acid sequence set forth as SEQ ID NO:34 and the three CDRs of the amino acid sequence set forth as SEQ ID NO:35.
  • the three CDRs of the amino acid sequence set forth as SEQ ID NO:34 are set forth in SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38.
  • the three CDRs of the amino acid sequence set forth as SEQ ID NO:35 are set forth in SEQ ID NO:39, SEQ ID NO:40, and SEQ ID NO:41.
  • the anti-sclerostin antibody or antigen-binding fragment thereof is selected from the group consisting of: an anti-sclerostin antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO:44; an anti-sclerostin antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 45; an anti-sclerostin antibody or antigen- binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO:44 and a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO:45; or an anti-sclerostin antibody or antigen-binding fragment thereof comprising the three CDRs of the amino acid sequence set forth as SEQ ID NO:44 and the three CDRs of the amino acid sequence set forth as SEQ ID NO:45.
  • the three CDRs of the amino acid sequence set forth as SEQ ID NO:44 are set forth in SEQ ID NO:46, SEQ ID NO:47, and SEQ ID NO:48.
  • the three CDRs of the amino acid sequence set forth as SEQ ID NO:45 are set forth in SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51.
  • the anti-sclerostin antibody or antigen-binding fragment thereof is an anti-sclerostin antibody.
  • the anti-sclerostin antibody is a chimeric antibody, a humanized antibody, or a human antibody.
  • the anti-sclerostin antibody is a monoclonal anti-sclerostin antibody or a human recombinant anti-sclerostin antibody.
  • the anti-sclerostin antibody is of the IgGi, IgG 2 or IgG 4 isotype.
  • the anti-sclerostin antibody or antigen-binding fragment thereof is an antigen-binding fragment of an antibody.
  • the antigen-binding fragment comprises an F(ab')2, Fab, Fab', Fv, Fc or Fd fragment.
  • a patient e.g., a mammal (e.g., a human), having CKD with evidence of MBD, including patients having an actual diagnosis of CKD-MBD, e.g., a stage 3-5 CKD patient (e.g., CKD-5D patient) having ROD, such as ABD.
  • a mammal e.g., a human
  • ROD ROD
  • an anti-sclerostin antibody or antigen-binding fragment thereof such as Antibody 1, 2, 3, 4 or 5, may be administered in accordance with the methods and uses of the disclosure either alone or in combination with other agents (e.g., one or more additional agents) and therapies, such as, e.g., in combination with additional sclerostin antagonists.
  • the anti-sclerostin antibody or antigen- binding fragment thereof may be administered either simultaneously with the other agent, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering the anti-sclerostin antibody in combination with other agents.
  • Additional agents for use in combination with the disclosed anti-sclerostin antibody or antigen-binding fragment thereof include, e.g., bone anabolics and bone anti-resorptives, and combinations thereof.
  • a bone anabolic agent may be a RANKL antibody (such as denosumab), parathyroid hormone (PTH), a PTH fragment or a PTH derivative e.g. PTH (1- 84) (such as Preos®), PTH (1-34) (such as Forteo®), PTH (1-36), PTH (1-38), PTH (1- 31)NH 2 or PTS 893.
  • the PTH may be administered orally in combination with a suitable oral carrier, such as those set forth in U.S. 5,773,647 (herein incorporated by reference in its entirety), e.g., N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5- CNAC) and pharmaceutically acceptable salts (e.g., the disodium salt of 5-CNAC) and esters thereof.
  • a bone resorption inhibitor may be a bisphosphonate (e.g., Fosamax® (alendronate), Actonel® (risedronate sodium), Boniva/Bonviva®
  • Selected Estrogen Receptor Modulator such as raloxifene, lasofoxifene, apeledoxifene, arzoxifene, FC1271, Tibolone (Livial ®)
  • estrogen and calcitonin e.g., a salmon calcitonin (sCT), such as Miacalcin®.
