PHARMACEUTICAL COMPOUND FOR THE TREATMENT OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

Abstract

The invention provides a polypeptide dimer comprising two gp130-Fc fusion peptides for use in the treatment of ASCVD in human patients, preferably of high-risk ASCVD in human patients, more preferably of very-high-risk ASCVD in human patients.

Claims

1. A polypeptide dimer comprising two gp130-Fc monomers, each monomer having at least 90% sequence identity to SEQ ID NO: 1, for use in the treatment of human patients with atherosclerotic cardiovascular disease (ASCVD).

2. The polypeptide dimer according to claim 1, for use in the manufacture of a medicament for treatment of human patients with ASCVD.

3. The polypeptide dimer for use according to any one of the preceding claims, wherein the ASCVD is very-high-risk ASCVD.

4. The polypeptide dimer for use according to any one of the preceding claims, wherein the monomers comprise the gp130 D6 domain comprising the amino acids at positions 585-595 of SEQ ID NO:1, an Fc domain hinge region comprising the amino acids at positions 609-612 of SEQ ID NO:1, and the monomers do not comprise a linker between the gp130 part and the Fc part.

5. The polypeptide dimer according to any one of the preceding claims, for use in the treatment of human patients with ASCVD, characterized in that the human patients are non-responders to treatment with or intolerant to treatment with one or more of a statin, ezetimibe, and an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9 inhibitor).

6. The polypeptide dimer for use in treatment according to any one of the preceding claims, characterized in that the human patient does not respond to or is intolerant to a combination of a statin and ezetimibe.

7. The polypeptide dimer for use in treatment according to any one of the preceding claims, characterized in that the human patient does not respond to or is intolerant to a combination of a statin and a PCSK9 inhibitor.

8. The polypeptide dimer for use in treatment according to any one of the preceding claims, characterized in that the human patient does not respond to or is intolerant to a combination of ezetimibe and a PCSK9 inhibitor.

9. The polypeptide dimer for use in treatment according to any one of the preceding claims, characterized in that the human patient does not respond to or is intolerant to a combination of a statin, ezetimibe, and a PCSK9 inhibitor.

10. The polypeptide dimer for use in treatment according to any one of the preceding claims, characterized in that the human patient is classified as a non-responder to one or more of a statin, ezetimibe, and a PCSK9 inhibitor based upon detection of a biomarker for non-response.

11. The polypeptide dimer for use in treatment according to any one of the preceding claims, characterized in that the biomarker for non-response to treatment with one or more of a statin, ezetimibe, and a PCSK9 inhibitor, is the insufficient reduction of blood levels of LDL cholesterol and/or plasma levels of LDL cholesterol and/or serum levels of LDL cholesterol compared to objective expectations based on the treatment targets in current guidelines, the dosing recommendations of the respective drugs, and/or the outcomes of clinical trials investigating changes of LDL cholesterol levels under treatment with the respective drugs.

12. The polypeptide dimer for use in treatment according to any one of the preceding claims, characterized in that the human patient does not respond to or is intolerant to lipid apheresis therapy.

13. The polypeptide dimer for use in treatment according to any one of the preceding claims, characterized in that the use reduces one or more of atherosclerotic plaque size, intima media thickness, and arterial wall inflammation.

14. The polypeptide dimer for use in treatment according to any one of the preceding claims, characterized in that the ASCVD is low density lipoprotein-driven ASCVD, triglyceride-driven ASCVD, lipoprotein a-driven ASCVD, chronic inflammatory disease-driven ASCVD, or inflammatory ASCVD.

15. The polypeptide dimer for use in treatment according to any one of the preceding claims, characterized in that the human patient has one or more of familial hypercholesterolemia, chronic kidney disease, diabetes mellitus, blood pressure greater than 180/110 mm Hg, and human immunodeficiency virus infection.

16. The polypeptide dimer for use in treatment according to any one of the preceding claims, characterized in that the use comprises a dose for administration of 60 mg to 1 g of the polypeptide dimer, preferably 150 to 600 mg.

17. The polypeptide dimer for use in treatment according to any one of the preceding claims, characterized in that the use is for administration once per every 1 to 4 weeks, preferably every 1 to 2 weeks.

18. A method for treating atherosclerotic cardiovascular disease (ASCVD) in a human patient, said method comprising administering to a patient in need thereof a therapeutically effective amount of a polypeptide dimer comprising two gp130-Fc monomers, each monomer having at least 90% sequence identity to SEQ ID NO: 1.

