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WO2003013568A1 - Therapie par modulation de cytokines - Google Patents

Therapie par modulation de cytokines

Info

Publication number
WO2003013568A1
WO2003013568A1 PCT/US2001/024391 US0124391W WO03013568A1 WO 2003013568 A1 WO2003013568 A1 WO 2003013568A1 US 0124391 W US0124391 W US 0124391W WO 03013568 A1 WO03013568 A1 WO 03013568A1
Authority
WO
WIPO (PCT)
Prior art keywords
cytokine
tnfα
epo
agent
patient
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2001/024391
Other languages
English (en)
Inventor
Loretta Itri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceuticals Inc
Original Assignee
Ortho McNeil Pharmaceutical Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ortho McNeil Pharmaceutical Inc filed Critical Ortho McNeil Pharmaceutical Inc
Priority to PCT/US2001/024391 priority Critical patent/WO2003013568A1/fr
Publication of WO2003013568A1 publication Critical patent/WO2003013568A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]

Definitions

  • Erythropoietin is a glycoprotein hormone produced by the kidney in response to tissue hypoxia that stimulates red blood cell production in the bone marrow.
  • the gene for erythropoietin has been cloned and expressed in Chinese hamster ovary (CHO) cells as described in United States Patent No. 4,703,008.
  • Recombinant human erythropoietin r-HuEPO, Epoetin alfa
  • r-HuEPO Epoetin alfa
  • Recombinant human erythropoietin acts by increasing the number of cells capable of differentiating into mature erythrocytes, triggering their differentiation and augmenting hemoglobin synthesis in developing erythroblasts (Krantz, S.B., Blood (1991) 77: 419- 434; Beckman, B.S. and Mason-Garcia, JVL, 77ze Faseb Journal (1991) 5: 2958-2964).
  • Epoetin alfa has been evaluated in normal subjects as well as in subjects with various anemic conditions. Epoetin alfa induces a brisk haematological response in normal human volunteers, provided that adequate supplies of iron are
  • Epoetin alfa is approved for sale in many countries for the treatment of anemia in chronic renal failure (dialysis and predialysis), anemia in zidovudine treated HIV positive patients (US), anemia in cancer patients receiving platinum-based chemotherapy, as a facilitator of autologous blood pre-donation, and as a perisurgical adjuvant to reduce the likelihood of requiring allogeneic blood transfusions in patients undergoing orthopedic surgery.
  • Epoetin alfa can correct anemia in cancer patients, at doses several times higher than those shown to be effective in renal patients.
  • Anemia may result from the disease itself, the effect of concomitantly administered chemotherapeutic agents, or a combination of both.
  • the condition often takes on the characteristics of the anemia of chronic disease (ACD).
  • ACD is associated with erythroid hypoplasia of the bone marrow, a somewhat shortened circulating life of red cells and decreased bone marrow re-utilization of iron. If erythropoietin levels are measured, they are found to be within the normal range, but inappropriately low for the degree of anemia.
  • the patient has a blunted erythropoietin response.
  • About 50-60% of anaemic cancer patients receiving chemotherapy responded with a hemoglobin rise of at least 2 g/dL to Epoetin alfa therapy given three times weekly at a dose of 150 IU/kg over a period of 12 weeks (Abels, R.I., Larholt, K.M., Krantz, K.D. and Bryant, E.C., Proceedings of the Beijing Symposium, Alpha Medical Press, Dayton, Ohio (1991) 121-141).
  • doses up to 300 IU kg were sometimes required, demonstrating the relative resistance to the effect of Epoetin alpha in these patients.
  • Tumor necrosis factor is part of a group of inflammatory cytokines that has been implicated in the pathologic changes seen in a number of diseases. TNF has been implicated as a contributing cause of fatigue, asthenia, anorexia and cachexia in a number of disorders. Elevated levels of TNF were associated with post-dialysis fatigue in one study (Dreisbach, A.W., Hendrickson, T., Beezhold, L.A., et al., Int. J. Artif. Organs (1998) 21:83-6) and were seen in patients with disorders of excessive daytime sleepiness in another.
  • TNF inhibition associated with the use of thalidomide has been exploited to treat the anorexia and cachexia of HIV disease (Haslett, P.A., J. Semin. Oncol. (1998) 25(6):53-57).
  • the "procachexic" characteristics of some inflammatory cytokines, and TNF in particular, were recently reviewed (Argiles, J.M. and L ⁇ pez-Soriano, F.J., Med. Res. Rev. (1999) 19:223-48).
  • TNF may act as a negative modulator of erythropoiesis.
  • murine models there are conflicting data regarding the ability to abrogate TNF mediated anemia. (Clibon, U., Bonewald, L., Caro, J., et al, Exp. Hematol (1990) 18:458-41; Johnson, C.S., Cook, C.A., Furmanski, P., Exp. Hxematol. (1990) 18:109-13.).
  • TNF blockade with a monoclonal antibody lead to improvement in the anemia of rheumatoid arthritis patients in one study (Davis, D., Charles, P.J., Potter, A., et al, Br. J. Rheumatol (1997) 36:950-6).
  • the present invention provides methods to determine the physiological relationship of cytokines in humans by administering a specific cytokine, or a specific anti-cytokine and then measuring changes in concentrations of other cytokines to produce a cytokine profile of a patient.
  • the present invention provides a method to produce cytokine modulation by EPO with or without an anti-Tumor Necrosis Factor compound.