  • Other variants of bone resorption inhibitors are disclosed in WO01/97788 and may be used in the invention.
  • Additional agents for use in combination with the disclosed anti-sclerostin antibody or antigen-binding fragment thereof include, e.g., progestin, androgen, lithium chloride, fluoride, and glucocorticosteroids (e.g., prednisone).
  • the bone resorption inhibitor is a bisphosphonate. In a further embodiment, the bone resorption inhibitor is a nitrogen-containing bisphosphonate. It is preferred that the bone resorption inhibitor is zoledronic acid for use in, such as
  • the binding agent When a therapeutically effective amount of an anti-sclerostin antibody or antigen- binding fragment thereof is administered orally, the binding agent will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the
  • compositions of the disclosure may additionally contain a solid carrier such as a gelatin or an adjuvant.
  • a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil (exercising caution in relation to peanut allergies), mineral oil, soybean oil, or sesame oil, or synthetic oils may be added.
  • the liquid form of the pharmaceutical composition may further contain components such as physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol.
  • the sclerostin antagonist When a therapeutically effective amount of an anti-sclerostin antibody or antigen- binding fragment thereof is administered by intravenous, cutaneous or subcutaneous injection, the sclerostin antagonist will be in the form of a pyrogen-free, parenterally acceptable solution.
  • a pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection may contain, in addition to the sclerostin antagonist, an isotonic vehicle such as sodium chloride, Ringer's, dextrose, dextrose and sodium chloride, lactated Ringer's, or other vehicle as known in the art.
  • compositions for use in the disclosed methods may be manufactured in conventional manner.
  • the pharmaceutical composition is preferably provided in lyophilized form.
  • a suitable aqueous carrier for example sterile water for injection or sterile buffered physiological saline.
  • a suitable aqueous carrier for example sterile water for injection or sterile buffered physiological saline.
  • a suitable aqueous carrier for example sterile water for injection or sterile buffered physiological saline.
  • a suitable aqueous carrier for example sterile water for injection or sterile buffered physiological saline.
  • albumin a suitable concentration is from about 0.5 to about 4.5% by weight of the saline solution.
  • Other formulations comprise liquid or lyophilized formulation.
  • the appropriate dosage will, of course, vary depending upon, for example, the particular sclerostin antagonist to be employed, the host, the mode of administration and the nature and severity of the condition being treated, and on the nature of prior treatments that the patient has undergone.
  • the attending health care provider will decide the amount of the sclerostin antagonist with which to treat each individual subject.
  • the attending health care provider may administer low doses of the sclerostin antagonist and observe the subject's response.
  • the initial dose(s) of sclerostin antagonist administered to a subject are high, and then are titrated downward until signs of relapse occur. Larger doses of the sclerostin antagonist may be administered until the optimal therapeutic effect is obtained for the subject, and at that point the dosage is not generally increased further.
  • An anti-sclerostin antibody or antigen-binding fragment is conveniently administered parenterally, intravenously, e.g. into the antecubital or other peripheral vein, intramuscularly, or subcutaneously.
  • the duration of intravenous (i.v.) therapy using a pharmaceutical composition of the present disclosure will vary, depending on the severity of the disease being treated and the condition and personal response of each individual patient.
  • subcutaneous (s.c.) therapy using a pharmaceutical composition of the present disclosure is also contemplated.
  • the health care provider will decide on the appropriate duration of i.v. or s.c. therapy and the timing of administration of the therapy, using the pharmaceutical composition of the present disclosure.
  • Satisfactory results are generally indicated to be obtained at dosages from about 0.05 mg to about 30 mg per kilogram body weight, more usually from about 0.1 mg to about 20 mg per kilogram body weight.
  • the frequency of dosing may be in the range from about once per day up to about once every three months, e.g., in the range from about once every 2 weeks up to about once every 12 weeks, e.g., once every four to eight weeks. The dosing frequency will depend on, inter alia, the phase of the treatment regimen.
