WO2017123549A1 - Méthodes de traitement ou de prévention d'une maladie du greffon contre l'hôte faisant appel à des héparinoïdes interagissant avec hmgb1 - Google Patents

Méthodes de traitement ou de prévention d'une maladie du greffon contre l'hôte faisant appel à des héparinoïdes interagissant avec hmgb1 Download PDF

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WO2017123549A1
WO2017123549A1 PCT/US2017/012861 US2017012861W WO2017123549A1 WO 2017123549 A1 WO2017123549 A1 WO 2017123549A1 US 2017012861 W US2017012861 W US 2017012861W WO 2017123549 A1 WO2017123549 A1 WO 2017123549A1
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gvhd
heparinoid
interacting heparinoid
hmgbl
hmgb
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Stephen Marcus
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Cantex Pharmaceuticals Inc
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Cantex Pharmaceuticals Inc
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • Acute graft-versus-host disease is a common complication of allogeneic hematopoietic cell transplant (HCT), and the most common life-threatening complication of allogeneic hematopoietic stem cell transplant (HSCT).
  • HCT allogeneic hematopoietic cell transplant
  • HSCT allogeneic hematopoietic stem cell transplant
  • Clinically significant acute GVHD occurs in 9 to 50 percent of patients who receive an allogeneic HSCT from a genotypically HLA-identical sibling, despite intensive prophylaxis with immunosuppressive agents, such as methotrexate, cyclosporine, corticosteroids, mycophenolate mofetil, or antithymocyte globulin.
  • Acute GVHD is more common following HSCT from matched unrelated donors and haploidentical donors.
  • GVHD is thought to be primarily a T cell-mediated disease that occurs when immune cells transplanted from a non-identical donor (the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction that causes disease in the transplant recipient.
  • the skin, gastrointestinal tract, and liver are the principal target organs in patients with acute GVHD.
  • Prophylaxis of acute graft-versus-host disease (GVHD) centers on immuno-suppression of the donor cells, either pharmacologically or via T cell depletion. There is no agreed-upon standard regimen, and clinical practice varies by institution.
  • GVHD graft-versus-host disease
  • GVHD Despite current therapies, GVHD remains a serious problem, limiting the use and effectiveness of HCT, including HSCT. Moreover, because most treatment options are based on the immunosuppression of donor T cells, which are responsible for the clinical manifestations of GVHD, and in certain HCT applications the infused T cells are required for therapeutic effect, treatment of GVHD must aim to balance the benefit of reducing GVHD with the potential harm of decreasing a graft- versus-tumor therapeutic effect. [0006] There is need for improved methods for preventing, treating, and attenuating GVHD. SUMMARY
  • graft-versus- host disease comprising administering a therapeutically effective amount of a substantially non-anticoagulating heparin or heparin derivative that is capable of inhibiting binding of HMGB 1 to TLR4 ("HMGB1 -interacting heparinoids").
  • the methods comprise treating and/or preventing acute graft versus host disease (GVHD) associated with allogeneic hematopoietic stem cell transplantation (HSCT).
  • HSCT allogeneic hematopoietic stem cell transplantation
  • the subject has GVHD that is refractory to corticosteroid treatment without the further administration of HMGB 1 -interacting heparinoids.
  • the heparinoid is administered intravenously.
  • the heparinoid is administered by bolus intravenous
  • a bolus dose is administered over less than a minute, about a minute, about 2 minutes, about 3 minutes, about 4 minutes, or about 5 minutes.
  • the heparinoid is administered by continuous intravenous infusion.
  • the heparinoid is administered as one or more bolus intravenous injections preceded and/or followed by continuous infusion.
  • the heparinoid is administered to the subject as a 4mg/kg bolus on Day 1 followed by a continuous intravenous infusion of 0.25 mg/kg/hr for days 1 through 5.
  • the heparinoid is administered subcutaneously.
  • the methods comprise administering HMGB1 -interacting heparinoids in combination with corticosteroids.
  • the corticosteroid is methylprednisolone.
  • the dose of methylprednisolone administered is in the range of 1-60 mg/kg.
  • the dose of methylprednisolone is 2 mg/kg/d given in 2 divided doses.
  • the dose of methylprednisolone is a range of 2mg/kg/d - lOmg/kg/d.
  • the treatment of heparinoids results in the resolution of acute GVHD in less than 42 days.
  • the time to resolution of acute GVHD is reduced in subjects administered heparinoids in combination with corticosteroids compared to subjects administered corticosteroids alone.
  • the corticosteroid is administered orally. In certain embodiments the corticosteroid is administered intravenously. In certain embodiments, the heparinoid is administered prior to the corticosteroid. In certain embodiments, the heparinoid is administered concurrently with the corticosteroid. In certain embodiments, the heparinoid is administered following corticosteroid administration.
