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JP-7856385-B2 - Tissue kallikrein 1 dosage form

JP7856385B2JP 7856385 B2JP7856385 B2JP 7856385B2JP-7856385-B2

Inventors

  • ポールス， リック
  • バードーン， トッド

Assignees

  • ダイアメディカ， インコーポレイテッド

Dates

Publication Date
20260511
Application Date
20180309
Priority Date
20170309

Claims (20)

  1. A subcutaneous formulation for use in a method of treating cerebral ischemia (ischemic stroke) in a subject, comprising a first human tissue kallikrein ( hKLK1 ) polypeptide and a second hKLK1 polypeptide , formulated at a total dose of approximately 2.0 μg /kg to approximately 5.0 μg/ kg of hKLK1 polypeptide , The first and second hKLK1 polypeptides are mature recombinant hKLK1 polypeptides containing amino acid sequences having at least 90% sequence identity with SEQ ID NO: 3 or 4. The first hKLK1 polypeptide has three N-linked glycans bound at residues 78, 84, and 141 as defined by SEQ ID NO: 3 or 4, and the second hKLK1 polypeptide has two N-linked glycans bound at residues 78 and 84 as defined by SEQ ID NO: 3 or 4, but not bound at residue 141. A subcutaneous dosage form in which the first hKLK1 polypeptide and the second hKLK1 polypeptide are present in a ratio of 45:55 to 55:45, and the preparation is not used in combination with insulin .
  2. 2. A subcutaneous formulation according to claim 1 , comprising a total dose of hKLK1 polypeptide of 2.0, 2.1, 2.2 , 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 μg/ kg.
  3. A subcutaneous dosage form formulation according to claim 1, comprising a total hKLK1 polypeptide subcutaneous dose of approximately 2.0 μg/kg to approximately 5.0 μg/kg, or approximately 2.0 μg/kg to approximately 4.0 μg/kg, or approximately 2.0 μg/kg to approximately 3.0 μg/kg, or approximately 3.0 μg/kg to approximately 5.0 μg/kg, or approximately 3.0 μg/kg to approximately 4.0 μg/kg, or approximately 2.5 μg/kg to approximately 3.5 μg/kg, or approximately 3 μg/ kg .
  4. The subcutaneous dosage form formulation according to any one of claims 1 to 3 , wherein the first h KLK1 polypeptide and the second h KLK1 polypeptide are present in the formulation in a ratio of approximately 50:50.
  5. The subcutaneous formulation according to any one of claims 1 to 4, wherein the h KLK1 polypeptide comprises an amino acid sequence having at least 95 % sequence identity with SEQ ID NO : 3 or 4 .
  6. The subcutaneous formulation according to claim 5 , wherein the h KLK1 polypeptide comprises the amino acid sequence of SEQ ID NO: 4 .
  7. A subcutaneous dosage form formulation according to any one of claims 1 to 6 , comprising a pharmaceutically acceptable excipient, diluent, adjuvant, or carrier.
  8. A subcutaneous formulation according to any one of claims 1 to 7 , substantially free of a glycosylated isoform (glycoform) of hKLK1 different from that of the first hKLK1 polypeptide or the second hKLK1 polypeptide .
  9. A subcutaneous formulation according to any one of claims 1 to 8, having an endotoxin level of less than about 1 EU per 1 mg of protein, less than about 100 ng of host cell protein per 1 mg of total protein, less than about 10 pg of host cell DNA per 1 mg of total protein, and/or being substantially free of aggregates (more than 95% appearing as a single peak by SEC HPLC).
  10. A subcutaneous formulation according to any one of claims 1 to 9 , further comprising a second agent selected from one or more (including combinations thereof) of angiotensin receptor blockers, edavalone, finelenone, and bardoxalon .
  11. The subcutaneous formulation according to claim 10, wherein the angiotensin receptor blocker is selected from one or more of losartan, azicilsartan, candesartan, eprosartan, fimasartan, irbesartan, olmesartan, supplementartan , telmisartan, and valsartan (including combinations thereof).
