WO2010115932A1 - Combinaison pour traitement de perte osseuse - Google Patents

Combinaison pour traitement de perte osseuse Download PDF

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Publication number
WO2010115932A1
WO2010115932A1 PCT/EP2010/054605 EP2010054605W WO2010115932A1 WO 2010115932 A1 WO2010115932 A1 WO 2010115932A1 EP 2010054605 W EP2010054605 W EP 2010054605W WO 2010115932 A1 WO2010115932 A1 WO 2010115932A1
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Prior art keywords
bone
resorption inhibitor
anabolic agent
administered
kit
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PCT/EP2010/054605
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English (en)
Inventor
Uwe Junker
Michaela Kneissel
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Novartis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • 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
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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

  • This invention is in the field of combinations for the treatment of bone loss.
  • Particularly the invention is in the field of osteoporosis treatment.
  • thai the only therapeutic on the market thai is anabolic and actually induces the build up of new bone is human parathyroid hormone (PTH).
  • PTH human parathyroid hormone
  • the only other current treatments available are bone resorption inhibitors thai prevent the resorption of bone.
  • Such treatments include btsphosphonates (such as zoledronic acid) and SERMs.
  • the invention provides a method of reducing bone loss in a subject comprising co-administering a high dose of a bone anabolic agent and a high dose of a bone resorption inhibitor.
  • the dosages referred to herein are considered to be ''high" doses ibr the purposes of the invention.
  • the invention further provides a method of inducing bone growth in a subject suffering from bone loss comprising co-administering a high dose of a bone anabolic agent and a high dose of a bone resorption inhibitor,
  • the invention further provides use of a high dose of a bone anabolic agent co-administered with a high dose of a bone resorption inhibitor for the treatment of bone loss.
  • the invention further provides use of a bone anabolic agent in the manufacture of a medicament for the treatment of bone loss, wherein the medicament is used in conjunction with a bone resorption inhibitor.
  • the invention further provides use of a bone resorption inhibitor in the manufacture of a medicament for the treatment of bone loxss, wherein the medicament is used in conjunction with a bone anabolic agent.
  • the invention further provides use of a bone anabolic agent in the manufacture of a medicament for the treatment of bone loss in a patient, wherein said patient has been pre-treated with a bone resorption inhibitor.
  • the invention further provides use of a bone resorption inhibitor in the manufacture of a medicament for the treatment of bone loss in a patient, wherein said patient has been pre-treated with a bone anabolic agent.
  • Bone anabolic agents are agents which cause the active build up of new bone, rather than inhibiting the resorption of bone.
  • the bone anabolic agent may be an anti-sclerostin antibody.
  • anti-sclerostin antibodies have been disclosed in references 4-1 1. Any of the antibodies disclosed in these references may be used in the invention.
  • an antibody comprising a heavy chain comprising SEQ ID NOs:245, 246 and 247 and a light chain comprising SEQ ID NOs:78, 79 and 80 of reference 11 may be used in the invention.
  • a preferred antibody for use with the invention is an anti-sclerostin antibody as disclosed in reference 12 (the complete contents of which are incorporated herein by reference). Particularly preferred is the antibody MOR05813.
  • MOR05813 (referred to herein as 'BPS804') has a V H domain with amino acid SEQ ID NO: 1 and a V L domain with amino acid SEQ ID NO: 2.
  • Other anti-sclerostin antibodies useful with the present invention may include one or more (1, 2, 3, 4, S or 6) CDRs from MOR05813.
  • the CDRs in the heavy chain are SEQ ID NOs: 3, 4 & 5.
  • the CDRs in the light chain are SEQ ID NOs: 6, 7 & 8.
  • the MOR05813 variable domains may be expressed as SEQ ID NOs: 9 and 10 to give a functional antibody
  • the MOR05813 V H CDRs may be expressed along with V H framework regions (e.g., V H human framework regions) to give a functional antibody
  • the MOR05813 V L CDRs may be expressed along with V L framework regions (e.g., V L human framework regions) to give a functional antibody
  • MOR05813 V H and V L CDRS may be expressed along with V H and V L framework regions (e.g., V H and V L human framework regions) to give a functional antibody (e.g., human or humanized).