  • oral nonabsorbable steroids such as a budesonide and beclomethasone, are administered in combination with the heparinoid and systemic corticosteroid.
  • corticosteroids e.g., triamcinolone 0.1%) may be administered to a subject in combination with heparinoids.
  • the methods comprise administering HMGB l -interacting heparinoids with continued administration of the original immunosuppressive prophylaxis (CSP A or tacrolimus [FK506]).
  • CSP A or tacrolimus [FK506] the original immunosuppressive prophylaxis
  • the heparinoid is administered in combination with one or more of ATG, CSP,
  • mycophenolate mofetil anti-IL-2 receptor, anti-CD5-specific immunotoxin, and a pan T-cell ricin A-chain immunotoxin (XomaZyme).
  • Figure 1 depicts the results of an enzyme-linked immunosorbant assay of HMGB l binding to TLR2 in the presence of varying concentrations of a substantially non- anticoagulating heparin derivative, 2-0, 3-O-desulfated heparin (ODSH).
  • a substantially non- anticoagulating heparin derivative 2-0, 3-O-desulfated heparin (ODSH).
  • Figure 2 depicts the results of an enzyme-linked immunosorbant assay of HMGB l binding to TLR4 in the presence of varying concentrations of ODSH.
  • HMGB l -interacting heparinoids HMGB l -interacting heparinoids
  • the subject has received an allogeneic hematopoietic stem cell transplantation (HSCT).
  • HSCT allogeneic hematopoietic stem cell transplantation
  • the methods are useful for treating or preventing acute GVHD associated with HSCT.
  • the subject has GVHD that is refractory to corticosteroid treatment, which is the current standard of care, without the further administration of HMGBl -interacting heparinoids.
  • the methods comprise administering HMGBl -interacting heparinoids in combination with corticosteroids.
  • the heparinoids are administered prior to, concurrently or following treatment with corticosteroids.
  • the methods and compositions of the invention reduce the need for high dosages of immunosuppressive agents or inhibition or depletion of T-cells during HSCT.
  • the methods and compositions of the invention improve the success rate of HSCT and response to HSCT for the treatment of disorders, such as cancer.
  • the methods improve the symptoms of GVHD, such as liver function and gastrointestinal symptoms, such as intestinal inflammation and diarrhea.
  • the subject has improved liver function after treatment with HMGBl - interacting heparinoids compared to subjects with GVHD not treated with HMGB l - interacting heparinoids.
  • the subject has reduced intestinal or gastrointestinal tract damage after treatment with HMGB 1 -interacting heparinoids compared to subjects with GVHD not treated with HMGBl -interacting heparinoids.
  • the subject has reduced skin injury after treatment with HMGBl -interacting heparinoids compared to subjects with GVHD not treated with HMGBl -interacting heparinoids.
  • the subject at risk for GVHD has a reduced probability of developing GVHD after treatment with HMGBl -interacting heparinoids compared to subjects at risk for GVHD not treated with HMGBl -interacting heparinoids.
  • the subject is in complete remission 28 days after initiation of treatment with HMGBl -interacting heparinoids.
  • the subject has a reduced probability of relapse of GVHD after treatment with HMGB l - interacting heparinoids compared to subjects with GVHD not treated with HMGB l - interacting heparinoids.
  • the subject has a reduced probability of relapse related mortality due to GVHD after treatment with HMGB l -interacting heparinoids compared to subjects with GVHD not treated with HMGBl -interacting heparinoids.
  • the subject has a reduced probability of progression to chronic GVHD after treatment with HMGBl -interacting heparinoids compared to subjects with GVHD not treated with HMGB l -interacting heparinoids. In select embodiments, the subject has an increased probability of overall survival after treatment with HMGBl -interacting heparinoids compared to subjects with GVHD not treated with HMGBl -interacting heparinoids.
  • ameliorating refers to any therapeutically beneficial result in the treatment of a disease state, e.g., GVHD disease state, including prophylaxis, lessening in the severity or progression, remission, or cure thereof.
  • in situ refers to processes that occur in a living cell growing separate from a living organism, e.g., growing in tissue culture.
  • in vivo refers to processes that occur in a living organism.
  • mammal as used herein includes both humans and non-humans and includes but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines.
  • therapeutically effective amount is an amount that is effective to ameliorate a symptom of a disease.
  • a therapeutically effective amount can be a
  • prophylaxis can be considered therapy.
  • HMGBl-interacting heparinoids for use in the methods described herein are heparins or heparin derivatives that capable of inhibiting binding of HMGBl to TLR ("HMGBl- interacting heparinoids") at concentrations that are substantially non-anticoagulating.
