Granted Patent B2

US 12,274,737 · App. 17/215,991 · Granted Apr 15, 2025

Inventors: Harald Rau (Dossenheim, DE); Susanne Kindermann (Liestal, CH); Torben Leßmann (Neustadt an der Weinstrasse, DE); Grethe Norskov Rasmussen (Farum, DK); Ulrich Hersel (Heidelberg, DE); Thomas Wegge (Heidelberg, DE); Kennett Sprogøe (Holte, DK)

Assignee: Ascendis Pharma Endocrinology Division A/S

A61K38/27A61K47/60A61K47/65C07K14/61

Abstract

Claims (56)

1. A method of treating a growth hormone (GH) related disease, wherein the method comprises administering once weekly an effective amount of a prodrug conjugate of the human growth hormone (hGH) to a patient having a GH related disease and wherein the prodrug conjugate of the human growth hormone (hGH) is of formula (AA)

hGH-NH-L a -S 0   (AA),

wherein

hGH-NH represents the hGH residue;

L a represents a functional group, which is self hydrolysable (auto-cleavable) by an auto-cleavage inducing group Ga; and

S 0 is a polymer chain having a molecular weight of at least 5 kDa and comprising an at least first branching structure BS 1 , the at least first branching structure BS 1 comprising an at least second polymer chain S 1 having a molecular weight of at least 4 kDa, wherein at least one of S 0 , BS 1 , S 1 further comprises the auto-cleavage inducing group G a and wherein the branching structure BS 1 further comprises an at least third polymer chain S 2 having a molecular weight of at least 4 kDa or at least one of S 0 , S 1 comprises an at least second branching structure B S 2 comprising the at least third polymer chain S 2 having a molecular weight of at least 4 kDa and wherein the molecular weight of the prodrug conjugate without the hGH-NH is at least 25 kDa and at most 1000 kDa.

2. The method of claim 1 , wherein the molecular weight of the prodrug without the hGH-NH is at least 30 kDa and at most 120 kDa.

3. The method of claim 1 , wherein the molecular weight of the prodrug without the hGH-NH is at least 40 kDa and at most 100 kDa.

4. The method of claim 1 , wherein the molecular weight of the prodrug without the hGH-NH is at least 40 kDa and at most 90 kDa.

5. The method of claim 1 , wherein L a is selected from the group consisting of and C(O)—O—, and C(O)—, which form together with the primary amino group of hGH a carbamate or amide group resulting in formula (AA1) or (AA2)

hGH-NH—C(O)O—S 0   (AA1),

hGH-NH—C(O)—S 0   (AA2).

6. The method of claim 1 , wherein L a forms together with the amino group of hGH a carbamate functional group, the cleavage of said group is induced by a hydroxyl or amino group of G a via 1,4- or 1,6 benzyl elimination of S 0 , wherein G a contains ester, carbonate, carbamate, or amide bonds that undergo rate-limiting transformation.

7. The method of claim 1 , wherein G a is an aromatic ring or fluorenylmethyl directly attached to a carbamate functional group formed by L a and the primary amino group of hGH.

8. The method of claim 1 , wherein at least one of the branching structures BS 1 , BS 2 comprises a further fourth polymer chain S 3 having a molecular weight of at least 4 kDa or one of S 0 , S 1 , S 2 comprises a third branching structure BS 3 comprising the at least fourth polymer chain S 3 having a molecular weight of at least 4 kDa.

9. The method of claim 1 , wherein the at least three chains S 0 , S 1 , S 2 are independently based on a polymer selected from the group consisting of polyalkyloxy polymers, hyaluronic acid and derivatives thereof, polyvinyl alcohols, polyoxazolines, polyanhydrides, poly(ortho esters), polycarbonates, polyurethanes, polyacrylic acids, polyacrylamides, polyacrylates, polymethacrylates, polyorganophosphazenes, polysiloxanes, polyvinylpyrrolidone, polycyanoacrylates, and polyesters.