  • the anti-sclerostin antibody dose may be from about 1 mg/kg to about 500 mg/kg, or about 10 mg/kg to about 400 mg/kg, or about 100 mg/kg to about 350 mg/kg, or about 200 mg/kg to about 300 mg/kg.
  • Antibody is usually administered on multiple occasions. Intervals between single dosages can be, for example, weekly, monthly, every three months or yearly. Intervals can also be irregular as indicated by measuring blood levels of antibody to the target antigen in the patient. In some methods, dosage is adjusted to achieve a plasma antibody concentration of about 1 to about 1000 ⁇ g/ml and in some methods about 25 to about 300 ⁇ g/ml.
  • antibody can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the antibody in the patient. In general, human antibodies show the longest half-life, followed by humanized antibodies, chimeric antibodies, and nonhuman antibodies. Pegylation technology may be used to increase the antibody half-life.
  • the dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated or until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regime.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present disclosure employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • the dose may be about 5 mg/kg to about 300 mg/kg, or about 10 mg/kg to about 200 mg/kg, or about 20 mg/kg to about 100 mg/kg, about 10 mg/kg to about 40 mg/kg, or about 30 mg/kg to about 50 mg/kg.
  • the anti-sclerostin antibody e.g., Antibody 1
  • the anti-sclerostin antibody may be administered as about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 75 mg/kg, about 100 mg/kg, about 125 mg/kg, or about 150 mg/kg.
  • the anti-sclerostin antibody e.g., Antibody 1, 2, 3, 4 or 5, is administered subcutaneously as about 0.1, about 0.3, about 1, about 3, about 5, about 10, or about 20 mg/kg or intravenously as about 1, about 5, about 10 or about 20 mg/kg.
  • the anti-sclerostin antibody e.g., Antibody 1, 2, 3, 4 or 5 is administered daily, twice in a week, weekly, every other week, monthly (every 4 weeks), every other month (every 8 weeks), quarterly, every six months, or yearly.
  • the anti-sclerostin antibody e.g., Antibody 1, 2, 3, 4 or 5 is administered singly (i.e., only once) or multiply.
  • mg/kg means mg drug per kg body weight of the patient to be treated.
  • the total dose of anti-sclerostin antibody given to a patient over the course of a year may be about 500 mg to about 50,000 mg, or about 1000 mg to about 10,000 mg.
  • compositions, kits and uses two or more anti- sclerostin antibodies, e.g., with the same or with different binding specificities (e.g., binding the same epitope but having a different binding affinity or binding a different epitope) are administered simultaneously or sequentially (with or without additional agents), in which case the dosage of each antibody administered falls within the ranges indicated.
  • two or more anti- sclerostin antibodies e.g., with the same or with different binding specificities (e.g., binding the same epitope but having a different binding affinity or binding a different epitope) are administered simultaneously or sequentially (with or without additional agents), in which case the dosage of each antibody administered falls within the ranges indicated.
  • the sclerostin antagonist is administered with at least one additional agent selected from the group consisting of a bisphosphonate (zoledronic acid, alendronate, risedronate), denusomab/Prolia, estrogen, tibolone, progestin, androgen, a PTH or ⁇ analog, lithium chloride, fluoride,
  • glucocorticosteroids e.g., prednisone
  • SERMs raloxifene, tamoxifen
  • strontium ranelate and cathepsin K inhibitors e.g., strontium ranelate and cathepsin K inhibitors.
  • kits useful for treating a patient having CKD with evidence of MBD, including patients having an actual diagnosis of CKD-MBD, e.g., a stage 3-5 CKD patient (e.g., CKD-5D patient) having ROD, such as ABD.
  • kits may comprise at least one anti-sclerostin antibody or antigen-binding fragment thereof, e.g., Antibody 1, 2, 3, 4 or 5, preferably Antibody 1, or a pharmaceutical composition comprising at least one one anti-sclerostin antibody or antigen-binding fragment thereof, e.g., Antibody 1.