  • Modulation of cytokines by administration of a therapeutic amount of EPO or with a combination of EPO and an anti- Tumor Necrosis Factor compound provides a novel means to treat diseases caused by aberrant concentrations of one or more cytokines in a patient and to alter the concentrations of cytokines to a desired level.
  • the present invention further provides methods to modulate the concentration of a specific cytokine or cytokine profile of a patient by administering a therapeutic regimen of a different cytokine, or an anti-cytokine agent, or a combination thereof.
  • the present invention also provides methods to produce cytokine gene expression profiles in response to EPO treatment in patients, modulate cytokine gene expression using EPO treatment and identifying the specific cytokines that are modulated in a patient treated with EPO.
  • Cytokines and hormones are produced and circulate within the body of an animal within concentration ranges that correspond with the biological activity of the cytokine.
  • the level of cytokine production by specific cells is controlled by specific cellular stimuli and the rate of metabolic clearance is controlled by the nature of the cytokine (polypeptide structure and glycosylation) and by the metabolic activity of the liver and filtration by the kidneys.
  • There are other mechanisms to modulate cytokine activity including inactivation of the cytokine by enzymatic nicking or by naturally occurring antagonists, for example soluble IL-1 receptor antagonist (IL-lra). Circulating soluble receptors or neutralizing antibodies are other well-known means to reduce the functional quantity of circulating cytokine.
  • cytokines exist in a homeostatic basis with each other and with other physiological systems, including metabolic and neurologic hormone control systems. For example, as described above, in human studies there is an association between circulating TNF levels and the need for increased doses of epoetin alpha in hemodialysis patients. There is no direct association known between these two cytokines; they are not currently known to cross-react with the other's receptor. The inventors contemplate that there is a physiologically relevant association between elevated TNF ⁇ and the biological activity of EPO, or vis a versa, that is not readily apparent using in vitro models or even known animal models.
  • TNF ⁇ chronic over expression results in disruption of metabolic homeostasis, resulting in metabolic wasting (cachexia) most likely through suppression of synthesis of lipoprotein lipase, an enzyme needed to release fatty acids bound to lipoproteins.
  • metabolic wasting a metabolic wasting
  • reduced levels of TNF ⁇ resulted in increased hemoglobin levels, despite only one known cytokine, EPO, being associated with this physiological response (Navaro, J F et al (1999) Scand J. Urol Nephrol 33(2) 121 - 125).
  • EPO cytokine
  • decreasing the levels of a cytokine, for instance TNF ⁇ may modulate the concentration of other cytokines, which could also be monitored in human subjects by the methods of the present invention.
  • TNF ⁇ cytokine
  • this method will greatly increase the rate to which beneficial therapeutic regimens will be developed and applied to the treatment of humans.
  • cytokine homeostasis The actual basis of cytokine homeostasis is likely to vary in different patient populations. For example patients with HIV or malignancies suffer from cachexia because of an imbalance of TNF ⁇ . Diabetic patients have disrupted homeostasis of their glucose metabolism either by modulated insulin levels, modulated glucagon levels, or a modulated receptor response to insulin. Various autoimmune diseases including rheumatoid arthritis and lupus are a result in disruption in the control of immune function, and have been associated with altered cytokine levels.
  • the methods of the present invention provide a means to treat different patient populations by administering a therapeutic amount of one agent and monitoring changes in the overall cytokine homeostasis, despite the fact that different patient populations will respond differently to different amounts of cytokine, for example EPO as described above.
  • the methods of the present invention of administering an agent in humans, and monitoring riiRNA levels of gene expression or new cytokine protein production is generally applicable to wide variety patient groups.
  • Erythropoietin is a preferred cytokine to administer therapeutically because it is well tolerated by the patient, as described above, and is well defined clinically in many different patient populations.
  • Administration of EPO has been demonstrated to increase hemoglobin and reticulocyte counts, not induce fever, and not induce immune response over repeated administration. EPO can be administered over a broad concentration range without detrimental effects.
  • the method of the present invention is a method to determine the physiological relationship of cytokines and producing changes in the cytokine profile of a patient comprising the steps: a) administering one or more specific cytokines, and b) measuring changes in concentrations of other cytokines.
  • the present invention is also applicable to producing changes in cytokines upon suppression of another cytokine. This could be achieved by a method to determine the physiological relationship of cytokines and producing changes in the cytokine profile of a patient comprising the steps: a) administering one or more specific anti-cytokine agent, and b) measuring changes in concentrations of other cytokines.
  • the present invention is also applicable to making changes in the cytokine profile of a patient comprising the steps: a) administering a therapeutic regimen of one or more anti-cytokine agents, and b) administering a therapeutic regimen of one or more different cytokine, and c) measuring changes in concentrations of other cytokines, wherein steps (a) and (b) can be in either order, or concurrently.
  • ELISA enzyme linked immunoassays
  • RNA is extracted from white blood cells and linearly amplified an estimated 10 6 -fold using commercially available RNA polymerase enzymes by methods well known in the art (Maniatis, T., Fritsch, E.F., Sambrook, J. in Molecular Cloning: A Laboratory Manual, 2 n Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989).
  • aRNA individually amplified RNA
  • a microarray a.k.a. chip
  • human cDNAs for example cytokine cDNA's
  • non-specific cDNAs for example plant or insect cDNAs (for the determination of non-specific nucleic acid hybridization).