  • the HMGB l-interacting heparinoid inhibits binding of HMGBl to TLR4 with an IC 50 of about 0.20 ⁇ or less in the assay set forth in Example 1. in some embodiments, the HMGBl-interacting heparinoid inhibits binding of HMGBl to TLR4 in the assay described in Example 1 with an IC 50 of about 0.15 ⁇ , 0.10 ⁇ , even 0.09 ⁇ or less. In certain embodiments, the HMGB l-interacting heparinoid inhibits binding of HMGB l to TLR4 in the assay described in Example 1 with an IC 50 of about 0.07 ⁇ , 0.06 ⁇ , or 0.05 ⁇ or less.
  • the HMGB l-interacting heparinoid inhibits binding of HMGBl to TLR4 with an IC 50 of about 0.05 ⁇ g/ml or less, about 0.04 ⁇ g/ml or less, about 0.03 ⁇ g/ml or less, about 0.02 ⁇ g/ml or less, or about 0.01 ⁇ / ⁇ 1 or less in the assay set forth in Example 1.
  • the HMGB 1 -interacting heparinoid inhibits binding of HMGB1 to TLR4 with an IC 90 of about 0.7 ⁇ g/ml or less, about 0.6 ⁇ g/ml or less, about 0.5 ⁇ g/ml or less, or about 0.4 ⁇ g/ml or less in the assay set forth in Example 1.
  • the heparinoid is characterized by an IC 50 of about 0.01 ⁇ g/ml and an IC 90 of about 0.5 ⁇ g/ml as determined by the method in Example 1.
  • the HMGB1 -interacting heparinoid is capable of inhibiting HMGB1/TLR4 interaction, as measured by the method set forth in Example 1, which is about the same as an equivalent weight of unfractionated heparin.
  • the HMGB1 -interacting heparinoid is capable of effecting at least 20% inhibition of the binding of HMGB1 to TLR4 in the assay set forth in Example 1 at a concentration that, if achieved in plasma, would not effect substantial anticoagulation.
  • the HMGB 1 -interacting heparinoid is capable of effecting at least 25% inhibition of the binding of HMGB 1 to TLR4 in the assay set forth in Example 1 at a concentration that, if achieved in plasma, would not effect substantial anticoagulation.
  • the HMGB 1 -interacting heparinoid is capable of effecting at least 30 %, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60% inhibition of the binding of HMGB 1 to TLR4 in the assay set forth in Example 1 at a concentration that, if achieved in plasma, would not effect substantial anticoagulation.
  • the HMGB1 -interacting heparinoid is capable of effecting at least 65%, at least 70%, at least 80%, at least 85%, even at least 90%, 91%, 92%, 93%, 94%, 95% inhibition of the binding of HMGB 1 to TLR4 in the assay set forth in Example 1 at a concentration that, if achieved in plasma, would not effect substantial anticoagulation.
  • the HMGB1 -interacting heparinoid is capable of effecting at least 96%, 97% even at least 98% inhibition of the binding of HMGB1 to TLR4 in the assay set forth in Example 1 at a concentration that, if achieved in plasma, would not effect substantial anticoagulation.
  • the HMGB1 -interacting heparinoid is capable of binding to HMGB1 under physiological conditions.
  • the HMGB 1 -interacting heparinoids have an average molecular weight from about 2 kDa to about 15 kDa. In some embodiments, the HMGB1- interacting heparinoids have an average molecular weight of at least about 2 kDa, at least about 3 kDa, at least about 4 kDa, at least about 5 kDa, at least about 6 kDa, or at least about 7 kDa.
  • the HMGB1 -interacting heparinoids have an average molecular weight of less than about 15 kDa, less than about 14 kDa, less than about 13 kDa, less than about 12 kDa, less than about 11 kDa, less than about 10 kDa, or less than about 9kDa.
  • the average molecular weight of the HMGB l -interacting heparinoid is selected from about 2 kDa, 3 kDa, 4 kDa, 5 kDa, 6 kDa, 7 kDa, 8 kDa, 9 kDa, 10 kDa, 11 kDa, 12 kDa, 13 kDa, 14 kDa, 15 kDa, 16 kDa, 17 kDa, 18 kDa, or a range that includes any of these values as endpoints.
  • Molecular weight of heparinoids can be determined by methods know in the art; for purposes of this disclosure, molecular weight is determined by size exclusion chromatography as described in Lapierre et al., Glycobiology 6(3):355-366 (1996); Fryer et al. , J. Pharmacol. Exp. Ther. 282:208-219(1997), incorporated herein by reference in its entirety.
  • the HMGBl -interacting heparinoid is a derivative of unfractionated heparin that is substantially desulfated at the 2-0 position of a-L-iduronic acid (referred to herein as the "2-0 position") and/or 3-0 position of D-glucosamine-N-sulfate (6- sulfate) (referred to herein as the "3-0 position").
  • the 2-0, 3-O-desulfated heparin derivative is not substantially desulfated at the 6-0 or N positions.
