IP Library › Granted Patent US 12,233,106
Granted Patent B2
US 12,233,106 · App. 17/811,748 · Granted Feb 25, 2025

C-type natriuretic peptide variants to treat skeletal dysplasia in children

Inventors: Jonathan Day (Buckinghamshire, GB); Elena Fisheleva (Novato, CA)
Assignee: BIOMARIN PHARMACEUTICAL INC.
A61K38/2242A61K9/0019A61K38/1709A61K47/10A61K47/12A61K47/183A61K9/19
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Quick Facts
Patent No.
US 12,233,106
App. No.
17/811,748
Granted
Feb 25, 2025
Kind
B2
Abstract

treatment of skeletal dysplasias in children, and improvement in one or more symptoms of skeletal dysplasias, such as long bone growth or growth velocity, by administering variants of C-type natriuretic peptide (CNP) is described.

Claims (263)

1. A method of treating skeletal dysplasia in a subject about 0 month to about 2 years old comprising administering to the subject a composition comprising a C-type natriuretic peptide (CNP) variant in an amount effective to treat the skeletal dysplasia in the subject, wherein the CNP variant is selected from the group consisting of:

(Pro-Gly-CNP37)

(SEQ ID NO: 1)

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Gly-CNP53)

(SEQ ID NO: 2)

GDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMS

GLGC;

(Pro-CNP53)

(SEQ ID NO: 3)

PDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMS

GLGC;

(Met-CNP53)

(SEQ ID NO: 4)

MDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMS

GLGC;

[CNP-53(M48N)]

(SEQ ID NO:)

DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSG

LGC;

(CNP-52)

(SEQ ID NO: 6)

LRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGL

GC;

(CNP-51)

(SEQ ID NO: 7)

RVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLG

C;

(CNP-50)

(SEQ ID NO: 8)

VDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLG

C;

(CNP-49)

(SEQ ID NO: 9)

DTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-48)

(SEQ ID NO: 10)

TKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-47)

(SEQ ID NO: 11)

KSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-46)

(SEQ ID NO: 12)

SRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-45)

(SEQ ID NO: 13)

RAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-44)

(SEQ ID NO: 14)

AAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-43)

(SEQ ID NO: 15)

AWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-42)

(SEQ ID NO:16)

WARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-41)

(SEQ ID NO: 17)

ARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-40)

(SEQ ID NO: 18)

RLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-39)

(SEQ ID NO: 19)

LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-38)

(SEQ ID NO: 20)

LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-37)

(SEQ ID NO: 21)

QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-36)

(SEQ ID NO: 22)

EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-35)

(SEQ ID NO: 23)

HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-34)

(SEQ ID NO: 24)

PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-33)

(SEQ ID NO: 25)

NARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-32)

(SEQ ID NO: 26)

ARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-31)

(SEQ ID NO: 27)

RKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-30)

(SEQ ID NO: 28)

KYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-29)

(SEQ ID NO: 29)

YKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-28)

(SEQ ID NO: 30)

KGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-27)

(SEQ ID NO: 31)

GANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-26)

(SEQ ID NO: 32)

ANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-25)

(SEQ ID NO: 33)

NKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-24)

(SEQ ID NO: 34)

KKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-23)

(SEQ ID NO: 35)

KGLSKGCFGLKLDRIGSMSGLGC;

(CNP-21)

(SEQ ID NO: 36)

LSKGCFGLKLDRIGSMSGLGC;

(CNP-20)

(SEQ ID NO: 37)

SKGCFGLKLDRIGSMSGLGC;

(CNP-19)

(SEQ ID NO: 38)

KGCFGLKLDRIGSMSGLGC;

(CNP-18)

(SEQ ID NO: 39)

GCFGLKLDRIGSMSGLGC;

[CNP37(M32N)

(SEQ ID NO: 40)

QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Pro-CNP37)

(SEQ ID NO: 41)

PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Met-CNP37)

(SEQ ID NO: 42)

MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Gly-CNP37)

(SEQ ID NO: 43)

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

[Gly-CNP37(M32N)]

(SEQ ID NO: 44)

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Met-Gly-CNP37)

(SEQ ID NO: 45)

MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(HSA-CNP27)

(SEQ ID NO: 46)

GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC;

[HSA-CNP27 (M22N)]

(SEQ ID NO: 47)

GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Pro-HSA-CNP27)

(SEQ ID NO: 48)

PGHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Met-HSA-CNP27)

(SEQ ID NO: 49)

MGHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC;

[CNP27(K4, 5, 9R)]

(SEQ ID NO: 50)

GANRRGLSRGCFGLKLDRIGSMSGLGC;

[CNP27(K4, 5, 9R, M22N)]

(SEQ ID NO: 51)

GANRRGLSRGCFGLKLDRIGSNSGLGC;

[Pro-CNP27(K4, 5, 9R)]

(SEQ ID NO: 52)

PGANRRGLSRGCFGLKLDRIGSMSGLGC;

[Met-CNP27(K4, 5, 9R)]

(SEQ ID NO: 53)

MGANRRGLSRGCFGLKLDRIGSMSGLGC;

[PEG1 K-CNP27(K4, 5, 9R)]

(SEQ ID NO: 54)

PEG1K-GANRRGLSRGCFGLKLDRIGSMSGLGC;

[PEG1 K-CNP27(K4, 5, 9R, M22N)]

(SEQ ID NO: 55)

PEG1K-GANRRGLSRGCFGLKLDRIGSNSGLGC;

[PEG1K-Pro-CNP27(K4, 5, 9R)]

(SEQ ID NO: 56)

PEG1K-PGANRRGLSRGCFGLKLDRIGSMSGLGC;