  • cytokine concentrations or cytokine gene expression levels after the patient is treated with a therapeutic regimen comprising a specific cytokine, for example EPO or in combination with a specific anti-cytokine, for example an anti-Tumor Necrosis Factor Compound.
  • a therapeutic regimen comprising a specific cytokine, for example EPO or in combination with a specific anti-cytokine, for example an anti-Tumor Necrosis Factor Compound.
  • the therapeutic regimen comprising a specific cytokine, for example EPO, or in combination with a specific anti-cytokine, for example an anti-Tumor Necrosis Factor Compound can be used to treat disease states that are associated with over or under expression of genes that are known to be modulated by the therapeutic regimen.
  • a specific cytokine for example EPO
  • a specific anti-cytokine for example an anti-Tumor Necrosis Factor Compound
  • Heterogeneity among patients with respect to gene expression which presumably reflects, at least in part, different sensory modalities transmitted can be cataloged and statistically analyzed for significance.
  • the coupling of immunochemistry, aRNA and DNA chip analysis can be done.
  • chips containing a larger number of cDNAs i.e., >10,000 can be completed to more fully identify differential gene expression.
  • Cataloging heterogeneity with respect to gene expression in response to a therapeutic regimen will provide a greater understanding in the observed variability of response to the therapeutic regimen and clinical effects observed during and after the therapeutic regimen comprising a cytokine, for example EPO, or in combination with an anti-cytokine, for example an anti-Tumor Necrosis Factor Compound.
  • TNF inflammatory cytokines
  • IL-l ⁇ IL-l ⁇
  • IL-l ⁇ inflammatory cytokines
  • IL-l ⁇ results in fever, acute phase plasma protein production, and initiates metabolic wasting (cachexia).
  • TNF can also alter the balance of the procoagulation and anticoagulation by the vascular endothelium.
  • Overexpression of TNF leads to increased levels of TL-6 and this is associated with bone marrow suppression.
  • TNF ⁇ vascular smooth muscle tone
  • cytokines that regulate lymphocyte activation, growth and differentiation, TL-2, TL-4, TGF ⁇ is likely to affect autoimmune disease states in individuals with over expressed cytokines and immunosuppression in individuals with under expressed cytokines.
  • This class of cytokines is primarily produced by CD4+ and CD8+ T cells, and activates the function of other effector cells, including macrophages, endothelial cells, NK cells, B cells, eosinophils, and other T cells, in a non-specific manner.
  • cytokines that regulate Immune-Mediated inflammation INF ⁇ , TNF ⁇ , EL-5, EL- 10, and IL-12 is likely to affect conditioned mediated by such responses.
  • Hematopoietic Cytokines This class of cytokines directs maturation of hematopoietic stem cells through progressive expansion and irreversible differentiation to form various leukocyte lineage, and erythrocytes.
  • the known members of this class of cytokines includes IL-3, GM-CSF, M-CSF, G-CSF, JL-7, EPO, IL-9, and IL-11. Overexpression or under expression of any of these cytokines is likely to disrupt the appropriate numbers of individual cell lineage.
  • EPO Erythropoietin
  • EPO molecules may include small organic or inorganic molecules, synthetic or natural amino acid peptides, purified protein from recombinant or natural expression systems, or synthetic or natural nucleic acid sequences, or any chemical derivatives of the aforementioned.
  • the generally preferred form of EPO is purified, recombinant EPO, distributed under the trademarks of EPREX® or ERYPO®.
  • Epoetin alfa is a sterile, clear, colorless, aqueous solution for injection, that is provided in prefilled, single-use syringes containing either 4,000 or 10,000 IU epoetin alfa (a recombinant human erythropoietin) and 2.5 mg/mL human serum albumin in 0.4 mL (4,000 IU syringe) or 1.0 mL (10,000 IU syringe) of phosphate buffer.
  • Erythropoietin shall include those proteins and other organic molecules that have the biological activity of human erythropoietin, as well as erythropoietin analogs, erythropoietin isoforms, erythropoietin mimetics, erythropoietin fragments, hybrid erythropoietin proteins, altered carbohydrate sialic acid content erythropoietin proteins, erythropoietin receptor agonists, renal erythropoietin, brain erythropoietin, oligomers and multimers of the above, homologues of the above, and muteins of the above, including but not limited to muteins having increased or decreased glycosylatin sites, regardless of the biological activity of same, and further regardless of the method of synthesis or manufacture thereof including but not limited to naturally occurring, recombinant, synthetic, transgenic, and gene activated methods.
  • anti- cytokine compound refers to drug products that decrease the amount of circulating, active cytokine.
  • the compound may achieve this by decreasing the amount of cytokine mRNA transcription, by increasing the rate of cytokine mRNA degradation, by decreasing mRNA translation into cytokine, or by decreasing cellular secretion of the cytokine.
  • Other suitable anti-cytokine compounds work by increasing the rate of clearance or decreasing the amount of functional cytokine protein in circulation.
  • the anti-cytokine compounds may be administered as combinations in order to maximize modulation of the cytokine profile of a patient since agents can be selected that act as cytokine inhibitors at different points in cytokine synthesis and pharmacokinetic activity.
  • anti- Tumor Necrosis Factor Compound refers to drug products that decrease the amount of circulating, active TNF ⁇ .
  • the compound may achieve this by decreasing the amount of cellular TNF ⁇ mRNA transcription, by decreasing mRNA translation into TNF ⁇ protein, or by decreasing cellular secretion of TNF ⁇ .