  • antibody means a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an epitope, e.g. an epitope found on scierostin, as described above.
  • antibody includes whole antibodies (such as monoclonal, chimeric, humanised and human antibodies), including single- chain whole antibodies, and antigen-binding fragments thereof.
  • antibody includes antigen-binding antibody fragments, including single-chain antibodies, which can comprise the variable regions alone, or in combination, with all or part of the following polypeptide elements: hinge region, CH 1 , CH 2 , and CH 3 domains of an antibody molecule.
  • Antibody 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 cither a V L or V H domain.
  • Examples include: (i) a Fab fragment, a monovalent fragment consisting of the V L , V H , C L and CH 1 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 Vu and CH 1 domains; (iv) a Fv fragment consisting of the V
  • CDR complementarity determining region
  • the term ''antibody'' includes single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, telrabodies, v-NAR and bis-scFv (see, e.g., Hollinger & Hudson, Nature Biotechnology, 23, 9, 1126-1136 (2005)).
  • Antigen binding portions of antibodies can be grafted into scaffolds based on polypeptides such as Fibronectin type Hl (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies).
  • Antigen binding portions can be incorporated into single chain molecules comprising a pair of tandem Fv segments (VH-CHl-VH-CHl ) which, together with complementary light chain polypeptides, form a pair of antigen binding regions (Zapata el at.. Protein Eng. 8(10): 1057- 1062 (1995); and U.S. Pat No. 5,641,870).
  • the VH CDRl , 2 and 3 sequences and VL CDRl, 2 and 3 sequences can be "mixed and matched" (i.e., CDRs from different antibodies can be mixed and matched), although each antibody must contain a VH CDRl, 2 and 3 and a VL CDRl, 2 and 3 to create other antksclerostin antibodies. Sclerostin binding of such "mixed and matched" antibodies can be tested using the binding assays described in WO2009/047356.
  • VH CDR sequences When VH CDR sequences are mixed and matched, the CDRl, CDR2 and/or CDR3 sequence from a particular VH sequence should be replaced with a structurally similar CDR sequence ⁇ s).
  • VL CDR sequences when VL CDR sequences are mixed and matched, the CDRI , CDK2 and/or CDR3 sequence from a particular VL sequence should be replaced with a structurally similar CDR sequence(s).
  • novel 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 for monoclonal antibodies of the present invention.
  • the 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.
  • the dose may be about 5 mg/kg to about 300 mg/kg, or about 10 mg/kg to about 200 mg/kg.
  • mg/kg means nig drug per kg body weight of the patient to be treated.
  • the total dose of anii-sclerostin antibody given to a patient over the course of a year may be about SOOmg to about 50,000mg.
  • the bone anabolic agent may be a RANKL antibody (such as denosumab), parathyroid hormone (PTH), a PTU fragment or a PTH derivative e.g. PTH (1-84) ⁇ such as PreosTM), PTH (1-34) (such as FoiteoTM), PTH (1-36), PTH (1-38), PTH (1-3DNH2 or PTS 893.
  • PTH parathyroid hormone
  • PTH is administered as the bone anabolic agent, the dosage will typically be 20 ⁇ g or 40 ⁇ g daily.
  • the PTH is administered in a single daily dose.
  • the PTH is administered in a twice daily dose.
  • the PTH (e.g., PTH (1-36), PTH (1-38)) is 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 ⁇ chlorosal-cyloyl)-8-aminocapryHe acid (5-CNAC) and pharmaceutically acceptable salts (e.g., the disodium salt of 5-CNAC) and esters thereof.
  • 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 ⁇ chlorosal-cyloyl)-8-aminocapryHe acid (5-CNAC) and pharmaceutically acceptable salts (e.g., the disodium salt of 5-CNAC) and esters thereof.
  • bone resorption inhibitors include, but are not limited to, bisphosphonales (e.g. » Fosamax' M (alendronate), Actonel TM (risedronate sodium), Boniva/Bonviva 1M (ibandronic acid), ZometaTM (zoledronic acid), AclastaTM/ReclastTM (zoledronic acid), olpadronate, neridronate, etidronate, ciodronate, skelid, bonefbs), Selected Estrogen Receptor Modulators (SERMs, such as raloxifene, lasofoxifene, apeledoxifene, arzoxifene, FC 1271 , Tibolone (Livial ⁇ )X estrogen and calcitonin.