  • kits may comprise means for administering the sclerostin antagonist (e.g., a syringe, an autoinjector or a prefilled pen) and instructions for use.
  • sclerostin antagonist e.g., a syringe, an autoinjector or a prefilled pen
  • kits may contain additional therapeutic agents for treating CKD with evidence of MBD, for delivery in combination with the enclosed sclerostin antagonist(s), e.g., an anti-sclerostin antibody or fragment thereof, e.g., Antibody 1, 2, 3, 4 or 5, preferably Antibody 1.
  • kits for use in treating a patient having CKD with evidence of MBD including patients having an actual diagnosis of CKD-MBD, e.g., a stage 3-5 CKD patient (e.g., CKD-5D patient) having ROD, such as ABD, comprising: a) a therapeutically effective amount of an anti-sclerostin antibody or antigen-binding fragment thereof selected from the group consisting of Antibody 1, Antibody 2, Antibody 3, Antibody 4 and Antibody 5; b) optionally, means for administering said anti-sclerostin antibody or antigen binding fragment thereof to the patient; c) optionally, at least one additional agent selected from the group consisting of a bisphosphonate (zoledronic acid, alendronate, risedronate), denusomab/Prolia, estrogen, tibolone, progestin, androgen, a PTH or PTH analog, lithium chloride, fluoride, glucocorticosteroids (e.
  • the anti-sclerostin antibody or antigen-binding fragment thereof binds to human sclerostin with a K D less than 10 nM as determined by surface plasmon resonance or a biosensor system; has an IC 50 less than
  • 1 uM as measured in a cell-based Wnt signaling assay in HEK293 cell lines in the presence of sclerostin has an IC 50 less than 1 uM as measured in BMP2-induced mineralization assay in MC3T3 cells in the presence of sclerostin; has an IC50 less than 1 uM as measured in
  • LRP6/sclerostin ELISA has an IC50 less than 1 uM as measured in BMP6 Smadl phosphorylation assay in MC3T3-E1 cell line in the presence of sclerostin.
  • the anti-sclerostin antibody or antigen binding fragment thereof is selected from the group consisting of: an anti- sclerostin antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO:4; an anti-sclerostin antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO:5; an anti-sclerostin antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 4 and a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO:5; and an anti-sclerostin antibody or antigen- binding fragment thereof comprising the three Complementarity-Determining Regions (CDRs) of the amino acid sequence set forth as SEQ ID NO:4 and the three CDRs of the amino acid sequence set forth as SEQ ID NO:5.
  • CDRs Complementarity-Determining Region
  • the anti-sclerostin antibody or antigen binding fragment thereof comprises the three CDRs set forth in SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8. In some embodiments of the disclosed methods, uses or kits, the anti-sclerostin antibody or antigen binding fragment thereof comprises the three CDRs set forth in SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11. In some embodiments of the disclosed methods, uses or kits, the anti-sclerostin antibody or antigen binding fragment thereof an anti-sclerostin antibody.
  • the anti-sclerostin antibody is a chimeric antibody, a humanized antibody, or a human antibody.
  • the anti-sclerostin antibody is a monoclonal anti-sclerostin antibody or a human recombinant anti-sclerostin antibody, e.g, of the IgGi, Igd or IgG4 isotype.
  • the anti-sclerostin antibody or antigen binding fragment thereof is an antigen-binding fragment of an antibody, e.g., a F(ab')2, Fab, Fab', Fv, Fc or Fd fragment.
  • Antibody 1 was administered i.v. to healthy postmenopausal women with low bone mineral density (T-score of >-2.5 and ⁇ -1.0 at either lumbar spine or total hip determined by DXA) to study safety, tolerability, and pharmacokinetic/ pharmacodynamic (PK PD) data after single escalating doses of Antibody 1 ranging from 0.1 mg/kg, 0.5 mg/kg, 2.5 mg/kg, 10 mg/kg to 20 mg/kg. Study A2101) was completed as planned and met its primary objective. Antibody 1 at all dose levels (0.1 to 20mg/kg) was safe and well tolerated.