  • the HMGBl -interacting heparinoid is at least 85%, at least 90%, at least 95%, or at least 99% desulfated at the 2-0 position. In some embodiments, the HMGBl -interacting heparinoids are at least 85%, at least 90%, at least 95%, or at least 99% desulfated at the 3-0 position. In some embodiments, the HMGB l -interacting heparinoids are at least 85%, at least 90%, at least 95%, at least 99% desulfated at the 2-0 position and the 3-0 position.
  • the substantially 2-0, 3-0 desulfated HMGB l -interacting heparinoid for use in the methods described herein are compositions in which the
  • polysaccharide chains have an average molecular weight of at least about 8 kDa.
  • the substantially 2-0, 3-0 desulfated HMGBl -interacting heparinoids have an average molecular weight of greater than about 8 kDa.
  • the substantially 2-0, 3-0 desulfated HMGBl -interacting heparinoids have an average molecular weight ranging from about 8 kDa to about 15 kDa.
  • the substantially 2- O, 3-0 desulfated HMGB l -interacting heparinoids for use in the methods described herein have an average molecular weight that ranges in size from about 11 kDa to about 13 kDa.
  • the HMGBl -interacting heparinoid is a substantially 2-0, 3-0 desulfated heparin, referred to herein as ODSH.
  • ODSH for use in the above-described methods can be prepared from bovine or porcine heparin.
  • ODSH is synthesized by cold alkaline hydrolysis of USP porcine intestinal heparin, which removes the 2-0 and 3-0 sulfates, leaving N- and 6-0 sulfates on D-glucosamine sugars and carboxylates on a-L-iduronic acid sugars substantially intact (Fryer et al, J. Pharmacol.
  • ODSH can be produced with an average molecular weight of about 11.7 ⁇ 0.3 kDa. Additional methods for the preparation of substantially 2-0, 3-0 desulfated HMGBl -interacting heparinoids may also be found, for example, in U.S. Patent nos. 5,668,118, 5,912,237, and 6,489,311, and WO 2009/015183, the contents of which are incorporated herein in their entirety, and in U.S. Patent Nos. 5,296,471; 5,969, 100; and 5,808,021.
  • ODSH is substantially non-anticoagulating: administered to a subject at a dose that is equivalent in weight to a fully-anticoagulating dose of unfractionated heparin, the clotting time measured in an aPTT assay is no greater than 45 seconds, and typically in the upper range of normal, where normal clotting time ranges from about 27 to 35 seconds.
  • unfractionated heparin administered to a subject at a fully anticoagulant dose causes time to clot to range from about 60 to about 85 seconds in an aPTT assay.
  • the HMGB 1 -interacting heparinoid is substantially non-anticoagulating as measured by its effect on aPTT.
  • the HMGBl -interacting heparinoid if administered to a subject at a dose that is weight equivalent to a fully-anticoagulating dose of unfractionated heparin, the clotting time measured in an aPTT assay is no greater than 45 seconds.
  • ODSH's anticoagulant activity is its anti-X a activity which can be determined in an assay carried out using plasma treated with Russell viper venom.
  • ODSH exhibited less than 9 U of anticoagulant activity/mg in the USP
  • anticoagulant assay e.g., 7 ⁇ 0.3 U
  • less than 5 U of anti-X a activity/mg e.g., 1.9 ⁇ 0.1 U/mg
  • less than 2 U of anti-II a activity/mg e.g., 1.2 ⁇ 0.1 U/mg
  • unfractionated heparin which has an activity of 165-190 U/mg in all three assays; Rao et al., Am. J. Physiol. 299:C97-C110 (2010).
  • the HMGB1- interacting heparinoid exhibits less than 9 U of anticoagulant activity/mg in the USP anticoagulant assay, and/or less than 5 U of anti-X a activity/mg, and/or less than 2 U of anti- IIa activity/mg.
  • ODSH has a low affinity for anti-thrombin III (Kd ⁇ 339 ⁇ or 4 mg/ml vs. 1.56 ⁇ or 22 ⁇ g/ml for unfractionated heparin), consistent with the observed low level of anticoagulant activity, measured as described in Rao et al., supra, at page C98.
  • the HMGB1 -interacting heparinoid has a low affinity for anti- thrombin III (Kd ⁇ 339 ⁇ or 4 mg/ml).
  • the HMGB 1 -interacting heparinoids have no more than 40% of the anticoagulating activity of an equal weight of unfractionated heparin by any one or more of the above-described tests.
  • the HMGB 1 -interacting heparinoid has no more than 35%, no more than 30%, no more than 20%, no more than 10%, no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, or no more than 1% of the anticoagulating activity of an equal weight of unfractionated heparin by any one or more of the above-described tests.
  • the HMGB 1 -interacting heparinoid does not trigger platelet activation and does not induce heparin-induced thrombocytopenia (HIT).
  • Platelet activation can be determined using a serotonin release assay, for example as described in U.S. Pat. No.