  • SERMs Selected Estrogen Receptor Modulators
  • the bone resorption inhibitor is a bisphosphonate.
  • the bone resorption inhibitor is a nitrogen- containing bisphosphonate.
  • the bone resorption inhibitor is calcitonin (e.g., a salmon calcitonin (sCT), such as Miacalcin' M ).
  • sCT salmon calcitonin
  • the sCT is administered orally in combination with a suitable oral carrier, such as those set forth in U.S.
  • 5-CNAC and pharmaceutically acceptable salts (e.g., the disodium salt of 5-CNAC) and esters thereof, ⁇ n certain embodiments, sCT may be administered with PTH and the disodium salt of 5-CNAC.
  • the bone resorption inhibitor is 'zoledronic acid, such as Aclasta 1M /Reclast IM .
  • a bone resorption inhibitor such as a bisphosphonate
  • the dose may be from about 1 mg/yr to about 10 mg/yr, or about 2 mg/yr to about 8 mg/yr, or about 4 mg/yr to about 6 mg/yr.
  • Such dosages particularly apply to more potent bisphosphonates, such as zoledr ⁇ nic acid when administered intravenously.
  • bone resorption inhibitors such as bisphosphonates other than zoledronic ac ⁇ d are less potent (see table 1 of reference 2), but may be used in the co-treatment of the invention, albeit at higher doses (for example, zoledronic acid is 10,00Ox more potent than etidronate).
  • the dose may be about 1 mg/yr to about 50,000mg/yr, or about 10mg/yr to about 10OO ⁇ nig/yr, or about 100mg/yr to about 1000mg/yr,
  • Bone loss can refer to any condition which results in a loss of bone.
  • a loss of bone is understood to mean a decrease in bone mineral density over time and/or a decrease in bone strength over time.
  • Various methods for measuring bone mineral density are known in the art and include Dual energy X-ray absorptiometry (DEXA) » peripheral Dual energy X-ray absorptiometry (P-DEXA), dual photon absorptiometry (DPA), ultrasound and quantitative computed tomography (QCT).
  • DEXA Dual energy X-ray absorptiometry
  • P-DEXA peripheral Dual energy X-ray absorptiometry
  • DPA dual photon absorptiometry
  • QCT quantitative computed tomography
  • Such bone loss may be due to a condition of abnormally increased bone turnover, for example due to osteoporosis (including postmenopausal osteoporosis, male osteoporosis, glucocorticosteroid induced osteoporosis and juvenile osteoporosis); osteopenia; hormone deficiency (vitamin D deficiency, tnalc and female hypogonadism); hormone excess (hyperprolactinaemia, excess glucocorticoid, hyperthyroidism , hyperparathyroidism); nutritional factors (digestive abnormalities, malabsorption syndromes); Paget's disease; other forms of bone loss due to medication; osteoarthritis; Renal bone disease; inflammatory disorders (Crohn's disease, rheumatoid arthritis); immobilisation; space travel; osteoporosis caused through neoplastic bone marrow disorders; osteogenesis imperfecta; hypophosphatasia; osteoporosis following hormone replacement therapy and genetic disorders and inborn errors of metabolism that cause bone
  • Gaucher' s disease, osteogenesis imperfecta, collagen disorders Other diseases and disorders that may be treated by the combination of the invention include * achondroplasia, cleidocranial dysostosis, enchondromatosis, fibrous dysplasia, hypophosphatemic rickets, Marfan 1 s syndrome, multiple hereditary exoioses, neurofibromatosis, osteopetrosis, osteopoikilosis, sclerotic lesions, fractures, periodontal disease, pseudoarthrosis, pyogenic osteomyelitis, periodontal disease, anti-epileptic drug induced bone loss, primary and secondary, renal osteodystrophy, infiltrative disorders of bone, oral bone loss, osteonecrosis of the jaw, juvenile Paget's disease, melorheostosis, metabolic bone diseases, mastocytosis, sickle cell anemia/disease, organ transplant related bone loss, kidney transplant related bone loss, systemic lupus erythematosus, an
  • Combinations of the invention may also be useful for improving outcomes in orthopedic procedures, dental procedures, implant surgery, joint replacement, bone grafting, bone cosmetic surgery and bone repair such as fracture healing, nonunion healing, delayed union healing and facial reconstruction.
