Granted Patent B2

US 12,514,906 · App. 18/425,954 · Granted Jan 6, 2026

Inventors: Sherry Bullens (Novato, CA); Stuart Bunting (Novato, CA); Tianwei Chou (Novato, CA); Augustus O. Okhamafe (Concord, CA); Christopher P. Price (Pullach, DE); Daniel J. Wendt (Novato, CA); Clarence Yap (Novato, CA)

Assignee: BIOMARIN PHARMACEUTICAL INC.

A61K38/2242A61K9/0019A61K9/19A61K38/1709A61K47/10A61K47/12A61K47/183A61K47/20A61K47/26

Abstract

Claims (107)

1 . A kit comprising,

a composition comprising a CNP variant peptide selected from the group consisting of:

[CNP-37(M32N); SEQ ID NO: 1]

QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Met-CNP-37; SEQ ID NO: 2)

MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Pro-CNP-37; SEQ ID NO: 3)

PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

[Gly-CNP-37(M32N); SEQ ID NO: 4]

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Pro-Gly-CNP-37; SEQ ID NO: 5)

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Met-Gly-CNP-37; SEQ ID NO: 6)

MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; and

(Gly-CNP-37 or CNP-38; SEQ ID NO: 7)

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,

wherein said CNP variant peptide is in a formulation comprising citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine, and polysorbate 80, and wherein the composition is lyophilized in a vial;

and instructions for use.

2 . A method of treating skeletal dysplasia in a subject comprising the step of administering to said subject a composition comprising a CNP variant peptide in an amount of at least 7.5 μg/kg of said CNP variant peptide, wherein said CNP variant peptide is selected from the group consisting of:

[CNP-37(M32N); SEQ ID NO: 1]

QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Met-CNP-37; SEQ ID NO: 2)

MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Pro-CNP-37; SEQ ID NO: 3)

PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

[Gly-CNP-37(M32N); SEQ ID NO: 4]

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Pro-Gly-CNP-37; SEQ ID NO: 5)

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Met-Gly-CNP-37; SEQ ID NO: 6)

MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; and

(Gly-CNP-37 or CNP-38; SEQ ID NO: 7)

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,

wherein said CNP variant peptide is in a formulation comprising citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine, and polysorbate 80;

wherein said composition comprises about 0.5 mq/ml to about 2.0 mg/ml of said CNP peptide variant; and

wherein said step of administering treats said skeletal dysplasia in said subject.

3 . The method of claim 2 , wherein the treatment results in an improvement in one or more symptoms of skeletal dysplasia, and wherein said improvement is selected from the group consisting of increased absolute growth, increased growth velocity, increased computed tomography (QCT) or bone mineral density (BMD), improvement in growth plate morphology, increased long bone growth, improvement in spine morphology, improved elbow joint range of motion, and decreased sleep apnea.

4 . The method of claim 2 , wherein the skeletal dysplasia is selected form the group consisting of achondroplasia, hypochondroplasia, short stature, dwarfism, osteochondrodysplasias, thanatophoric dysplasia, osteogenesis imperfecta, achondrogenesis, chondrodysplasia punctata , homozygous achondroplasia, camptomelic dysplasia, congenital lethal hypophosphatasia, perinatal lethal type of osteogenesis imperfecta, short-rib polydactyly syndromes, 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, and spondyloepimetaphyseal dysplasia.

5 . The method of claim 2 , wherein said composition is administered once daily.

6 . The method of claim 5 , wherein said composition is administered once daily over a period of at least 6 months.

7 . The method of claim 2 , wherein said composition is administered subcutaneously.

8 . The method of claim 2 , comprising administering said composition comprising said CNP variant peptide to said subject in an amount of at least about 15 μg/kg per day of said CNP variant peptide.

9 . The method of claim 2 , wherein the formulation is lyophilized, is in liquid form, or is reconstituted from a lyophilized formulation.

10 . The method of claim 2 , wherein, in the formulation, citric acid monohydrate is present at a concentration of from about 0.15 mg/ml to about 0.40 mg/ml, sodium citrate dihydrate is present at a concentration of from about 0.5 mg/ml to about 1.5 mg/ml, trehalose dihydrate is present at a concentration of from about 30 mg/ml to about 70 mg/ml, D-mannitol is present at a concentration of from about 10 mg/ml to about 20 mg/ml, L-methionine is present at a concentration of from about 0.5 mg/ml to about 1.5 mg/ml, and polysorbate 80 is present at a concentration of from about 0.01 mg/ml to about 0.1 mg/ml.

