US 12,303,553 B2
Long-acting growth hormone dosage forms with superior efficacy to daily somatropin
Kennett Sprogøe, Hellerup (DK)
Assigned to ASCENDIS PHARMA ENDOCRINOLOGY DIVISION A/S, Hellerup (DK)
Appl. No. 17/310,993
Filed by Ascendis Pharma Endocrinology Division A/S, Hellerup (DK)
PCT Filed Mar. 3, 2020, PCT No. PCT/EP2020/055513
§ 371(c)(1), (2) Date Sep. 3, 2021,
PCT Pub. No. WO2020/178273, PCT Pub. Date Sep. 10, 2020.
Claims priority of application No. 19160459 (EP), filed on Mar. 4, 2019.
Prior Publication US 2022/0088147 A1, Mar. 24, 2022
Int. Cl. A61K 38/27 (2006.01); A61K 9/00 (2006.01); A61K 9/19 (2006.01); A61P 5/06 (2006.01)
CPC A61K 38/27 (2013.01) [A61P 5/06 (2018.01)] 12 Claims
 
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)

OG Complex Work Unit Chemistry
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;
═Y1, ═Y5 are selected independently from the group consisting of ═O and ═S;
—Y2—, —Y3— are selected from the group consisting of —O— and —S—;
—Y4— is selected from the group consisting of —O—, —NR5— and —C(R6R6a)—;
—R1 is a carrier;
—R2, —R3, —R5, —R6, —R6a 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;
—R4 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 C1-20 alkyl optionally interrupted by one or more groups selected from the group consisting of C3-10 cycloalkyl, 8- to 30-membered carbopolycyclyl, 3- to 10-membered heterocyclyl, —C(O)—, —C(O)N(R7)—, —O—, —S— and —N(R7)—;
-Nu is a nucleophile selected from the group consisting of —N(R7R7a), —N(R7OH), —N(R7)—N(R7aR7b), —S(R7), —COOH,

OG Complex Work Unit Chemistry
—Ar— is selected from the group consisting of

OG Complex Work Unit Chemistry
wherein
dashed lines indicate attachment to the rest of the long-acting growth hormone,
—Z1— is selected from the group consisting of —O—, —S— and —N(R7)—, and
—Z2— is —N(R7)—; and
—R7, —R7a, —R7b are independently of each other selected from the group consisting of —H, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
wherein the long-acting growth hormone of formula (Ia) and (Ib) is optionally further substituted.