  • the combination may be administered before, during and/or after the procedure, replacement, graft, surgery or repair.
  • die bone loss being treated is due to severe osteoporosis.
  • Severe osteoporosis patients have a bone density T-score of ⁇ -3. T-scores are measured by DHXA and compare a patient's bone density to the optimal peak bone density for their gender. It is reported as number of standard deviations below the average. A T-score of greater than minus 1 is considered normal.
  • a T-score of minus 1 to minus 2.5 is considered osteopenia, and a risk for developing osteoporosis.
  • a T-score of less than minus 2.5 is diagnostic of osteoporosis, while a T-score of less than minus 3 is considered to be diagnostic of severe osteoporosis.
  • the type of bone loss being treated is bone loss due to osteoporosis.
  • treatment'' or "treat'' as used herein refer to both prophylactic (e.g., delaying the onset of symptoms) or preventative treatment as well as curative or disease modifying treatment, including treatment of patients at risk of contracting a disease which will result in bone loss or suspected to have contracted a disease which will result in bone loss as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition which results in bone loss.
  • the invention may be used for the prophylactic treatment of osteoporosis.
  • the invention may be used for the treatment of patients at in one embodiment, the patient being treated is one who has been identified as being at risk of suffering from osteoporosis.
  • This embodiment includes both (i) patients at risk of fractures, and (ii) patients not at risk of fractures.
  • a patient may be identified by looking at, for example, nutritional intake, family history, genetic markers, medical examination, serological bone biomarkers, and bone mineral density by DEXA, and overall fracture assessment by FR AXTM,
  • the patient is 40 years of age or older, 50 years of age or older. 60 years of age or older, or 70 years of age or older,
  • the patient is a postmenopausal woman.
  • the patient is one who is non-responsive to treatment with parathyroid hormone, an analogue or fragment thereof.
  • the patient is one for whom treatment with parathyroid hormone, an analogue or fragment thereof is comraindicated.
  • the bone anabolic agent used is an anti-sclerostin antibody, preferably BPS804.
  • high doses of the bone anabolic agent and bone resorption inhibitor are administered to the subject.
  • the administration may be simultaneous or sequential. If the bone anabolic agent and bone resorption inhibitor are administered sequentially, they may be administered in any order.
  • the time between administration of the bone anabolic agent and bone resorption inhibitor is about 24 hours or less, about 12 hours or less, about 6 hours or less, about 3 hours or less, or about one hour or less.
  • the time between administration of the bone anabolic agent and the bone resorption inhibitor may be about 1 month, about 3 months, or about 6 months.
  • the bone resorption inhibitor may be administered about 6 months (e.g., 6 months) after administration of the bone anabolic agent.
  • the co-administration of the bone anabolic agent and anti-resorptive agent may take place about once annually, about once every 6 months or about once every 3 months.
  • the co-administration may be a once-only treatment. If the co-administration of the bone anabolic agent and anti-rcsorptive agent is intended as a preventative measure, i.e. to treat a person at risk of suffering bone loss (for example, someone at risk of developing osteoporosis), then the medicaments may be administered about once a year, about once every two years, about once every five years or once only.
  • Example dosage regimes include : 1) Quarterly administration ⁇ i.e. every 3 months): about 5 to about 50 mg/kg antksderostin antibody wilh about 0.5 Io about 1.5 mg zolcdronic acid, 2) Half- yearly administration (i.e.
  • Such dosage regimes may be administered by IV infusion.
  • Io give several doses of the bone anabolic agent before the first dose of bone resorption inhibitor is administered, and such dosage regimens are encompassed within the scope of the invention.
  • a patient may receive several doses of a bone anabolic agent before receiving a dose of a bone resorption inhibitor.
  • a patient may receive one, two, three or more doses of bone anabolic agent prior to receiving a dose of bone resorption inhibitor.