  • the heparinoid is capable of binding platelet factor 4, also referred to as chemokine (C-X-C motif) ligand 4 (CXCL4).
  • compositions of the invention are provided.
  • HMGB1 -interacting heparinoids for use in the methods described herein are typically formulated in pharmaceutical compositions.
  • These compositions can comprise, in addition to one or more of the heparinoids, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • a pharmaceutically acceptable excipient e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes.
  • compositions for oral administration can be in tablet, capsule, powder or liquid form.
  • a tablet can include a solid carrier such as gelatin or an adjuvant.
  • Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilizers, buffers, antioxidants and/or other additives can be included, as required.
  • HMGB1 -interacting heparinoids for use in the methods described herein are administered in a "therapeutically effective amount” or “prophylactically effective amount” (for purposes the present disclosure, prophylaxis is considered a subgenus of therapy), this being sufficient to show benefit to the individual.
  • the actual amount administered, and rate and time-course of administration will depend on the nature and severity of protein aggregation disease being treated. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980.
  • a composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
  • compositions formulated for i.v. administration are provided.
  • compositions of the heparinoid are formulated in volumes and concentrations suitable for intravenous administration. In some embodiments, the composition is formulated for bolus administration. In certain embodiments,
  • compositions of the heparinoid are formulated in volumes and concentrations suitable for intravenous infusion.
  • Typical embodiments formulated for intravenous administration comprise the heparinoid in concentrations of at least about 10 mg/ml.
  • the heparinoid is present in a concentration of at least about 15 mg/ml, at least about 20 mg/ml, at least about 30 mg/ml, at least about 40 mg/ml, at least about 50 mg/ml.
  • the heparinoid is packaged in sterile-filled 10 ml glass vials containing an isotonic 50 mg/ml solution of heparinoid in buffered saline.
  • compositions formulated for s.c. administration are provided.
  • the pharmaceutical composition is formulated for subcutaneous administration.
  • the heparinoid is associated with multivalent cations.
  • the association may be as a salt, ion/counterion, complex, binding, coordination or any other chemically relevant association. The exact nature of the association will be readily apparent to a person of skill in the art depending on the form of the composition.
  • the multivalent cations are selected from cations having a charge of +2, +3, +4, or greater.
  • the multivalent cation is an ion that contains both positive and negative charges, with a net charge greater than +1.
  • Exemplary multivalent cations include metal ions, amino acids, and other organic and inorganic cations.
  • the ion is a metal ion that is Zn , Ca , Mg or Fe .
  • the cation is Ca 2+ .
  • the cation is Mg 2+ .
  • the heparinoid is associated primarily with one species of multivalent cation. In other embodiments, the heparinoid is associated with several different multivalent cation species. In specific embodiments, the heparinoid is associated with Mg 2+ and Ca 2+ .
  • multivalent cations may be introduced to the heparinoid composition at any step.
  • the heparinoid is substantially desulfated at the 2-0 and 3-0 positions, and the multivalent cation is present during alkaline hydrolysis of the heparin starting material.
  • the multivalent cation is present as the chloride salt.
  • the multivalent cation is present as the hydroxide salt.
  • the chloride salt is preferred for use during solution phase alkaline hydrolysis.
  • the hydroxide salt is preferred for use during solid phase alkaline hydrolysis.
  • the hydroxide salt is preferred for use when alkaline hydrolysis is performed as a paste.
  • Certain multivalent cations may affect the level of desulfation if present during alkaline hydrolysis, and may be used to achieve desired levels of desulfation.
  • the amount of the multivalent cation may be titrated to control the amount of desulfation as described in U.S. Patent no. 5,296,471 at Example 4 therein.
  • the multivalent cation concentration used should be adjusted based on both the desired level of desulfation and the desired concentration of the final product.
  • concentration used during alkaline hydrolysis may be substantially less than the molar heparin concentration.
  • the molar ratio (multivalent catiomheparin) is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5, or any ranges composed of those values.
  • the concentration of the multivalent cation used during alkaline hydrolysis is about 0.01 mM, 0.05 mM, 0.1 mM, 0.5 mM, 1 mM, 5 mM, 10 mM, 20 mM, 50 mM, lOOmM, 250 mM, 500 mM or 1M or any range composed of those numbers.
  • primarily monovalent cations are present during the cold alkaline hydrolysis step, and the multivalent cation is added later, during reconstitution of the lyophilate.
  • either MgCl 2 or CaCl 2 is added at high concentration during reconstitution of the lyophilate.
  • the multivalent cation concentration used during reconstitution may be equal to the concentration of the cation used during alkaline hydrolysis.
  • the multivalent cation concentration is at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9- fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 50-fold, 75-fold, 100-fold, 150-fold, 200- fold, 250-fold, 500-fold, or 1000-fold the concentration of the cation used during alkaline hydrolysis.
