Granted Patent B2

US 12,303,553 · App. 17/310,993 · Granted May 20, 2025

Inventor: Kennett Sprogøe (Hellerup, DK)

Assignee: ASCENDIS PHARMA ENDOCRINOLOGY DIVISION A/S

A61K38/27A61P5/06

Abstract

Claims (45)

1. A method of treating growth hormone deficiency in a patient who is a non-responder to treatment with daily human growth hormone, the method comprising the step of administering a therapeutically effective amount of a long-acting growth hormone or a pharmaceutical formulation comprising such long-acting growth hormone, wherein the patient has previously been treated with daily administration of a human growth hormone of SEQ ID NO: 1 in a dose ranging from 0.17 mg/kg/week to 0.30 mg/kg/week and has an annualized height velocity of less than 8.0 cm per year, wherein the long-acting growth hormone is of formula (Ia) or (Ib)

wherein

-D is a hGH moiety connected to the rest of the molecule through an amine functional group;

n is 0, 1, 2, 3, or 4;

—X— is a chemical bond or a spacer;

═Y 1 , ═Y 5 are selected independently from the group consisting of ═O and ═S;

—Y 2 —, —Y 3 — are selected from the group consisting of —O— and —S—;

—Y 4 — is selected from the group consisting of —O—, —NR 5 — and —C(R 6 R 6a )—;

—R 1 is a carrier;

—R 2 , —R 3 , —R 5 , —R 6 , —R 6a are independently of each other selected from the group consisting of —H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl;

—R 4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl;

—W— is selected from the group consisting of C 1-20 alkyl optionally interrupted by one or more groups selected from the group consisting of C 3-10 cycloalkyl, 8- to 30-membered carbopolycyclyl, 3- to 10-membered heterocyclyl, —C(O)—, —C(O)N(R 7 )—, —O—, —S— and —N(R 7 )—;

-Nu is a nucleophile selected from the group consisting of —N(R 7 R 7a ), —N(R 7 OH), —N(R 7 )—N(R 7a R 7b ), —S(R 7 ), —COOH,

—Ar— is selected from the group consisting of

wherein

dashed lines indicate attachment to the rest of the long-acting growth hormone,

—Z 1 — is selected from the group consisting of —O—, —S— and —N(R 7 )—, and

—Z 2 — is —N(R 7 )—; and

—R 7 , —R 7a , —R 7b are independently of each other selected from the group consisting of —H, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;

wherein the long-acting growth hormone of formula (Ia) and (Ib) is optionally further substituted.

2. The method of claim 1 , wherein the growth hormone deficiency is growth hormone deficiency in children.

3. The method of claim 1 , wherein the long acting growth hormone is administered in consecutive administrations 1 week apart.

4. The method of claim 1 , wherein the pharmaceutical formulation is a dry formulation.

5. The method of claim 1 , wherein the long-acting growth hormone is ACP-011.

6. The method of claim 1 , wherein —R 1 of formula (Ia) and (Ib) comprises a moiety of formula (II)

wherein

—BP 1 <, —BP 2 <, —BP 3 < are independently of each other selected from the group consisting of —N< and —C(R 8 )<;

R 8 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;

—P 1 , —P 2 , —P 3 , —P 4 are independently of each other a PEG-based chain comprising at least 40% PEG and having a molecular weight ranging from 5 to 30 kDa;

—C 1 —, —C 2 — are independently of each other selected from the group consisting of C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more R 9 , which are the same or different and wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R 10 )—, —S(O) 2 N(R 10 )—, —S(O) N(R 10 )—, —S(O) 2 —, —S(O)—, —N(R 10 )S(O) 2 N(R 10a )—, —S—,

—N(R 10 )—, —OC(OR 10 ) (R 10a )—, —N(R 10 )C(O)N(R 10a )—, and —OC(O)N(R 10 )—;

each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each Tis independently optionally substituted with one or more R 9 , which are the same or different;

each R 9 is independently selected from the group consisting of halogen, —CN, oxo (═O), —COOR 11 , —OR 11 , —C(O) R 11 , —C(O)N(R 11 R 11a ), —S(O) 2 N(R 11 R 11a ), —S(O) N(R 11 R 11a ), —S(O) 2 R 11 , —S(O) R 11 , —N(R 11 )S(O) 2 N(R 11a R 11b ), —SR 11 , —N(R 11 R 11a ), —NO 2 , —OC(O) R 11 , —N(R 11 ) C(O) R 11a , —N(R 11 )S(O) 2 R 11a , —N(R 11 ) S(O) R 11a , —N(R 11 ) C(O) OR 11a , —N(R 11 )C(O)N(R 11a R 11b ), —OC(O)N(R 11 R 11a ), and C 1-6 alkyl; wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and

each R 10 , R 10a , R 11 , R 11a and R 11b is independently selected from the group consisting of —H, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.

7. The method of claim 1 , wherein —R 1 comprises a moiety of formula (IIc):

wherein

p1, p2, p3, p4 are independently an integer ranging from 170 to 284.

8. The method of claim 1 , wherein the long-acting growth hormone is a polymeric hGH prodrug of formula (IV)

wherein

D is a hGH moiety connected to the rest of the molecule through an amine functional group; and

p1, p2, p3, p4 are independently an integer ranging from 170 to 284.

9. The method of claim 8 , wherein p1, p2, p3, p4 are independently an integer ranging from 198 to 255.

10. The method of claim 9 , wherein the hGH moiety is a polypeptide of SEQ ID NO:1.

11. The method of claim 10 , wherein each administration of the long-acting growth hormone is at a dose of at least 0.16 mg/kg/week human growth hormone equivalents.

12. The method of claim 1 , wherein the dose-of the long-acting growth hormone ranges from 0.24 mg/kg/week to 0.3 mg/kg/week human growth hormone equivalents.

Assignments (2)

Priority Claims (1)

Continuity (1)

References Cited (221)