  12. The subcutaneous dosage form formulation according to any one of claims 1 to 11, wherein subcutaneous administration of the subcutaneous dosage form formulation achieves a therapeutically effective serum level of the h KLK1 polypeptide in the subject, and optionally maintains the therapeutically effective serum level for about or at least about 2, 4, 6, 8, 10, 12, 24, 23, 48, 60, 72, 84, 96 hours or more, or for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, or 14 days or more after subcutaneous administration.
  13. The subcutaneous formulation according to claim 12 , wherein the therapeutically effective serum level is approximately 1.0 to approximately 5.0 ng/ml, or approximately 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 mg/ml.
  14. The subcutaneous dosage form formulation according to any one of claims 1 to 13, wherein the administration of the subcutaneous dosage form formulation achieves an improved pharmacokinetic profile or biological effect compared to formulations formulated with a total dose of h KLK1 polypeptide of at least about 15 μg/kg, or at least about 20 μg/kg, or at least about 50 μg/kg, or at least about 100 μg/kg, or at least about 400 μg/kg or more.
  15. The subcutaneous dosage form formulation according to any one of claims 1 to 14, wherein the method comprises administering the subcutaneous dosage form formulation to the subject as an administration plan of approximately once or twice per day, once or twice every two days, once or twice every three days, once or twice every four days, once or twice every five days, once or twice every six days , and once or twice every week.
  16. The subcutaneous dosage form according to claim 15 , wherein the method includes administering the subcutaneous dosage form to the subject as an administration plan of approximately once a day every three days.
  17. The method comprises intravenously administering one intravenous dosage form to the subject, and then optionally administering one or more subcutaneous dosage forms to the subject subcutaneously as part of a dosage schedule of approximately once or twice per day, once or twice every two days, once or twice every three days, once or twice every four days, once or twice every five days, once or twice every six days, or once or twice every week, wherein the intravenous dosage form comprises the first hKLK1 polypeptide and the second hKLK1 polypeptide administered before the subcutaneous dosage form and formulated at a total dose of 0.5 to 1.0 μg/kg of hKLK1 polypeptide, and the first hKLK1 polypeptide and the second hKLK1 polypeptide are present in the intravenous dosage form in a ratio of 45:55 to 55:45 , according to any one of claims 1 to 16 .
  18. The subcutaneous formulation according to claim 17, wherein the intravenous administration achieves a therapeutically effective serum level of the h KLK1 polypeptide in the subject approximately 0.5, 1, 2, 3, or 4 hours after the intravenous administration, or less than approximately 0.5, 1, 2, 3, or 4 hours after the intravenous administration, and the subcutaneous administration maintains the therapeutically effective serum level for approximately or at least approximately 2, 4, 6, 8, 10, 12, 24, 23, 48, 60, 72, 84, 96 hours or more, or for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or more after the subcutaneous administration.
  19. The subcutaneous formulation according to any one of claims 1 to 18, wherein the method comprises administering a second agent selected from one or more (including combinations thereof) of angiotensin receptor blockers, edavalone, finelenone , and bardoxalone as part of the same or different formulation or composition.
  20. The subcutaneous formulation according to claim 19, wherein the angiotensin receptor blocker is selected from one or more of losartan, azilsartan, candesartan, eprosartan, fimasartan, irbesartan, olmesartan, supplementartan, telmisartan , and valsartan (including combinations thereof).