  • Roy A. Black, et. al, from Immunex Corporation has discovered a compound that inhibits the enzyme that releases TNF from cell surfaces (Nature, 370, 218(1994)). This compound, called TNF- ⁇ protease enzyme inhibitor, curbs production of soluble TNF.
  • Other suitable anti-TNF ⁇ compounds could work by increasing the rate of clearance or decreasing the amount of functional TNF ⁇ in circulation.
  • Preferred anti-TNF ⁇ compounds are Thalidomide, Pentoxifylline, Infliximab, glucocorticoids, and Etanercept.
  • the anti-TNF ⁇ compounds may be administered as combinations in order to maximize modulation of TNF since these agents acts as TNF ⁇ inhibitors at a different points in TNF synthesis and pharmacokinetic activity.
  • Pentoxifylline inhibits TNF- ⁇ gene transcription (Doherty, et al, Surgery (1991) 110:192), while thalidomide enhances TNF- ⁇ m-RNA degradation (Moreira, et al., 1993) and glucocorticoids such as dexamethasone inhibit TNF- ⁇ m-RNA translation (Han, et. al, J. Exp. Med. (1990) 172:391).
  • Infliximab and Etanercept act by reducing the amount of circulating, active TNF ⁇ .
  • Pentoxifylline decreases circulating TNF ⁇ at the Standard dose of 400 mg 3 times daily. Pentoxifylline inhibits TNF- ⁇ gene transcription (Doherty, et al, Surgery (1991) 110:192).
  • Glucocorticoids such as dexamethasone inhibit TNF- ⁇ m-RNA translation.
  • Desamethasone is administered orally, intramuscularly, or intravenously in the dose range of 8-40 mg (pediatric dose: 0.25-0.5 mg/kg). If given intravenously, dexamethasone should be given over 10-15 minutes, since rapid administration may cause sensations of generalized warmth, pharyngeal tingling or burning, or acute transient perianal and/or rectal pain.
  • Methylprednisolone is also administered orally, intramuscularly, or intravenously at doses and schedules that vary from 40-500 mg every 6-12 hours for up to 20 doses.
  • Thalidomide N- phthalidoglutarimide may act by enhancing TNF- ⁇ m-RNA degradation (Shannon, et al Amer. Society for Microbiology Ann. Mtg Configur (1990) Abs. U-53). Thalidomide is given by oral administration in the range of about 30 mg to 1500 mg per 24 hours, preferably 200 to 500 mg per 24 hours for an adult human weighting 70 kg.
  • REMICADETM is a monoclonal antibody that blocks the biological activity of circulating TNF ⁇ . Infliximab does not neutralize TNF ⁇ (lymphotoxin ⁇ ), a related cytokine that utilizes the same receptors as TNF ⁇ . Remicade is supplied as a sterile, white, lyophilized powder for intravenous infusion. Following reconstitution with 10 mL of Sterile Water for Injection, USP, the resulting pH is approximately 7.2. Each single-use vial contains 100 mg Infliximab, 500 mg sucrose, 0.5 mg polysorbate 80, 2.2 mg monobasic sodium phosphate and 6.1 mg dibasic sodium phosphate. No preservatives are present.
  • ENBRELTM is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgGl.
  • the Fc component of Etanercept contains the j2 domain, the C H 3 domain and hinge region, but not the C H I domain of IgGl.
  • Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons.
  • ENBRELTM is supplied as a sterile, white, preservative-free, lyophilized powder for parenteral administration after reconstitution with 1 mL of the supplied Sterile Bacteriostatic Water for Injection, USP (containing 0.9% benzyl alcohol). Following reconstitution, the solution of ENBRELTM is clear and colorless, with a pH of 7.4 ⁇ 0.3. Each single- use vial of ENBRELTM contains 25 mg Etanercept, 40 mg mannitol, 10 mg sucrose, and 1.2 mg tromethamine. ENBRELTM is administered as a single subcutaneous (SC) injection.
  • SC subcutaneous
  • the study will be a double-blind, randomized, placebo controlled trial.
  • cancer patients with treatment related anemia will be assigned in a 1:1 randomization to receive either epoetin alfa plus placebo (Regimen A) or epoetin alfa plus Etanercept (Regimen B).
  • Patients who do not achieve an increase in hemoglobin of 1 g/dl without transfusion after four weeks of treatment will receive an increased dose epoetin alfa during weeks 5-8.
  • Patients on Regimen A (epoetin alfa + placebo) who do not achieve an increase in hemoglobin of 2 g/dl over baseline by week 9 will be crossed over to Regimen B in an 8 week open label extension phase.
  • Patients on Regimen B who do not achieve a 2 g/dl increase in hemoglobin over baseline by week 9 will be taken off study. Responding patients will continue on their assigned treatment and blinding will be maintained for 16 weeks.
  • TNF ⁇ levels by EPO in patients administered EPO + placebo will be determined by differential protein expression and compared to the baseline values (TNF ⁇ levels prior to any treatment) and EPO+ETAN (Regimen B).
  • the modulation of TNF ⁇ by EPO + ETAN will be compared to established data of ETAN alone to determine if the anti-TNF ⁇ compound exhibits synergy with EPO in suppression of TNF ⁇ .