10. The method of claim 1 , wherein the at least three chains S 0 , S 1 , S 2 are based on a polyalkoxy polymer.

11. The method of claim 1 , wherein the shortest distance between the attachment site of S 0 to L a and the first branching structure BS 1 measured as connected atoms is less than 50 atoms.

12. The method of claim 11 , wherein the shortest distance is less than 20 atoms.

13. The method of claim 1 , wherein S 0 is of formula (AAA1)

wherein

G a is an auto-cleavage inducing group;

S 00 is CH 2 ; or C(O);

S 0A is an alkylene chain having from 1 to 20 carbon atoms, which is optionally interrupted or terminated by one or more groups, cycles or heteroatoms selected from the group consisting of optionally substituted heterocycle; O; S; C(O); and NH;

BS 1 , BS 2 , BS 3 are independently selected from the group consisting of N; and CH;

S 0B , S 1A are independently an alkylene chain having from 1 to 200 carbon atoms, which is optionally interrupted or terminated by one or more groups, cycles or heteroatoms selected from the group consisting of optionally substituted heterocycle; O; S; C(O); and NH;

S 0C , S 1B , are (C(O)) n2 (CH 2 ) n1 (OCH 2 CH 2 ) n OCH 3 , wherein each n is independently an integer from 100 to 500, each n1 is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8, and n2 is 0 or 1;

S 2 , S 3 are independently hydrogen; or (C(O)) n2 (CH 2 ) n1 (OCH 2 CH 2 ) n OCH 3 , wherein each n is independently an integer from 100 to 500, each n1 is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8, and n2 is 0 or 1, provided that at least one of S 2 , S 3 is other than hydrogen;

R 2 , R 3 are selected independently from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tertiary butyl.

14. The method of claim 1 , wherein G a is OC(O)—R and R is of formula (I), which is

wherein R1, R4, R5 are selected independently from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl; and

n=1 or 2.

15. The method of claim 14 , wherein R is selected from the group consisting of:

16. The method of claim 1 , wherein L a -S 0 is represented by formula (AAA2),

wherein the dashed line indicates the attachment to the primary amino group of hGH so that L a and the amino group form an amide bond;

X is C(R 4 R 4a ); N(R 4 ); O; C(R 4 R 4a )—C(R 5 R 5a ); C(R 5 R 5a )—C(R 4 R 4a ); C(R 4 R 4a )—N(R 6 ); N(R 6 )—C(R 4 R 4a ); C(R 4 R 4a )—O; or O—C(R 4 R 4a );

X 1 is C; or S(O);

X 2 is C(R 7 , R 7a ); or C(R 7 , R 7a )—C(R 8 , R 8a );

R 1 , R 1a , R 2 , R 2a , R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 7 , R 7a , R 8 , R 8a are independently selected from the group consisting of H; and C 1-4 alkyl; or

optionally, one or more of the pairs R 1a /R 4a , R 1a /R 5a , R 4a /R 5a , R 4a /R 5a , R 7a /R 8a form a chemical bond;

optionally, one or more of the pairs R 1 /R 1a , R 2 /R 2a , R 4 /R 4a , R 5 /R 5a , R 7 /R 7a , R 8 /R 8a are joined together with the atom to which they are attached to form a C 3-7 cycloalkyl; or 4 to 7 membered heterocyclyl;

optionally, one or more of the pairs R 1 /R 4 , R 1 /R 5 , R 1 /R 6 , R 4 /R 5 , R 7 /R 8 , R 2 /R 3 are joined together with the atoms to which they are attached to form a ring A;

optionally, R 3 /R 3a are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered heterocycle;

A is selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; C 3-10 cycloalkyl; 4 to 7 membered heterocyclyl; and 9 to 11 membered heterobicyclyl; and

wherein S 0 is substituted with one group L 2 -Z and optionally further substituted, provided that the hydrogen marked with the asterisk in formula (I) is not replaced by a substituent; wherein