  • the PTH may be administered daily, while the bone resorption inhibitor is administered about once every 3 months, about once every 6 months, about once every 12 months or once only.
  • the exact dosage frequency of the bone anabolic agent and bone resorption inhibitor may depend on various factors, such as effectiveness, speed of dosing and speed of action, Factors may also include the relative potency of the active ingredient, mode of administration, sex, age, weight and individual condition of the person being treated. Minor adjustments to the dosing frequency may be made by the attending physician to take into account these factors.
  • a co-administration of the invention may further comprise a dose of vitamin D.
  • a dose may be of about 10,000- about 600,000IU, about 50,000- about 300,000111 or about 100,000- about 20O 5 OOOIU with each administration of the bone anabolic agent and bone resorption inhibitor.
  • the vitamin D may be parenterally administered in a single high dose (e.g. intravenously, intramuscularly, or subcutaneously; monthly, every 3 months, every 4 months, every 6 months or every 12 months).
  • the vitamin D may be administered by a regular oral dose. If administered in a daily oral dose, the typical daily dose is 4G0-800IIK
  • the vitamin D may be provided separately to the bone anabolic agent and the bone resorption inhibitor, In another embodiment, the vitamin D may be provided as a single composition with a bisphosphonate, such as described in reference 14. Thus, if provided, the vitamin D may be co-administered with the bone anabolic agent and the bone resorption inhibitor in a simultaneous, sequential or separate manner.
  • vitamin D as used herein defines any active form of vitamin D, such as 25- dihydroxyvitamin D, or a metabolite thereof, or a non-active precursor thereof, for example 25- hydroxyvitamin D3 (25-hydroxycholecalciferot, ealcifediol), vitamin D3 (cholecalciferol), vitamin D2 (ergoealciferol), l ⁇ Hydroxycholecalciferol (alfacalcidol), 1,25- dihydroxycholecakiferol (cachriol), dihydroxytachysterol, doxercalciferol, provitamin D3 (7- dehydrocholestero! and Vitamin D derivatives such as falecaicitriol, maxacalcitol and paricalcitol.
  • Vitamin D derivatives such as falecaicitriol, maxacalcitol and paricalcitol.
  • the vitamin D is provided as a non-activated precursor to 25-hydroxy vitamin D, for example in the form of cholecalciferol or ergoealciferol. In one embodiment the vitamin D is provided as cholecalciferol.
  • the bone anabolic agent and bone resorption inhibitor are preferably administered parenterally (e.g. intravenously, intramuscularly, or subcutaneously). They may be administered by injection or by infusion. If administered by infusion, the infusion may be administered over a period of 15 minutes or more.
  • the bone anabolic agent and bone resorption inhibitor may be provided in separate containers and administered separately (but sliii simultaneously or sequentially). Alternatively, the bone anabolic agent and bone resorption inhibitor may be provided in (he same container. For example, the bone anabolic agent and bone resorption inhibitor may be provided in a two- or three-compartment infusion set (bag) such as described in references 15-18.
  • the bone anabolic agent and bone resorption inhibitor may independently be provided as pre-concentrates, to be diluted prior to administration, or as ready-to-use solutions. Alternatively, the bone anabolic agent and bone resorption inhibitor may be provided as lyophilisates. Furthermore, if the bone resorption inhibitor is a bisphosphonate, it may be provided as a fat emulsion or a dispersion. If dilution is required, then this should be done with a pharmaceutically acceptable diluent.
  • the anabolic agent and bone resorption inhibitor are preferably provided in one or more heat-sterilisable plastics containers.
  • the particular mode of administration and the dosage may be adjusted by the attending physician taking into account the particulars of the patient, especially age, weight, lifestyle, activity level, hormonal status (e.g. postmenopausal) and bone mineral density as appropriate.
  • the bone anabolic agent and bone resorption inhibitor may be administered in any order.
  • the administration may take place in the order: ABC, BCA, CAB, ACB, BCA.
  • BAC wherein A is the bone anabolic agent, B is the bone resorption inhibitor and C is the optional vitamin D.
  • the administration may be preceded, succeeded or interspersed with administration of PBS or another physiological buffer.