  • corticosteroids other than for occasional use for anti- emesis or pre-treatment for a medication
  • Randomization will be used to avoid bias in the assignment of patients to treatment, to increase the likelihood that subject attributes are evenly balanced across groups, and to enhance the validity of comparisons across treatment groups.
  • Investigators and patients will be blinded to the identity of Etanercept and placebo to enhance the validity of comparisons that are subject to observer bias or the placebo effect (e.g. -QoL end points).
  • EPO will be given to all patients in an open label manner. Patients will be assigned randomly to each treatment regimen.
  • Pre-Randomization Phase (Baseline) The following evaluations and procedures are to be performed within 14 days prior to randomization unless otherwise specified. All laboratory tests and QoL and cognitive measures must be performed prior to the start of the first chemotherapy course after randomization.
  • Subjects will be assigned to treatment groups based on a computer-generated randomization schedule. The randomization will be balanced by using permuted blocks and will be stratified by center and type of cancer. Based on this randomization code, the study drug will be packaged and labeled for each subject. [Subject numbers] [Medication code numbers] will be preprinted on the study drug labels and assigned sequentially as subjects qualify for the study and are randomized to treatment.
  • the Etanercept or placebo drug container will have a two-part, tear-off label with directions for use and other information on each part.
  • the tear-off section of the label will contain a concealed area identifying the study drug (e.g., active or placebo) and will be removed and attached to the subject's CRF when the drug is dispensed.
  • the second part of the label will remain affixed to the study drug container and will contain all identifying information except for the identity of the drug contained.
  • the study drugs will be identical in appearance and will be packaged in identical containers.
  • the blind should not be broken.
  • the blind should be broken only if specific emergency treatment would be dictated by knowing the treatment status of the subject. In such cases, the investigator must contact the sponsor. If the investigator is unable to contact the sponsor, the investigator may in an emergency determine the identity of the treatment by exposing the concealed area of the label attached to the subject's CRF. Individual code breaks by the investigator will normally result in withdrawal of the subject from the trial. The date, time, and reason for the unblinding must be documented on the appropriate page of the CRF (Study Completion Information) and the sponsor must be informed as soon as possible.
  • the randomization schedule will not be revealed to study subjects, parents or guardians, investigators and clinical staff, or site managers until all subjects have completed the double-blind phase of the trial.
  • the investigator will call the study sponsor with the week 9 hemoglobin results. If a patient is a non-responder, the study sponsor will inform the investigator of the patient's treatment assignment. Patients who do not respond to EPO + ETAN (Regimen B) will proceed to Off Study Evaluation procedures. Non-responding patients treated on EPO + placebo (Regimen A) will be treated with EPO + ETAN for an additional 8 weeks in an open label extension phase. Non-responding patients treated with EPO+ETAN who subsequently respond indicate synergistic action of the anti-tumor necrosis factor agent with EPO. Comparison of the response of patients treated with EPO or with EPO+ETAN will further indicate synergistic action of the combination therapy.
  • patients should remain blinded to study-related test results prior to the completion of each set of QoL and cognitive measures.
  • the treating physician may provide laboratory results as soon as the forms are completed for that visit.
  • evaluations For patients receiving every-three-week chemotherapy, evaluations should be completed at least 3 days following the end of the last dose of chemotherapy. For patients receiving every four week chemotherapy, evaluations should be completed within 3 days prior to the scheduled chemotherapy course.
  • Serum TNF ⁇ and anti-TNF ⁇ levels • FACT-An, Linear Analog Scale Assessment (LASA), CLOX and EXIT 25 within 3 days prior to the administration of chemotherapy
  • EPO will be started at a dose of 40,000 U per week given SC, without regard to the timing of chemotherapy. If at the evaluation prior to the week 5 dose the hemoglobin has not increased by at least 1 g/dl over the baseline value, the dose of EPO will be increased to 60,000 U per week for weeks 5-8. If the hemoglobin increases by at least 2 g/dl over baseline at the time of the week 9 evaluation, the patient will be considered a responder. Responders will continue to receive the dose of EPO given during weeks 5-8 until week 16. Non-responders will be offered the opportunity to receive EPO + ETAN in an
  • Placebo injections will be given at a dose of 1 ml SC, at a site separate from the EPO site, on days 1 and 4 of each week (day 1 is counted as the day the EPO and placebo are given together).
  • the patient should receive two doses of placebo during week 8, prior to the week 9 evaluation.
  • Responders will continue to receive placebo in a blinded manner through week 16.
  • Two placebo injections should be given in week 16, prior to the off study evaluation.
  • Non-responders will be offered the opportunity to receive EPO + ETAN in an 8 week open label extension.
  • EPO will be started at a dose of 40,000 U per week given SC, without regard to the timing of chemotherapy. If at the evaluation prior to the week 5 dose the hemoglobin has not increased by at least 1 g/dl over the baseline value, the dose of EPO will be increased to 60,000 U per week for weeks 5-8. If the hemoglobin increases by at least 2 g/dl over baseline at the time of the week 9 evaluation, the patient will be considered a responder. Responders will continue to receive the dose of EPO given during weeks 5-8 until week 16. Non-responders will proceed to the Off Study Evaluation at week 9.
  • ETAN injections will be given at a dose of 25 mg (1 ml) SC, at a site separate from the EPO site, on days 1 and 4 of each week (day 1 is counted as the day the EPO and ETAN are given together).