11 . The method of claim 2 , wherein, in the formulation, citric acid monohydrate is present at a concentration of about 0.28 mg/ml, sodium citrate dihydrate is present at a concentration of about 1.08 mg/ml, trehalose dihydrate is present at a concentration of about 58.01 mg/ml, D-mannitol is present at a concentration of about 15 mg/ml, L-methionine is present at a concentration of about 0.73 mg/ml, and polysorbate 80 is present at a concentration of about 0.05 mg/ml.

12 . The method of claim 2 , wherein the formulation is preservative-free.

13 . The method of claim 2 , wherein the formulation has a pH of between about 5.0 and about 6.0.

14 . A method of increasing long bone growth in a subject in need thereof, said method comprising the step of administering to said subject a composition comprising a CNP variant peptide in an amount of at least 7.5 μg/kg of said CNP variant peptide, wherein said CNP variant peptide is selected from the group consisting of:

[CNP-37(M32N); SEQ ID NO: 1]

QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Met-CNP-37; SEQ ID NO: 2)

MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Pro-CNP-37; SEQ ID NO: 3)

PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

[Gly-CNP-37(M32N); SEQ ID NO: 4]

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Pro-Gly-CNP-37; SEQ ID NO: 5)

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Met-Gly-CNP-37; SEQ ID NO: 6)

MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; and

(Gly-CNP-37 or CNP-38; SEQ ID NO: 7)

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,

wherein said CNP variant peptide is in a formulation comprising citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine, and polysorbate 80;

wherein said composition comprises about 0.5 mq/ml to about 2.0 mq/ml of said CNP peptide variant; and

wherein said step of administering increases long bone growth in said subject.

15 . A method of increasing growth velocity in a subject in need thereof, said method comprising the step of administering a composition comprising a CNP variant peptide to said subject in an amount of at least 7.5 μg/kg, wherein said CNP variant peptide is selected from the group consisting of:

[CNP-37(M32N); SEQ ID NO: 1]

QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Met-CNP-37; SEQ ID NO: 2)

MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Pro-CNP-37; SEQ ID NO: 3)

PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

[Gly-CNP-37(M32N); SEQ ID NO: 4]

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Pro-Gly-CNP-37; SEQ ID NO: 5)

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Met-Gly-CNP-37; SEQ ID NO: 6)

MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; and

(Gly-CNP-37 or CNP-38; SEQ ID NO: 7)

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,

wherein said CNP variant peptide is in a formulation comprising citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine, and polysorbate 80;

wherein said composition comprises about 0.5 mq/ml to about 2.0 mq/ml of said CNP peptide variant; and

wherein said step of administering increases growth velocity in said subject.

16 . The method of claim 15 , wherein the increase in growth velocity is an increase in annualized growth velocity as measured by standing height of at least 25% above baseline in said subject.

17 . The method of claim 15 that results in:

(i) a change in the upper body length to lower body length ratio of between −0.05 and 0.05;

(ii) a change in the upper arm length to forearm length ratio of between −0.05 to 0.05; and/or

iii) a change in the upper leg length to lower leg length ratio of between −0.05 and 0.05.

18 . The method of claim 15 , wherein said composition is administered daily, 3 times weekly, twice weekly, once weekly, or once every two weeks.

19 . A method of treating skeletal dysplasia in a subject comprising the step of administering to said subject a composition comprising a CNP variant peptide in an amount of at least 7.5 μg/kg of said CNP variant peptide, wherein said CNP variant peptide is selected from the group consisting of:

[CNP-37(M32N); SEQ ID NO: 1]

QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Met-CNP-37; SEQ ID NO: 2)

MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Pro-CNP-37; SEQ ID NO: 3)

PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

[Gly-CNP-37(M32N); SEQ ID NO: 4]

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Pro-Gly-CNP-37; SEQ ID NO: 5)

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Met-Gly-CNP-37; SEQ ID NO: 6)

MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; and

(Gly-CNP-37 or CNP-38; SEQ ID NO: 7)

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC,

wherein said CNP variant peptide is in a formulation comprising citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine, and polysorbate 80;

wherein said composition comprises about 10.0 mg/ml±9.9 mg/ml of said CNP peptide variant; and

wherein said step of administering treats said skeletal dysplasia in said subject.

Assignments (2)

Continuity (6)

References Cited (57)