Description

FIGURE LEGENDS

[0040] FIG. 1: Inhibition of IL-6 trans-signaling reduces intima media thickness and atherosclerotic plaque size in end-stage atherosclerosis. The figure shows representative images of the ultrasound evaluation of Patient 1 at baseline and 12 weeks after the beginning of olamkicept treatment (4 infusions of 600 mg i.v. biweekly; Table 1); (A) Intima media thickness (IMT) before therapy: right carotid artery 0.93 mm, left 0.98 mm (not shown); (B) IMT after therapy: right 0.86 mm, left 0.89 mm (not shown); (C) Abdominal aorta before therapy showing an atherosclerotic plaque; (D) Same site of the abdominal aorta after resolution of the atherosclerotic plaque under olamkicept treatment.

[0041] FIG. 2: Inhibition of IL-6 trans-signaling reduces arterial wall inflammation and macrophage infiltration of atherosclerotic plaques in end-stage atherosclerosis. The figure shows arterial wall inflammation in the carotid arteries of Patient 2 (A) at baseline and (B) 11 weeks after the beginning of olamkicept treatment (6 infusions of 600 mg i.v. biweekly; Table 1). In the representative axial computed tomography (CT), .sup.18fluorodeoxyglucose positron emission tomography (.sup.18FDG PET), and fused images (.sup.18FDG PET/CT), regions of interest are highlighted by bold circles (artery) and narrow circles (vein). Mean and maximum target-to-background ratio (TBR.sub.mean and TBR.sub.max) are listed below.

[0042]

TABLE-US-00001 TABLE 1 Patient characteristics Days 0 3 7 14 21 28 42 56 70 73 77 84 Patient 1 Leukocytes [×10.sup.9/L] 6.2 8.16 7.16 9.03 — 6.04 6.02 — — — 6.77 — Hemoglobin [g/dL] 15.5 15.3 15.1 14.9 — 15.0 15.0 — — — 15.6 — Platelet [×10.sup.9/L] 168 171 166 166 — 140 151 — — — 177 — International Normalized Ratio 0.95 0.98 0.99 0.99 — 1.03 0.98 — — — 0.95 — D-dimer [mg/L] 0.24 <0.22 <0.22 0.32 — 0.28 0.31 — — — 0.28 — Sodium [mmol/L] 138 140 139 139 — 139 138 — — — 139 — Potassium [mmol/L] 3.67 3.56 3.87 3.59 — 3.44 3.52 — — — 3.94 — Calcium, albumin- 2.14 2.1 2.21 2.15 — — — — — — 2.23 — corrected [mmol/L] Glomerular filtration 76 75 73 69 — 82 73 — — — 79 — rate [mL/min/1.73] Apolipoprotein B [mg/dL] 46 43 55 60 — 55 62 — — — 59 — Bilirubin [μmol/L] 25.5 24.7 29.3 26.4 — 35.5 31.1 — — — 26.4 — Creatine kinase [U/L] 197 204 270 251 — 294 294 — — — 227 — Alanine amino-transferase [U/L] 42.0 39.3 46.7 43.1 — 51.1 56.1 — — — 36.2 — γ-glutamyl transferase [U/L] 20 21 23 23 — 21 21 — — — 22 — Lipase [U/L] 32 34 27 26 — 26 24 — — — 27 — Interleukin-6 [pg/mL] <1.5 4.1 3.6 2.6 — 2.8 3.7 — — — <1.5 — Soluble interleukin-6 receptor 40.13 — — 37.95 — 38.18 35.78 — — — 42.53 — [ng/mL] Soluble gp130 (including 485.53 — — 808.95 — 990.12 1019.64 — — — 596.91 — olamkicept) [ng/mL] Patient 2 Leukocytes [×10.sup.9/L] 10.7 10.4 — 10.2 10.8 11.0 10.7 11.9 10.3 8.54 11.0 — Hemoglobin [g/dL] 15.6 16.7 — 15.7 16.1 15.7 15.3 15.5 15.9 15.6 16.1 — Platelet [×10.sup.9/L] 200 203 — 173 179 193 175 178 195 84 191 — International Normalized Ratio 1.01 — — 1.02 0.99 096 1.05 1.01 1.06 — — — D-dimer |mg/L] 0.34 — — 0.31 0.34 0.47 0.32 0.26 0.32 — — — Sodium [mmol/L] 141 140 — 143 143 139 140 144 140 — — — Potassium [mmol/L] 3.84 3.75 — 3.91 3.99 4.05 3.94 4.03 3.92 — — — Calcium, albumin- 2.38 2.44 — 2.44 — — — 2.54 2.49 — 2.4 — corrected [mmol/L] Glomerular filtration 60 68 — 60 67 73 63 60 63 — — — rate [mL/min/1.73] Apolipoprotein B [mg/dL] 51 — — 56.0 61.0 53.0 51.0 51.0 53.0 — 66.0 — Bilirubin [μmol/L] 7.4 8.3 — 9.1 9.0 7.4 8.5 5.1 8.8 — — — Creatine kinase [U/L] 42 37 — 28 37 30 27 54 35 — — — Alanine amino-transferase [U/L] 13.8 15.5 — 15.0 16.8 13.0 19.0 15.9 13.8 — — — γ-glutamyl transferase [U/L] 40 41 — 32 39 39 37 38 40 — — — Lipase [U/L] 33 41 — 33 34 36 32 29 33 — — — Interleukin-6 [pg/mL] 4.8 32.0 — 9.8 24.3 12.0 11.7 15.5 11.7 40.6 26.8 — Soluble interleukin-6 receptor 60.84 — — 61.18 — 66.67 70.45 53.86 60.84 64.15 54.54 — [ng/mL] Soluble gp130 (including 319.12 — — 983.41 — 1094.79 1281.33 1061.24 1014.27 2620.65 1865.10 — olamkicept) [ng/mL]