  • the patient should receive two doses of ETAN during week 8, prior to the week 9 evaluation. Responders will continue in ETAN through week 16. Two ETAN injections should be given during week 16 and prior to the off study evaluation. Non-responders will proceed to the off study evaluation at week 9.
  • ETAN EPO dose of 60.000 U/week at week 8 will continue on that dose for weeks 9-12.
  • ETAN will be given at a dose of 25 mg SC, at a site separate from the EPO site, on days 1 and 4 of each week (day 1 is counted as the day the EPO and placebo are given together).
  • ETAN will be started on the day of the week 9 EPO dose and continue until 2 doses are given during week 12. If the evaluation at week 13 indicates at least a 1- g/dl increase in hemoglobin over the week 9 value or a 2 g/dl increase over the baseline value, then the patient will be considered a responder and continue on study through week 16. ETAN should continue until 2 doses are given in week 16. The patient then will proceed to the Off Study Evaluation. If the patient is a non- responder at week 13, then the patient will proceed to the Off Study Evaluation.
  • ETAN ETAN will be given at a dose of 25 mg SC, at a site separate from the EPO site, on days 1 and 4 of each week (day 1 is counted as the day the EPO and placebo are given together).
  • the first dose of ETAN will be given on the day of the week 9 EPO dose and continue until 2 doses are given during week 12. If the evaluation at week 13 indicates at least a 1 g/dl increase in hemoglobin over the week 9 value, or a 2 g/dl increase over the baseline value, then the patient will continue on study through week 16 at the same dose of EPO. ETAN should continue until 2 doses are given during week 16 EPO.
  • EPO Dose Adjustment of EPO If the hemoglobin is > 13 g/dl on 2 consecutive evaluations, EPO should be withheld until the hemoglobin drops to 12 g/dl. EPO should then be resumed at 75% of the last dose given before discontinuation. If the hemoglobin increases by > 1.3 g/dl in a 2 week period, EPO should be continued at 75% of the previous dose. Patients who Develop Sepsis
  • Epoetin alfa 40,000 U/ml should be brought to room temperature and drawn up into a plastic syringe immediately prior to administration by SC injection according to standard techniques.
  • the EPO and ETAN/placebo may be given at the same time on day 1 of each week, but should be administered at separate sites.
  • Each vial of EPO should be used only once.
  • the maximum injection volume per site is 2 ml.
  • ETAN Study medication (ETAN/placebo) should be reconstituted with 1 ml of the supplied sterile bacteriostatic water for injection, USP (0.9% benzyl alcohol).
  • the diluent should be slowly injected into the vial. Some foaming may occur. To avoid excessive foaming, do not shake or agitate vigorously. Swirl gently until dissolution occurs, usually over less than 5 minutes. The solution should be clear and colorless.
  • the medication should then be drawn up into a plastic syringe and administered SC as soon as possible after reconstitution. New injections should be given at least 1 inch from an old site and never into areas where the skin is tender, bruised, hard or red.
  • Part 2 of the two-part vial label Prior to injection of the study medication, Part 2 of the two-part vial label is to be attached to the subject's case report form after entry of the subject's initials and number, and the date of study medication administration. Each vial of study medication should be used only once. Iron
  • Iron deficiency may develop during the use of EPO and may limit the efficacy of EPO if left untreated. If laboratory evidence of iron deficiency develops during the study, the patient should be given 150-200 mg of elemental iron per day. The appropriate formulation of the iron supplement is left to the discretion of the treating physician.
  • Patients may be transfused with packed red blood cells when judged to be necessary by the physician of record.
  • a hemoglobin level should be obtained at the time the type and cross-match specimen is drawn.
  • the pre-transfusion hemoglobin value, along with the number of units used and the total volume transfused, should be recorded in the case report form.
  • the sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which prohibited therapies are administered.
  • ⁇ Response is defined as a 2g/dl or greater increase in the hemoglobin when compared to the Baseline value.
  • ⁇ Significant weight loss will be defined as Off Study Weight divided by Baseline Weight less than 0.90.
  • ⁇ Disease status will be defined according the current version of the RECIST Criteria issued by the National Cancer Institute.
  • RNA is extracted from the white blood cell samples with Micro RNA Isolation Kit (Stratagene, San Diego, CA). The pellet is resuspended in 11 ⁇ l of RNase free H2O, 1 ⁇ l of which is saved and used as a negative control for reverse transcription PCR (no RT control), and the remaining (10 ⁇ l) is processed for RT-PCR and RNA amplification.
  • RT Reverse Transcription
  • First stand synthesis is completed by adding together 10 ⁇ l of purified RNA from above and 1 ⁇ l of 0.5 mg/ml T7-oligodT primer (5'TCTAGTCGACGGCCAGTGAATTGTAATACGACTCACTATAGGGC
  • Ampliscribe T7 Transcription Kit (Epicentre Technologies) is used: 8 ⁇ l double-stranded cDNA, 2 ⁇ l of 10X Ampliscribe T7 buffer, 1.5 ⁇ l of each 100 mM ATP, CTP, GTP and UTP, 2 ⁇ l 0.1 M DTT and 2 ⁇ l of T7 RNA Polymerase, at 42°C for 3 hours. The aRNA is washed 3X in a Microcon-100 column, collected, and dried down to 10 ⁇ l.