  • the concentration of the multivalent cation used during reconstitution is about 0.1 M, 0.5 M, 1 M, 2 M, 3 M, 4 M, 5 M, or greater. Most preferably, the
  • Excess cations can be removed by any method known to those in the art.
  • One preferred method of removing excess cations is the use of a desalting column.
  • Another preferred method of removing excess cations is dialysis.
  • the solution preferably has about equal, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9- fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 50-fold, 75-fold, 100-fold, 150-fold, 200- fold, 250-fold, 500-fold, or 1000-fold greater multivalent cation concentration to monovalent cation concentration.
  • the solution may also be free or substantially free of monovalent cations.
  • the pharmaceutical composition is between 0.1 mg/mL and 600 mg/mL. In certain embodiments, the final concentration of partially desulfated heparin in the pharmaceutical composition is between 200 mg/mL and 400 mg/mL.
  • the concentration of heparinoid is greater than about 25 mg/mL. In certain embodiments, the concentration of heparinoid is greater than about 50 mg/mL. In a variety of embodiments, the concentration of heparinoid is greater than about 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, or 100 mg/mL.
  • the heparinoid is present in the pharmaceutical composition in a concentration greater than about 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, or even greater than about 190 mg/mL or 200 mg/mL.
  • the heparinoid is present in the pharmaceutical composition at a concentration of about 175 mg/mL.
  • the heparinoid is present in the pharmaceutical composition at a concentration of about 200 mg/mL.
  • the heparinoid is present in the pharmaceutical composition at a concentration of 400 mg/mL.
  • the concentration of the heparinoid is 50 mg/mL to
  • the concentration is 50 mg/mL, 100 mg/mL, 150 mg/mL, 200 mg/mL, 250 mg/mL, 300 mg/mL, 350 mg/mL, 400 mg/mL, 450 mg/mL or 500 mg/mL. In certain currently preferred embodiments, the concentration is 200 mg/mL, 300 mg/mL or 400 mg/mL.
  • the pharmaceutical composition has a viscosity of less than about 100 cP. In various embodiments, the pharmaceutical composition has a viscosity of less than about 80 cP. In certain embodiments, the pharmaceutical composition has a viscosity of less than about 60 cP. In particular embodiments, the pharmaceutical composition has a viscosity of less than about 20 cP.
  • the pharmaceutical composition has an osmolality less than about 2500 mOsm/kg. In various embodiments, the pharmaceutical composition has an osmolality between about 150 mOsm/kg and about 500 mOsm/kg. In certain embodiments, the pharmaceutical composition has an osmolality between about 275 mOsm/kg and about 300 mOsm/kg. In a particular embodiment, the pharmaceutical composition has an osmolality of about 285 mOsm/kg. In a specific embodiment, the pharmaceutical composition is isotonic.
  • the heparinoid is administered at an intravenous bolus dose of at least about 2 mg/kg, at least about 3 mg/kg, at least about 4 mg/kg, at least about 5 mg/kg, at least about 6 mg/kg, at least about 7 mg/kg, at least about 8 mg/kg, at least about 9 mg/kg, even at least about 10 mg/kg.
  • the bolus is at least about 15 mg/kg, even at least about 20 mg/kg.
  • the bolus is about 4 mg/kg.
  • the bolus is about 8 mg/kg.
  • the bolus is about 20 mg/kg.
  • the heparinoid is administered in a bolus of from about 2 to about 25 mg/kg, from about 2 mg/kg to about 20 mg/kg, from about 2 mg/kg to about 15 mg/kg, from about 3 mg/kg to about 10 mg/kg, or from about 4 mg/kg to about 8 mg/kg.
  • the heparinoid is administered as an intravenous infusion.
  • the infusion is at a dose rate of at least about 0.1 mg/kg/hr, at least about 0.2 mg/kg/hr, at least about 0.3 mg/kg/hr, at least about 0.4 mg/kg/hr, at least about 0.5 mg/kg/hr, at least about 1 mg/kg/hr, even at least about 2 mg/kg/hr.
  • the heparinoid is administered at an infusion rate of no more than about 5 mg/kg/hr. In certain embodiments, the heparinoid is administered at an infusion rate of no more than about 4 mg/kg/hr, 3 mg/kg/hr, about 2 mg/kg/hr, even no more than about 1 mg/kg/hr.
  • infusions at the above-described dose rates are administered continuously for up to 7 days. In certain embodiments infusions at the above-described dose rates are administered continuously for up to 6 days, 5 days, 4 days, or 3 days. In some embodiments, infusions at the above-described dose rates are administered continuously for up to 2 days or up to 24 hours. In some embodiments, infusions at the above-described rates are administered for up to 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 16 hours, or up to 24 hours or more. In certain embodiments, the infusions at the above described dose rates are administered for the duration of each cycle of treatment.