TABLE-US-00002 TABLE 2 Treatment schedule, diagnostics, and metabolic parameters Days 0 3 7 14 21 28 42 56 70 73 77 84 Patient 1 Olamkicept x — — x — x x — — — — — Ultrasound x — — — — — — — — — — x Cholesterol [mmol/L] 2.8 2.9 3.2 3.6 — 3.1 3.3 — — — 3.2 — HDL (high-density lipoprotein) 1.59 1.48 1.65 1.65 — 1.35 1.6 — — — 1.56 — cholesterol [mmol/L] LDL (low-density lipoprotein) 1.32 1.21 1.57 1.89 — 1.55 1.79 — — — 1.65 — cholesterol [mmol/L] Triglycerides [mmol/L] 0.8 1.8 0.8 0.9 — 1.0 0.8 — — — 1.1 — Lipoprotein (a) [nmol/L] 296.6 267.1 276.7 291.3 — 336.7 283.7 — — — 303.1 — high-sensitivity C-reactive protein 0.37 <0.3 0.6 <0.3 — 0.37 0.68 — — — 0.65 — [mg/dL] HbA1c (glycated haemoglobin) [%] 5.0 — — — — — — — — — 5.2 — Patient 2 Olamkicept x — — x — x x x x — — — PET/CT x — — — — — — — — — x — Cholesterol [mmol/L] 2.7 3.1 — 2.9 3.1 2.9 2.6 2.6 2.7 — 3.0 — HDL (high-density lipoprotein) 1.0 1.15 — 1.08 1.05 1.03 0.97 1.04 0.97 — 1.19 — cholesterol [mmol/L] LDL (low-density lipoprotein) 1.3 1.65 — 1.4 1.62 1.36 1.21 1.27 1.34 — 1.48 — cholesterol [mmol/L] Triglycerides [mmol/L] 2.2 2.2 — 2.0 2.4 2.0 2.2 2.1 2.2 — 1.7 — Lipoprotein (a) [nmol/L] 238.7 250.2 — 227.2 236.7 241.1 234.2 225.7 243.0 — 231.7 — high-sensitivity C-reactive protein 9.18 3.33 — 12.7 7.06 9.99 11.2 18.9 14.4 4.1 7.14 — [mg/dL] HbA1c (glycated haemoglobin) [%] 6.7 — — — — — — — — — 6.5 —