Description

Cross-reference of Related Applications This application claims priority under § 119(e) of the United States Patent Act to U.S. Provisional Patent Application No. 62/567,406 filed on 3 October 2017, U.S. Provisional Patent Application No. 62/516,463 filed on 7 June 2017, and U.S. Provisional Patent Application No. 62/469,385 filed on 9 March 2017, each of which is incorporated herein by reference in its entirety. Sequence Listing Description The sequence listing relating to this application is provided in text format instead of a paper copy and is incorporated herein by reference. The file name of this text file containing the sequence listing is DIAM_037_03WO_ST25.txt. This text file is 9KB in size, was created on March 9, 2018, and filed electronically via EFS-Web. Background Technology Embodiments of this disclosure relate to dosage forms of one or more tissue kallikrein-1 (KLK1) polypeptides having a total dose of KLK1 polypeptides ranging from about 0.1 μg/kg to about 10.0 μg/kg, including subcutaneous and intravenous dosage forms. Also provided are related devices and methods of use thereof for, for example, the treatment of ischemic and hemorrhagic conditions. Description of Related Technologies: All tissue kallikreins possess protease activity with substrate specificity similar to that of trypsin or chymotrypsin. The most characteristic activity of KLK1 is its enzymatic cleavage of kininogen, which produces bradykinin (BK)-like peptides collectively called kinins, directly or indirectly activating subtypes of both bradykinin receptors (BK-B1, BK-B2). Activation of BK receptors by kinins triggers numerous complex metabolic pathways in response to ischemia in the body, which may include improved blood flow (by vasodilation), anti-inflammatory responses, cell repair by angiogenesis or angiogenesis, and reduced apoptosis. Tissue-mediated kallikrein release increases blood flow in various tissues, including the kidneys and heart (see, e.g., Stone et al., Arterioscler Thromb Vasc Biol. 29:657-664, 2009), and a considerable number of scientific studies suggest that kallikrein therapy is likely one mode of addressing specific pathological conditions. Therefore, KLK1 is considered to have the potential to treat a wide range of clinical scenarios in which re-establishing blood flow and reducing inflammation in patients are essential for maintaining organ function, including brain, renal, and cardiac function. However, there remains a need to identify the optimal dosage form and route of administration to achieve and maintain therapeutic levels of KLK1 in humans. This disclosure addresses these and other needs. Stone et al. , Arterioscler Thromb Vasc Biol. 29:657-664, 2009 Brief Summary Embodiments of this disclosure relate to the unexpected finding that formulations of tissue kallikrein-1 (KLK1) have an inverse dose curve, where administration of a low-dose formulation up to a certain point in time exhibits an improved pharmacokinetic and/or activity profile compared to a high-dose formulation. Therefore, certain embodiments include dosage forms comprising one or more tissue kallikrein (KLK1) polypeptides formulated in a total KLK1 polypeptide dose of approximately 1.0 μg/kg to approximately 5.0 μg/kg or to approximately 10.0 μg/kg. In certain embodiments, the dosage forms are suitable for subcutaneous or intravenous administration. In some embodiments, the dosage forms are approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, Includes a total dose of KLK1 polypeptide of 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10 μg/kg (including all ranges in between). Specific dosage forms include total KLK1 polypeptide subcutaneous administration dosage forms of approximately 1.0 μg/kg to approximately 4.0 μg/kg, or approximately 1.0 μg/kg to approximately 3.0 μg/kg, or approximately 1.0 μg/kg to approximately 2.0 μg/kg, or approximately 2.0 μg/kg to approximately 5.0 μg/kg, or approximately 2.0 μg/kg to approximately 4.0 μg/kg, or approximately 2.0 μg/kg to approximately 3.0 μg/kg, or approximately 3.0 μg/kg to approximately 5.0 μg/kg, or approximately 3.0 μg/kg to approximately 4.0 μg/kg, or approximately 2.5 μg/kg to approximately 3.5 μg/kg, or approximately 3 μg/kg. Specific dosage forms include total KLK1 polypeptide intravenous dosage forms in doses of approximately 0.5 μg/kg to approximately 3.0 μg/kg, or approximately 0.5 μg/kg to approximately 2.0 μg/kg, or approximately 0.5 μg/kg to approximately 1.0 μg/kg, or approximately 0.5 μg/kg to approximately 0.8 μg/kg, or approximately 0.5 μg/kg to approx