  • the heparinoid is administered as an initial bolus of about 20 mg/kg, optionally followed by an infusion of up to about 2 mg/kg/ hour for up to about 4 hours, 8 hours, 12 hrs, 16 hours, even up to about 24 hours. In one embodiment, the heparinoid is administered as an initial bolus of about 8 mg/kg, optionally followed by an infusion of about 0.5 mg/kg/ hour for at least about 8 hours.
  • the heparinoid is administered as an intravenous bolus at a dose of about 4 mg/kg, optionally followed by an intravenous infusion of the heparinoid at a dose of about 0.25 mg/kg/hr - about 0.375 mg/kg/hr for at least 24 hours. In some embodiments, the heparinoid is administered as an intravenous bolus at a dose of about 4 mg/kg, followed by a continuous intravenous infusion at a rate of 0.25 mg/kg/hr for a total of 7 days.
  • heparinoid can be administered at doses ranging from about 25 mg to about 400 mg, about 50 mg to about 300 mg, or about 75 mg to about 200 mg, in volumes of 2.0 mL or less per injection.
  • the heparinoid at the above-described dosages are administered subcutaneously each day for up to 7 days.
  • the heparinoid at the above-described dosages are administered subcutaneously each day for up to 6 days, 5 days, 4 days, or 3 days.
  • heparinoid at the above-described dosages are administered subcutaneously for up to 2 days or up to 24 hours.
  • heparinoid at the above-described dosages are administered subcutaneously each day for the duration of the cycle of treatment. Duration and frequency of administration
  • the heparinoid is administered for up to 1 hour. In various embodiments, the heparinoid is administered for up to 4 hours. In certain embodiments, the heparinoid is administered for up to 6 hours, even up to 8 hours. In some embodiments, the heparinoid is administered for up to 12 hours, 18 hours, even up to 24 hours. In certain embodiments, the heparinoid is administered for up to 2 days, 3 days, 4 days, 5 days, 6 days, or a week or more. The heparinoid can be administered, in some embodiments, for periods of more than a week, including 1 month, 2 months, 3 months or more.
  • heparinoid administration is repeated. For example, in certain embodiments
  • heparinoid is administered once daily, twice daily, three times daily, four times daily, five times daily, every two days, every three days, every five days, once a week, once every two weeks, once a month, every other month, semi-annually, or annually.
  • the heparinoid is administered at regular intervals over a period of several weeks, followed by a period of rest, during which no heparinoid is administered.
  • heparinoid is administered for one, two, three, or more weeks, followed by one, two, three, or more weeks without heparinoid administration.
  • the repeated administration can be at the same dose or at a different dose.
  • the heparinoid can be administered in one or more bolus injections, one or more infusions, or one or more bolus injections followed or preceded by infusion.
  • the frequency of dosing can be based on and adjusted for the pharmacokinetic parameters of the heparinoid and the route of administration. Dosages are adjusted to provide sufficient levels of the heparinoid or to maintain the desired physiological effect, particularly a therapeutic effect. Any effective administration regimen regulating the timing and sequence of doses may be used, as discussed herein.
  • the pharmaceutical compositions can be administered in a single dose, multiple discrete doses, continuous infusion, sustained release depots, or combinations thereof, as required to maintain desired minimum level of the agent.
  • Daily dosages may vary, depending on the specific activity of the particular heparinoid.
  • a suitable dose may be calculated according to, among others, body weight, body surface area, or organ size.
  • the final dosage regimen will be determined by the attending physician in view of good medical practice, considering various factors that modify the action of drugs, e.g., the agent's specific activity, the severity of the disease state, the responsiveness of the patient, the age, condition, body weight, sex, and the like.
  • Additional factors that may be taken into account include time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Further refinement of the dosage appropriate for treatment involving any of the formulations mentioned herein is done by the skilled practitioner, especially in light of the dosage information and assays disclosed, as well as the pharmacokinetic data observed in clinical trials. The amount and/or frequency of the dosage can be altered, increased, or reduced, depending on the subject's response and in accordance with standard clinical practice. The proper dosage and treatment regimen can be established by monitoring the progress of therapy using conventional techniques known to skilled artisans. Appropriate dosages may be ascertained through use of established assays for determining concentration of the heparinoid in a body fluid or other sample together with dose response data.
  • the heparinoid is administered in a therapeutically effective temporal proximity to the treatment regimen with the other therapeutic.
  • Administration of a heparinoid can be concurrent with (at the same time), sequential to (at a different time but on the same day, e.g., during the same patient visit), or separate from (on a different day) the treatment with the other therapeutic.
  • the heparinoid is administered concurrently, sequentially, and/or separately from the other agent or therapy being administered.
  • the heparinoid can be administered before, after, or both before and after the other treatment.