TABLE-US-00003 SEQUENCE LISTING <210>   1 <211> 822 <212> PRT <213> Artificial Sequence <220> <223> polypeptide dimer comprising two gp130-Fc fusion peptides <220> <221> CHAIN <222> 585 . . . 595 <223> part of gp130 D6 domain <220> <221> CHAIN <222> 690 . . . 612 <223> part of Fc domain hinge region <400>   1 Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser Pro Glu Ser Pro Val Val 1               5                   10                  15 Gln Leu His Ser Asn Phe Thr Ala Val Cys Val Leu Lys Glu Lys Cys             20                  25                  30 Met Asp Tyr Phe His Val Asn Ala Asn Tyr Ile Val Trp Lys Thr Asn         35                  40                  45 His Phe Thr Ile Pro Lys Glu Gln Tyr Thr Ile Ile Asn Arg Thr Ala     50                  55                  60 Ser Ser Val Thr Phe Thr Asp Ile Ala Ser Leu Asn Ile Gln Leu Thr 65                  70                  75                  80 Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu Gln Asn Val Tyr Gly Ile                 85                  90                  95 Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys Pro Lys Asn Leu Ser Cys             100                 105                 110 Ile Val Asn Glu Gly Lys Lys Met Arg Cys Glu Trp Asp Gly Gly Arg         115                 120                 125 Glu Thr His Leu Glu Thr Asn Phe Thr Leu Lys Ser Glu Trp Ala Thr     130                 135                 140 His Lys Phe Ala Asp Cys Lys Ala Lys Arg Asp Thr Pro Thr Ser Cys 145                 150                 155                 160 Thr Val Asp Tyr Ser Thr Val Tyr Phe Val Asn Ile Glu Val Trp Val                 165                 170                 175 Glu Ala Glu Asn Ala Leu Gly Lys Val Thr Ser Asp His Ile Asn Phe             180                 185                 190 Asp Pro Val Tyr Lys Val Lys Pro Asn Pro Pro His Asn Leu Ser Val         195                 200                 205 Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu Thr Trp Thr Asn     210                 215                 220 Pro Ser Ile Lys Ser Val Ile Ile Leu Lys Tyr Asn Ile Gln Tyr Arg 225                 230                 235                 240 Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile Pro Pro Glu Asp Thr Ala                 245                 250                 255 Ser Thr Arg Ser Ser Phe Thr Val Gln Asp Leu Lys Pro Phe Thr Glu             260                 265                 270 Tyr Val Phe Arg Ile Arg Cys Met Lys Glu Asp Gly Lys Gly Tyr Trp         275                 280                 285 Ser Asp Trp Ser Glu Glu Ala Ser Gly Ile Thr Tyr Glu Asp Arg Pro     290                 295                 300 Ser Lys Ala Pro Ser Phe Trp Tyr Lys Ile Asp Pro Ser His Thr Gln 305                 310                 315                 320 Gly Tyr Arg Thr Val Gln Leu Val Trp Lys Thr Leu Pro Pro Phe Glu                 325                 330                 335 Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val Thr Leu Thr Arg Trp Lys             340                 345                 350 Ser His Leu Gln Asn Tyr Thr Val Asn Ala Thr Lys Leu Thr Val Asn         355                 360                 365 Leu Thr Asn Asp Arg Tyr Leu Ala Thr Leu Thr Val Arg Asn Leu Val     370                 375                 380 Gly Lys Ser Asp Ala Ala Val Leu Thr Ile Pro Ala Cys Asp Phe Gln 385                 390                 395                 400 Ala Thr His Pro Val Met Asp Leu Lys Ala Phe Pro Lys Asp Asn Met                 405                 410                 415 Leu Trp Val Glu Trp Thr Thr Pro Arg Glu Ser Val Lys Lys Tyr Ile             420                 425                 430 Leu Glu Trp Cys Val Leu Ser Asp Lys Ala Pro Cys Ile Thr Asp Trp         435                 440                 445 Gln Gln Glu Asp Gly Thr Val His Arg Thr Tyr Leu Arg Gly Asn Leu     450                 455                 460 Ala Glu Ser Lys Cys Tyr Leu Ile Thr Val Thr Pro Val Tyr Ala Asp 465                 470                 475                 480 Gly Pro Gly Ser Pro Glu Ser Ile Lys Ala Tyr Leu Lys Gln Ala Pro                 485                 490                 495 Pro Ser Lys Gly Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn Glu             500                 505                 510 Ala Val Leu Glu Trp Asp Gln Leu Pro Val Asp Val Gln Asn Gly Phe         515                 520                 525 Ile Arg Asn Tyr Thr Ile Phe Tyr Arg Thr Ile Ile Gly Asn Glu Thr     530                 535                 540 Ala Val Asn Val Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser Leu 545                 550                 555                 560 Thr Ser Asp Thr Leu Tyr Met Val Arg Met Ala Ala Tyr Thr Asp Glu                 565                 570                 575 Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe Ala             580                 585                 590 Gln Gly Glu Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu         595                 600                 605 Ala Glu Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp     610                 615                 620 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 625                 630                 635                 640 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly                 645                 650                 655 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn             660                 665                 670 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp         675                 680                 685 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro     690                 695                 700 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 705                 710                 715                 720 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn                 725                 730                 735 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile             740                 745                 750 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr         755                 760                 765 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys     770                 775                 780 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 785                 790                 795                 800 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu                 805                 810                 815 Ser Leu Ser Pro Gly Lys             820 <210>   2 <211>  11 <212> PRT <213> Artificial Sequence <220> <223> part of gp130 D6 domain, amino acids No 585 . . . 595 of SEQ ID NO: 1 <400>   2 Thr Phe Thr Thr Pro Lys Phe Ala Gln Gly Glu 1               5                   10 <210>   3 <211>   4 <212> PRT <213> Artificial Sequence <220> <223> part of Fc domain hinge region, amino acids No 609 . . . 612 of SEQ ID NO: 1 <400>   3 Ala Glu Gly Ala 1