L 2 is a single chemical bond or a spacer; and

Z is of formula (AAA2a)

wherein

S 00 is CH 2 ; or C(O);

S 0A is an alkylene chain having from 1 to 20 carbon atoms, which is optionally interrupted or terminated by one or more groups, cycles or heteroatoms selected from the group consisting of optionally substituted heterocycle; O; S; C(O); and NH;

BS 1 , BS 2 , BS 3 are independently selected from the group consisting of N; and CH;

S 0B , S 1A are independently an alkylene chain having from 1 to 200 carbon atoms, which is optionally interrupted or terminated by one or more groups, cycles or heteroatoms selected from the group consisting of optionally substituted heterocycle; O; S; C(O); and NH;

S 0C , S 1B are (C(O)) n2 (CH 2 ) n1 (OCH 2 CH 2 ) n OCH 3 , wherein each n is independently an integer from 100 to 500, each n1 is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8, and n2 is 0 or 1; and

S 2 , S 3 are independently hydrogen; or (C(O)) n2 (CH 2 ) n1 (OCH 2 CH 2 ) n OCH 3 , wherein each n is independently an integer from 100 to 500, each n1 is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8, and n2 is 0 or 1, provided that at least one of S 2 , S 3 is other than hydrogen.

17. The method of claim 1 , wherein the GH related disease is selected from the group consisting of growth hormone deficiency (“GHD”), adult onset growth hormone deficiency, Turner syndrome, Prader-Willi syndrome, short bowel syndrome, chronic renal insufficiency, small for gestational age (“SGA”), AIDS wasting, anti-ageing, rheumatoid arthritis, idiopathic small stature, short stature homeobox gene, somatopause, Noonan syndrome, skeletal dysplasia, Down syndrome, short stature associated with prolonged steroid use, Aarskog's syndrome, chronic renal disease, juvenile rheumatoid arthritis; cystic fibrosis, HIV-infection in children receiving HAART treatment; short stature in children born with very low birth weight but SGA; skeletal dysplasia; hypochondroplasia; achondroplasia; idiopathic short stature; GHD in adults; fractures in or of long bones, such as tibia, fibula, femur, humerus, radius, ulna, clavicula, metacarpea, metatarsea, and digit; fractures in or of spongious bones, such as the scull, base of hand, and base of food; patients after tendon or ligament surgery in hand, knee, or shoulder; distraction osteogenesis; disorders resulting from hip or discus replacement, meniscus repair, spinal fusions or prosthesis fixation; disorders resulting from fixing of osteosynthesis material; non-union or mal-union of fractures; disorders resulting from osteotomia; disorders resulting from graft implantation; articular cartilage degeneration in knee caused by trauma or arthritis; osteoporosis in patients with Turner syndrome; osteoporosis in men; adult patients in chronic dialysis (“APCD”); malnutritional associated cardiovascular disease in APCD; reversal of cachexia in APCD; cancer in APCD; chronic abstractive pulmonal disease in APCD; HIV in APCD; elderly with APCD; chronic liver disease in APCD, fatigue syndrome in APCD; Crohn's disease; impaired liver function; males with HIV infections; short bowel syndrome; central obesity; HIV-associated lipodystrophy syndrome; male infertility; patients after major elective surgery, alcohol/drug detoxification or neurological trauma; aging; frail elderly; osteo-arthritis; traumatically damaged cartilage; erectile dysfunction; fibromyalgia; memory disorders; depression; traumatic brain injury; subarachnoid haemorrhage; very low birth weight; metabolic syndrome; glucocorticoid myopathy; and short stature due to glucocorticoid treatment in children.

18. The method of claim 1 , wherein the GH related disease is growth hormone deficiency.

Priority Claims (3)

Continuity (4)

References Cited (220)