  • Antibody 1 led to dose related increases in bone formation markers (PINP, OC, BSAP) and a decrease in the resorption marker CTX-1 (Table 2).
  • Table 2 Table X Mean percent change from baseline in bone formation biomarkers PINP, OC, BSAP, and bone resorption biomarker CTX-1
  • BMD at the lumbar spine was greater than 2.5%, while a decrease was observed in the placebo group ( Figure 1).
  • the mean percent change in lumbar spine BMD with 20 mg/kg BPS804 was 2.8% and 3.7% at Day 85 and at end-of-study, respectively.
  • the purpose of the study is to evaluate the safety, tolerability, pharmacokinetics (PK) and bone response following a single i.v. dose of Antibody 1 in patients with CKD-5Don hemodialysis and evidence of MBD.
  • the study will also the question of whether the PK profile of Antibody 1 is altered in CKD-5D patients due to frequent hemodialysis or, for example, adherence of Antibody 1 or Antibody 1-sclerostin immune-complexes to the dialysis cartridge membrane.
  • PK analysis will be conducted following the first 48 hours blood sampling [including blood samples from pre-dose; 2 hr, 24 hr, 48 hr (pre-dialysis) and 48 hr (post-dialysis) and dialysate samples from 48 hr post-dialysis] to evaluate whether the concentration of BPS804 in the blood is affected by dialysis. If there are no significant safety concerns or PK effects following the 2-week safety review period, the remaining 8 subjects will be dosed with BPS804 20 mg/kg or placebo in a double-blind fashion following a 6:2 ratio (BPS804 : placebo).
  • the study aims to collect safety, tolerability, and pharmacokinetic/pharmacodynamic (PK/PD) data after a single dose of Antibody 1 administered i.v. to male and female patients with stage 5D CKD-MBD.
  • the study will be randomized, placebo-controlled and double- blind to ensure the robust comparison of adding Antibody 1 to current care of these patients with regard to efficacy and safety assessments.
  • serological bone biomarker and bone imaging assessments by 18 NaF-PET have been incorporated into this study to detect any changes in bone metabolism pre- and post-treatment.
  • the biologic activity of Antibody 1 as a bone anabolic agent will be assessed using dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT) scans pre- and post-treatment.
  • DXA dual-energy x-ray absorptiometry
  • QCT quantitative computed tomography
  • the study population will be comprised of male and female CKD-5D patients on stable hemodialysis, with evidence of mineral and bone disorder, and adynamic bone disease as evidence by low iPTH levels as per KDIGO guideline (intact PTH ⁇ 100 pg/mL) (Moe et al. 2009).
  • the study population represent a population that is at risk of developing low bone mineral density and bone fractures due to alterations in their mineral metabolism caused by the underlying CKD.
  • Ten patients will be randomized.
  • Antibody 1 caused an increase in BMD in preclinical studies and in the clinical study A2101 as measured by DXA at the lumbar spine. Therefore an increase in BMD in stage 5D CKD patients may be more easily detectable due to their underlying osteopenic / osteoporotic state and administration of Antibody 1 might offer some benefit in terms of increasing BMD.
  • Subject must be on maintenance renal replacement therapy (i.e., hemodialysis, hemofiltration or hemodiafiltration) 3 times per week, for > 3 months before screening with a stable dialysis prescription, as defined by no change in material (i.e., dialyzer, filter/ membrane) type and dialysis duration for > 4 weeks before screening and planned to be maintained the same throughout the study duration.
  • maintenance renal replacement therapy i.e., hemodialysis, hemofiltration or hemodiafiltration
  • the prescribed dose must be constant for at least 30 days prior to screening and should remain constant during the study duration.