  • the heparinoid in which the heparinoid is administered in combination with treatment with another therapeutic agent, can be administrated via the same or different route as the other therapeutic administered in temporal proximity. In some embodiments, the heparinoid is administered concurrently or sequentially by the same route. For example, in some embodiments, the heparinoid and the other therapeutic are
  • the heparinoid can further be administered separately (on a different day) from the other therapeutic by a different route, e.g., subcutaneously.
  • the heparinoid is administered intravenously on the same day, either at the same time (concurrently), a different time (sequentially), or both concurrently and sequentially with the other therapeutic, and is also administered subcutaneously on one or more days when the patient is not receiving other treatment.
  • the heparinoid is administered concurrently or sequentially by a different route.
  • the heparinoid can further be administered separately (on a different day) from the other therapeutic by the same or different route as that by which the other therapeutic is administered.
  • bioavailability of heparinoids by administering in combination with one or several glycerol esters of fatty acids.
  • Example 1 ODSH inhibits binding of HMGB1 to Toll Like Receptors
  • FIG. 1 shows the inhibition of HMGBl binding to TLR2 by ODSH.
  • FIG. 2 shows the inhibition of HMGBl binding to TLR4 by ODSH. Increased concentrations of ODSH inhibited the binding of HMGB l to both TLR2 and TLR4 in vitro.
  • Example 2 Phase II Clinical Trial of patients with refractory acute HVGD following HSCT with combination of ODSH and methylprednisolone
  • HMGBl -interacting heparinoid, ODSH to improve therapy of GVHD, and in particular, to confirm and quantify the efficacy of ODSH in combination with methylprednisolone for reducing the symptoms of GVHD in patients refractory to corticosteroid treatment alone.
  • Methylprednisolone and ODSH are administered concurrently. Methylprednisolone is administered at a dose of 2 mg/kg/d given in 2 divided doses for days 1 through 30. ODSH is administered to the subject as a 4mg/kg bolus on Day 1 followed by a continuous intravenous infusion of 0.25 mg/kg/hr for days 1 through 30.
  • Patients continue treatment for 30 days. Patients are assessed daily for evidence of disease-related complications (e.g., infection) and symptoms (e.g., pruritus). Patients are monitored for gastrointestinal function by upper endoscopy, rectal biopsy or colonoscopy and liver function. A more formal assessment is undertaken on day 5 and 7 after the initiation of therapy. At this time, the severity (grade) of acute GVHD is determined by the degree of involvement of the skin, liver, and gastrointestinal tract. Patients who demonstrate progression of disease by day 5 or nonresponse by day 7 are considered to have glucocorticoid and ODSH resistance.
  • disease-related complications e.g., infection
  • symptoms e.g., pruritus
  • Patients are monitored for gastrointestinal function by upper endoscopy, rectal biopsy or colonoscopy and liver function. A more formal assessment is undertaken on day 5 and 7 after the initiation of therapy. At this time, the severity (grade) of acute GVHD is determined by the degree of involvement of the skin, liver, and gastrointestinal
  • the primary endpoint of the clinical trial is complete remission of acute GVHD at day 28 after initiation of therapy. Additional endpoints include: relapse, relapse-related mortality, overall survival (OS), and the incidence of progression to chronic GVHD.
  • OS overall survival
  • Results demonstrate that administration of an HMGB1 -interacting heparinoid in combination with corticosteroids improves efficacy of treatment as compared to

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Abstract

L'invention concerne des méthodes de prévention et de traitement d'une maladie du greffon contre l'hôte (GVH), en particulier une GVH aiguë, notamment une GVH associée à une greffe de cellules souches hématopoïétiques (HSCT), par l'administration d'héparinoïdes interagissant avec HMGB1 à un sujet exposé à une GVH, ou souffrant de celle-ci. Dans des modes de réalisation préférés, les méthodes consistent à administrer l'héparinoïde interagissant avec HMGB1 en association avec des corticostéroïdes.
PCT/US2017/012861 2016-01-11 2017-01-10 Méthodes de traitement ou de prévention d'une maladie du greffon contre l'hôte faisant appel à des héparinoïdes interagissant avec hmgb1 Ceased WO2017123549A1 (fr)

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US10052346B2 (en) 2015-02-17 2018-08-21 Cantex Pharmaceuticals, Inc. Treatment of myelodysplastic syndromes with 2-O and,or 3-O desulfated heparinoids
US11229664B2 (en) 2012-05-09 2022-01-25 Cantex Pharmaceuticals, Inc. Treatment of myelosuppression

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11229664B2 (en) 2012-05-09 2022-01-25 Cantex Pharmaceuticals, Inc. Treatment of myelosuppression
US10052346B2 (en) 2015-02-17 2018-08-21 Cantex Pharmaceuticals, Inc. Treatment of myelodysplastic syndromes with 2-O and,or 3-O desulfated heparinoids

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