[PEG1 K-Met-CNP27(K4, 5, 9R)]

(SEQ ID NO: 57)

PEG1K-MGANRRGLSRGCFGLKLDRIGSMSGLGC;

[PEO12-CNP27(K4, 5, 9R)]

(SEQ ID NO: 58)

PEO12-GANRRGLSRGCFGLKLDRIGSMSGLGC;

[PEO12-CNP27(K4, 5, 9R, M22N)]

(SEQ ID NO: 59)

PEO12-GANRRGLSRGCFGLKLDRIGSNSGLGC;

[PEO12-Pro-CNP27(K4, 5, 9R)]

(SEQ ID NO: 60)

PEO12-PGANRRGLSRGCFGLKLDRIGSMSGLGC;

[PEO12-Met-CNP27(K4, 5, 9R)]

(SEQ ID NO: 61)

PEO12-MGANRRGLSRGCFGLKLDRIGSMSGLGC;

[PEO24-CNP27(K4, 5, 9R)]

(SEQ ID NO: 62)

PEO24-GANRRGLSRGCFGLKLDRIGSMSGLGC;

[PEO24-CNP27(K4, 5, 9R, M22N)]

(SEQ ID NO: 63)

PEO24-GANRRGLSRGCFGLKLDRIGSNSGLGC;

[PEO24-Pro-CNP27(K4, 5, 9R)]

(SEQ ID NO: 64)

PEO24-PGANRRGLSRGCFGLKLDRIGSMSGLGC;

and

[PEO24-Met-CNP27(K4, 5, 9R)]

(SEQ ID NO: 65)

PEO24-MGANRRGLSRGCFGLKLDRIGSMSGLGC.

2. The method of claim 1 , wherein

(a) said composition is administered once daily;

(b) said composition is administered once daily over a period of at least 6 months; or

(c) said composition is administered once daily over a period of at least 12 months.

3. The method of claim 1 , wherein the composition is administered to the subject via subcutaneous administration.

4. The method of claim 1 , wherein the composition is administered daily, every other day, 3 times weekly, 2 times weekly, or once weekly.

5. The method of claim 1 , wherein the composition is administered at a dose of 30 μg/kg.

6. The method of claim 1 , wherein the subject is about 6 months to about 2 years old.

7. The method of claim 1 , wherein the subject is about 0 to about 6 months old.

8. The method of claim 5 , wherein the dosage may be decreased to 15 μg/kg when the subject is 2 years old.

9. The method of claim 1 , wherein the skeletal dysplasia is selected from the group consisting of hypophosphatemic rickets, achondroplasia, hypochondroplasia, short stature, dwarfism, osteochondrodysplasias, thanatophoric dysplasia, osteogenesis imperfecta, achondrogenesis, chondrodysplasia punctata, homozygous achondroplasia, campomelic dysplasia, congenital lethal hypophosphatasia, perinatal lethal type of osteogenesis imperfecta, short-rib polydactyly syndromes, hypochondroplasia, rhizomelic type of chondrodysplasia punctata, Jansen-type metaphyseal dysplasia, spondyloepiphyseal dysplasia congenita, atelosteogenesis, diastrophic dysplasia, congenital short femur, Langer-type mesomelic dysplasia, Nievergelt-type mesomelic dysplasia, Robinow syndrome, Reinhardt syndrome, acrodysostosis, peripheral dysostosis, Kniest dysplasia, fibrochondrogenesis, Roberts syndrome, acromesomelic dysplasia, micromelia, Morquio syndrome, Kniest syndrome, metatrophic dysplasia, spondyloepimetaphyseal dysplasia, NPR2 mutation, SHOX mutation, Turner's syndrome/Leri Weill, PTPN11 mutations, Noonan's syndrome, and idiopathic short stature.

10. The method of claim 3 , wherein the skeletal dysplasia is achondroplasia.

11. The method of claim 1 , wherein the composition further comprises one or more pharmaceutical excipients.

12. The method of claim 11 , wherein the composition comprises citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine and polysorbate 80.

13. The method of claim 1 , wherein the CNP variant is selected from the group consisting of

(Pro-Gly-CNP-37)

(SEQ ID NO: 1)

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Gly-CNP-37)

(SEQ ID NO: 43)

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-38)

(SEQ ID NO: 20)

LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

[CNP-37(M32N)]

(SEQ ID NO: 40)

QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Met-CNP-37)

(SEQ ID NO: 42)

MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Pro-CNP-37)

(SEQ ID NO: 41)

PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

[Gly-CNP-37(M32N)

(SEQ ID NO: 44)

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Met-Gly-CNP-37)

(SEQ ID NO: 45)

MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-37)

(SEQ ID NO: 21)

QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-36)

(SEQ ID NO: 22)

EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-35)

(SEQ ID NO: 23)

HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

and

(CNP-34)

(SEQ ID NO: 24)

PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC.

14. The method of claim 1 , wherein the CNP variant is selected from the group consisting of

(SEQ ID NO: 1)

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC 

(Pro-Gly-CNP-37);

and

(SEQ ID NO: 20)

LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38).

Assignments (2)
SECURITY INTEREST Recorded Apr 27, 2026
From: BIOMARIN PHARMACEUTICAL INC.; AMICUS THERAPEUTICS, INC.
To: CITIBANK, N.A., AS COLLATERAL AGENT
Reel/Frame 075493/0968 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 7, 2022
From: DAY, JONATHAN; FISHELEVA, ELENA
To: BIOMARIN PHARMACEUTICAL INC.
Reel/Frame 061351/0833 →
Continuity (3)
Provisional Application 63350196 · Jun 8, 2022
Provisional Application 63220275 · Jul 9, 2021
Related Publication 20230140311A1 · May 4, 2023
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