  • the bone anabolic agent is administered first, this is followed by administration of vitamin D or PBS, and lastly a bone resorption inhibitor is administered.
  • kits comprising a bone anabolic agent a bone resorption inhibitor and instructions for use.
  • a kit may optionally further comprise vitamin I).
  • kits may further comprise a diluent and instructions for use.
  • the diluent for the bone anabolic agent may be a solution of the bone resorption inhibitor (tor example, a solution of zoledronic acid),
  • kits may optionally further comprise infusion bags or syringes in order to administer the bone anabolic agent, bone resorption inhibitor and optional vitamin D.
  • the bone anabolic agent, bone resorption inhibitor and optional vitamin D may be in separate infusion bags. If in separate infusion bags, a device may be provided to join the output of the infusion bags such that the patient receives the bone anabolic agent, bone resorption inhibitor and optional vitamin D simultaneously (i.e. through the same needle).
  • the invention provides a kit comprising a bone anabolic agent and a bone resorption inhibitor in a pre-filled multi-compartment (e.g. two-compartment) infusion bag (e.g. Figure 4A), along with instructions for use.
  • a pre-filled multi-compartment e.g. two-compartment
  • the multicompartment infusion bag may comprise at least three compartments (e.g. Figure 4B), at least one compartment of which contains vitamin D.
  • Multi-compartment infusion bags are known in the art, as described above.
  • a prc-fiUed bag may contain a bone anabolic agent and an anti-resorptive agent in separate compartments. Once the agent in the first compartment has been administered, the seal between the two compartments may be ruptured (e.g.
  • Such bags may optionally further comprise a third compartment containing vitamin D,
  • the separate agents to be administered to the patient are prevented from being mixed (and thus simultaneously administered), they are conveniently available in a single infusion bag for sequential administration.
  • the multi-compartment infusion bag may contain the active ingredients in lyophilised form and suitable diluents, In such an embodiment, the multicompartment infusion bag would contain at least four compartments separated by ruptureable seals.
  • the seal between the lyophilised first agent to be administered and its diluent would be ruptured to allow mixing. Once mixed, a further seal would be ruptured to allow administration.
  • the seal between the lyophilised second agent to be administered and its diluent would be ruptured to allow mixing. Once mixed, a further seal would be ruptured to allow administration.
  • pre- filled infusion bags contain about 300 to about 18000mg BPS804, about 600 to about 6000mg BPS804 or about 800 to about 3000mg BPS804.
  • pre-filled infusion bags contain about 0.5 to about 4.5mg Aclasta t M , about 1.5 to about 3.5mg AclastaTM, or about 2 to about 2.5mg Aclasta' M (i.e. about 0.5 to about 4.5mg z.oledron.ic acid, about 1.5 to about 3.5mg zoledronic acid, or about 2 to about 2.5mg zoledronic acid).
  • a mulli -compartment infusion bag contains (i) about lOOOmg BPS804 and about 1.5mg AclastaTM, (ii) about 3000mg BPS804 and about 2.5mg Aclasta 1M , or (iii) about 6000mg BPS804 and about 4.5mg AclaslaTM (i.e. (i) about lOOOmg BPS804 and about 1.5mg zoledronic acid, (H) about 3000mg BPS804 and about 2.5mg zoledronic acid, or (iii) about ⁇ OOOmg BPS804 and about 4.5mg zoledronic acid).
  • the BPS804 and zoledronic acid would be found in separate compartments of the multi-compartment infusion bag.
  • the BPS804 and zoledronic acid are provided as aqueous solutions.
  • Figure I shows the change in (A) bone mineral density and (B) bone mineral content over baseline in mouse tibia following a weekly dose of O, 1 , 10 or 100 mg/kg BPS804 or a single 300mg/kg treatment with BPS804.
  • Figure 2 shows the change in (A) bone mineral density and (B) bone mineral content over baseline in mouse tibia following four monthly treatments of 0. 1, 10 or 100mg/kg BPS804 with and without subsequent administration of a single iv dose of 100 ⁇ g/kg zoledronic acid.