  • the prescribed dose must be constant for at least 30 days prior to screening and should remain constant during the study duration.
  • Deviation from any entry criterion excludes a subject from enrollment into the study.
  • the 5:2 randomization allows comparison between the Antibody 1 regimen and the placebo group and is considered sufficient for comparison of safety and pharmacodynamic (PD) of the treatment regimen versus placebo.
  • the maximum intended dose in the current study is 20 mg/kg single iv administration, the same as the maximum tested dose in the clinical study A2101, which was well tolerated and no overt safety or organ-specific concerns were noted.
  • Dose levels of 10 and 20 mg/kg provided the maximum expected effect on circulating sclerostin levels in healthy postmenopausal women, with the 20 mg/kg dose providing statistical significant effects on bone formation biomarkers.
  • the 20 mg/kg dose exhibited significant changes from baseline BMD in the A2101 single dose clinical study.
  • the follow-up period is consistent with and based on information gained from the clinical study A2101 and is expected to cover the extent of any PK PD (i.e., target capture) response as well as allowing assessment of any potential impact from hemodialysis.
  • PK PD i.e., target capture
  • Placebo is used as comparator. Placebo patients will be compared informally to patients on active with respect to the safety profile.
  • Sost knockout mice with a targeted disruption of the Sost coding region were licensed from Deltagen, Inc., USA. Briefly, targeted ES cells derived from the 129/OlaHsd mouse substrain were used to generate chimeric mice, which were bred with C57BL/6 mice. Heterozygous Sost KO offspring was backcrossed for four generations to C57BL/6 mice and then interbred to generate homozygous Sost deficient mice, which were maintained on a mixed genetic background. All mice were kept in cages under standard laboratory conditions with constant temperature of 25°C and a 12-12-hour light-dark cycle.
  • mice were fed on a standard rodent diet (3302, Provimi Kliba SA, Switzerland) with water ad libitum. At 6 months of age, female Sost KO and their corresponding sex-matched wild-type littermate mice were sacrificed and blood and bone samples were collected. Protocols, handling, and care of the mice conformed to the Swiss federal law for animal protection under the control of the Basel-Stadt Cantonal Veterinary Office, Switzerland.
  • Fg/23 gene expression was analyzed with an ABI Prism 7900HT sequence detection system (Applied Biosystems) using TaqMan® Universal PCR Master Mix, mouse 18S TaqMan® assay reagent for normalization and mouse Fg/23 TaqMan® probe (Mm00445621_ml) according to the manufacturer's instructions (Applied Biosystems).
  • Serum was separated from whole blood using clot activator centrifugation tubes (Sarstedt). Serum Fgf23 levels were determined by ELISA detecting intact Fgf23 (Kainos) according to the manufacturer's recommendation using 50 ⁇ of serum samples.

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Abstract

La présente invention concerne un procédé de traitement des troubles minéraux et osseux (TMO) de la maladie rénale chronique (MRC), y compris de patients ayant un diagnostic de TMO-MCR, par exemple, des patients MRC stade 3-5 (par exemple, des patients MRC-5D) ayant une ostéodystrophie rénale (ODR), de préférence une maladie osseuse adynamique (ABD), par antagonisation de l'expression, de la sécrétion, de la signalisation et/ou de la fonction de la sclérostine, par exemple, en utilisant un anticorps anti-sclérostine ou un fragment de liaison de l'antigène de celui-ci (par exemple, l'anticorps 1).
PCT/IB2014/058619 2013-01-31 2014-01-28 Procédé de traitement des troubles minéraux et osseux de la maladie rénale chronique en utilisant des antagonistes de la sclérostine WO2014118705A1 (fr)

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WO2019227087A3 (fr) * 2018-05-25 2020-01-02 The Trustees Of Columbia University In The City Of New York Biomarqueurs du type d'ostéodystrophie rénale
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