  • 10 ⁇ l of aRNA from first round amplification is mixed together with 1 ⁇ l of lmg/ml random hexamers (Pharmacia), 70°C for 10 minutes, chilled on ice, equilibrated at room temperature for 10 minutes, then 4 ⁇ l 5X first stand buffer, 2 ⁇ l 0.1M DTT, 1 ⁇ l lOmM dNTPs, 1 ⁇ l RNasin and 1 ⁇ l Superscript RT II are added and incubated at room temperature for 5 minutes followed by 37°C for 1 hour. Then, 1 ⁇ l of RNase H is added and incubated at 37°C for 20 min.
  • 1 ⁇ l of aRNA from first round amplification is mixed together with 1 ⁇ l of lmg/ml random hexamers (Pharmacia), 70°C for 10 minutes, chilled on ice, equilibrated at room temperature for 10 minutes, then 4 ⁇ l 5X first stand buffer, 2 ⁇ l 0.1M D
  • Second strand cDNA synthesis 1 ⁇ l of 0.5 mg/ml T7-oligodT primer is added and incubated at 70°C for 5 minutes, 42°C for 10 minutes. Next, 30 ⁇ l of second strand synthesis buffer, 3 ⁇ l lOmM dNTPs, 4 ⁇ l Polymerse I, 1 ⁇ l E. coli RNase H, 1 ⁇ l E. coli DNA Ligase and 90 ⁇ l of RNase free H2O is added and incubated at 37°C for 2 hours. Then 2 ⁇ l of T4 DNA Polymerase is added atl6°C for 10 minutes. The double strand of cDNA is extracted with
  • cDNA is ready for second round T7 in vitro transcription as above and then a subsequent third round aRNA amplification.
  • Microarray Printing cDNA clones from whole white blood cells are printed on silylated slides (CEL Associates). cDNAs are PCR-amplified with 5' amino-linked primers and purified with Qiagen 96 PCR Purification Kits. The print spots are about 125 ⁇ m in diameter and are spaced 300 ⁇ m apart from center to center. Thirty plant genes are also printed on the slides as a control for non-specific hybridization.
  • Cy3 labeled cDNA probes are synthesized from aRNA of white blood cell
  • DRGs with Superscript Choice System for cDNA Synthesis (Gibco BRL). 5 ⁇ g aRNA, 3 ⁇ g random hexamer are mixed in a total volume of 26 ⁇ l (containing RNase free H O), heated to 70°C for 10 minutes and chilled on ice. Then,10 ⁇ l first strand buffer, 5 ⁇ l 0.1MDTT, 1.5 ⁇ l RNasin. 1 ⁇ l 25mMd(GAT)TP, 2 ⁇ l lmM dCTP, 2 ⁇ l Cy3-dCTP (Amersham) and 2.5 ⁇ l
  • the probes are vacuum dried and resuspended in 20 ⁇ l of hybridization buffer (5X SSC, 0.2% SDS) containing mouse Cotl DNA (Gibco BRL).
  • Printed glass slides are treated with sodium borohydrate solution (0.066M NaBH4, 0.06M Na AC) to ensure amino-linkage of cDNAs to the slides. Then, the slides are boiled in water for 2 minutes to denature the cDNA. Cy3 labeled probes are heated to 99°C for 5minutes, room temperature for 5 minutes and applied to the slides. The slides are covered with glass cover slips, sealed with DPX (Fluka) and hybridized at 60°C for 4-6 hours. At the end of hybridization slides are cooled to room temperature. The slides are washed in IX SSC, 0.2% SDS at 55°C for 5 minutes, 0.1X SSC, 0.2% SDS at 55°C for 5 minutes. After a quick rinse in 0.1X SSC, 0.2% SDS, the slides are air-blown dried and ready for scanning.
  • sodium borohydrate solution 0.066M NaBH4, 0.06M Na AC
  • Microarray Quantitation cDNA microarrays i.e., microscope slides
  • ScanArray 3000 General Scanning, Inc.
  • ImaGene Software Biodiscovery, Inc.
  • the intensity of each spot i.e., cDNA
  • the intensity of each spot is corrected by subtracting the immediate surrounding background.
  • the corrected intensities are normalized for each cDNA
  • each intensity is compared, via a one- sample t-test, to the 75-percentile value of 30 plant cDNAs that are present on each chip (representing non-specific nucleic acid hybridization).
  • the intensity for each cDNA from each patient set (patients within one therapeutic regimen, patient populations treated with different therapeutic regimens, and patient baseline) are grouped together respectively and intensity values are averaged for each corresponding cDNA.
  • Two-sample t test for one- tailed hypotheses is used to detect a gene expression difference between the different patient populations after a therapeutic regimen.
  • ELISA Commercial enemy linked immunoassays
  • R&D Systems R&D Systems, Minneapolis, MN or BioSource International
  • EPO or EPO/Anti-Tumor Necrosis Factor Compound Each assay is conducted according to the manufacture's instructions. Table 1 describes the assays that are conducted using serum drawn on each time point described above.
  • RNA is extracted from white blood cells of patients who received at least one doses of EPO or EPO+ETAN and is linearly amplified an estimated 10 6 -fold via T7 RNA polymerase.
  • one or more fluorescently labeled probes are synthesized from an individually amplified RNA (aRNA) and hybridized in triplicate to a microarray (a.k.a. chip) containing human cytokine cDNAs and other cDNA's such as plant cDNAs (for the determination of non-specific nucleic acid hybridization).
  • aRNA individually amplified RNA
  • a microarray a.k.a. chip
  • the binding of the labeled probe to a cytokine cDNA spot on the chip indicates the presence of mRNA encoding the cytokine.