  • Figure 3 shows percent change from baseline value in cross-sectional total bone mineral density of the distal femur metaphysis of aged intact or ovariectomized (OVX) O PI /IC mice as evaluated by pQCT. Mean +/- SEM. ANOVA, Dunnett, * p ⁇ .05, ** p ⁇ .01 versus OVX control; x p ⁇ .05, xx p ⁇ .01 single treatment versus combination treatment.
  • Figure 4 illustrates the 2 (A) or 3 (B) compartment infusion bag.
  • the arrow indicates the outlet to the patient, the dashed lines indicate rupt ⁇ reabte seals and the numbers indicate the compartments which may contain a bone anabolic, a bone anti-rcsorptive and/or vitamin D.
  • mice Female aged nude mice (7-month-old) were treated intravenously either weekly (n !!! 16 / group) with increasing doses of the anti-SOST antibody (1, 10, 100 mg/kg) for 4 months or they received a single dose of the anti-SOST antibody (300 mg/kg) (n !!! 8 / group). Changes in bone mineral density and content were monitored at monthly intervals in the proximal tibia mctaphysis by peripheral quantitative computed tomography (pQCT).
  • pQCT peripheral quantitative computed tomography
  • pQCT peripheral quantitative computed tomography
  • Example 3 Example dosage regimes for humans
  • the active agents are administered by iv infusion, sequentially.
  • BPS804 is administered first, followed by Aclasta I M (zoledronic acid).
  • Aclasta 1M (zoledronic acid) is administered within 24 hours of the BPS804 being administered.
  • Quarterly administration 5 to 50 mg/kg BPS804 with 0.5 to 1.5 mg AclastaTM (zoledronic acid)

Abstract

L'invention porte sur un nouveau régime de traitement pour perte osseuse, telle que celle qui se produit chez des patients atteints d'ostéoporose. Dans ledit régime, on administre aux patients une seule dose élevée d'un agent anabolique osseux et une seule dose élevée d'un inhibiteur de résorption osseuse.
PCT/EP2010/054605 2009-04-08 2010-04-07 Combinaison pour traitement de perte osseuse WO2010115932A1 (fr)

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WO2013101451A1 (fr) 2011-12-28 2013-07-04 Amgen Inc. Méthode de traitement d'une perte osseuse alvéolaire au moyen d'anticorps anti-sclérostine
WO2014006100A1 (fr) 2012-07-05 2014-01-09 Ucb Pharma S.A. Traitement de maladies osseuses
US8637643B2 (en) 2005-05-03 2014-01-28 Ucb Pharma, S.A. Sclerostin binding antibody
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CN104095863A (zh) * 2014-08-06 2014-10-15 国药集团国瑞药业有限公司 一种包含唑来膦酸的药物组合物及其制剂
US8986685B2 (en) 1998-11-27 2015-03-24 Ucb Pharma S.A. Compositions and methods for increasing bone mineralization
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JP2015536349A (ja) * 2012-11-21 2015-12-21 アムジエン・インコーポレーテツド ヘテロ二量体免疫グロブリン
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WO2018031454A1 (fr) 2016-08-08 2018-02-15 Amgen Inc. Procédé d'amélioration de la fixation du tissu conjonctif à l'aide d'anticorps anti-sclérostine.
WO2018115879A1 (fr) * 2016-12-21 2018-06-28 Mereo Biopharma 3 Limited Utilisation d'anticorps anti-sclérostine dans le traitement de l'ostéogenèse imparfaite
WO2019191534A1 (fr) 2018-03-30 2019-10-03 Amgen Inc. Variants d'anticorps anti-c-terminal
WO2020033788A1 (fr) 2018-08-10 2020-02-13 Amgen Inc. Procédé de préparation d'une formulation pharmaceutique d'anticorps
WO2020163763A1 (fr) * 2019-02-07 2020-08-13 The Regents Of The University Of California Méthode de traitement de l'ostéonécrose
WO2021030179A1 (fr) 2019-08-12 2021-02-18 Amgen Inc. Formulations d'anticorps anti-sclérostine
US11576970B2 (en) 2016-03-10 2023-02-14 UCB Biopharma SRL Pharmaceutical formulations
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US10273293B2 (en) 2005-05-03 2019-04-30 Amgen Inc. Method for inhibiting bone resorption
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