  • the amount of labeled probe bound to the cytokine cDNA spot on the chip indicates the amount of mRNA encoding the cytokine. In this manner a cytokine profile is established for each patient.
  • the coefficient of variation is calculated (CV or standard deviation/mean X 100%). More importantly, independent amplifications ( ⁇ 10 6 -fold) of different sets of the same white blood cell subtype from different patients yields quite similar expression patterns.
  • Heterogeneity with respect to gene expression which presumably reflects, at least in part, different sensory modalities transmitted can be cataloged and statistically analyzed for significance.
  • the coupling of immunochemistry, aRNA and DNA chip analysis can be done.
  • chips containing a larger number of cDNAs i.e., >10,000 can be completed to more fully identify differential gene expression including genes other than cytokine genes.
  • Cataloging heterogeneity with respect to gene expression in response to a therapeutic regimen of EPO or EPO/anti-TNF will provide a greater understanding in the observed variability of response to EPO or EPO/ Anti-TNF and clinical effects observed during and after a therapeutic regimen of EPO or EPO/Anti-TNF.

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Abstract

La présente invention propose des procédés pour la détermination d'une relation physiologique de différentes cytokines chez l'humain par l'administration d'un régime thérapeutique d'une cytokines, ou d'un anti-cytokine, ou d'une combinaison d'une cytokine et d'un anti-cytokine, et par la mesure des modifications en concentration d'autres cytokines. L'invention propose également des procédés pour la modulation de la concentration d'une cytokine cible par l'administration d'un régime thérapeutique d'une cytokine, ou d'un anti-cytokine, ou d'une combinaison d'une cytokine et d'un anti-cytokine, et par la mesure des modifications en concentration d'autres cytokines.
PCT/US2001/024391 2001-08-02 2001-08-02 Therapie par modulation de cytokines Ceased WO2003013568A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011028835A1 (fr) 2009-09-02 2011-03-10 Concert Pharmaceuticals, Inc. Dérivés de xanthine substitués
WO2012031138A2 (fr) 2010-09-01 2012-03-08 Concert Pharmaceuticals, Inc. Polymorphes de (s)-1-(4,4,6,6,6-pentadeutéro-5-hydroxyhexyl)-3-7-diméthyl-1h-purine-2,6(3h,7h)dione
WO2013013052A1 (fr) 2011-07-19 2013-01-24 Concert Pharmaceuticals, Inc. Dérivés de xanthine substitués
WO2013155465A1 (fr) 2012-04-13 2013-10-17 Concert Pharmaceuticals, Inc. Dérivés de xanthine substituée
WO2013159006A1 (fr) 2012-04-20 2013-10-24 Concert Pharmaceuticals, Inc. Polymorphes de (s)-1-(4,4,6,6,6-pentadeutéro-5-hydroxyhexyl)-3,7-diméthyl-1h-purine-2,6(3h,7h)-dione
WO2015160913A1 (fr) 2014-04-18 2015-10-22 Concert Pharmaceuticals, Inc. Méthodes de traitement de l'hyperglycémie
EP2963040A1 (fr) 2009-09-02 2016-01-06 Concert Pharmaceuticals Inc. Dérivés de xanthine substitués
EP3199203A1 (fr) 2008-02-29 2017-08-02 Concert Pharmaceuticals Inc. Dérivés de xanthine substitués

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6074643A (en) * 1993-09-09 2000-06-13 Cli Oncology, Inc. Site-directed chemotherapy of metastases

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6074643A (en) * 1993-09-09 2000-06-13 Cli Oncology, Inc. Site-directed chemotherapy of metastases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FALCONE ET AL.: "Clinical results of recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma: role of cytokines and monitoring of erythropoiesis", EUROPEAN JOURNAL OF HAEMATOLOGY, vol. 58, 1997, pages 314 - 319, XP002952551 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3199203A1 (fr) 2008-02-29 2017-08-02 Concert Pharmaceuticals Inc. Dérivés de xanthine substitués
WO2011028835A1 (fr) 2009-09-02 2011-03-10 Concert Pharmaceuticals, Inc. Dérivés de xanthine substitués
EP2963040A1 (fr) 2009-09-02 2016-01-06 Concert Pharmaceuticals Inc. Dérivés de xanthine substitués
WO2012031138A2 (fr) 2010-09-01 2012-03-08 Concert Pharmaceuticals, Inc. Polymorphes de (s)-1-(4,4,6,6,6-pentadeutéro-5-hydroxyhexyl)-3-7-diméthyl-1h-purine-2,6(3h,7h)dione
WO2013013052A1 (fr) 2011-07-19 2013-01-24 Concert Pharmaceuticals, Inc. Dérivés de xanthine substitués
WO2013155465A1 (fr) 2012-04-13 2013-10-17 Concert Pharmaceuticals, Inc. Dérivés de xanthine substituée
WO2013159006A1 (fr) 2012-04-20 2013-10-24 Concert Pharmaceuticals, Inc. Polymorphes de (s)-1-(4,4,6,6,6-pentadeutéro-5-hydroxyhexyl)-3,7-diméthyl-1h-purine-2,6(3h,7h)-dione
WO2015160913A1 (fr) 2014-04-18 2015-10-22 Concert Pharmaceuticals, Inc. Méthodes de traitement de l'hyperglycémie

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