WO2024104922A1 - Procédé d'amélioration de la fonction musculaire squelettique - Google Patents

Procédé d'amélioration de la fonction musculaire squelettique Download PDF

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WO2024104922A1
WO2024104922A1 PCT/EP2023/081497 EP2023081497W WO2024104922A1 WO 2024104922 A1 WO2024104922 A1 WO 2024104922A1 EP 2023081497 W EP2023081497 W EP 2023081497W WO 2024104922 A1 WO2024104922 A1 WO 2024104922A1
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npr
agonist
cnp
certain embodiments
subject
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PCT/EP2023/081497
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English (en)
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Bent Winding
Kennett Sprogøe
Mads Jens KJELGAARD- HANSEN
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Ascendis Pharma Growth Disorders A/S
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Priority claimed from PCT/EP2022/085414 external-priority patent/WO2023110758A1/fr
Application filed by Ascendis Pharma Growth Disorders A/S filed Critical Ascendis Pharma Growth Disorders A/S
Publication of WO2024104922A1 publication Critical patent/WO2024104922A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2242—Atrial natriuretic factor complex: Atriopeptins, atrial natriuretic protein [ANP]; Cardionatrin, Cardiodilatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention relates to methods for improving muscle function in a subject in need thereof, particularly for therapeutic use in conditions associated with a loss of muscle strength, muscle condition, and/or muscle pain.
  • Achondroplasia is the most common form of non-lethal skeletal dysplasia, affecting more than 250,000 people worldwide. Achondroplasia is caused by a pathogenic variant in the gene that codes for fibroblast growth factor receptor 3 (FGFR3) and is transmitted as an autosomal dominant trait. FGFR3 is a negative regulator of long bone development and is highly expressed in the growth plate chondrocytes.
  • FGFR3 fibroblast growth factor receptor 3
  • FGFR3 inhibitors may act on the receptor itself or on its the downstream signalling pathways in order to inhibit FGFR3 signalling. Suitable examples of FGFR3 inhibitors therefore include tyrosine kinase inhibitors (such as infigratinib, pemigatinib, futibatinib, erdafitinib or TYRA-300), C-type natriuretic peptide (CNP), FGFR3 siRNA and FGFR3 antisense oligonucleotides.
  • tyrosine kinase inhibitors such as infigratinib, pemigatinib, futibatinib, erdafitinib or TYRA-300
  • CNP C-type natriuretic peptide
  • FGFR3 siRNA FGFR3 antisense oligonucleotides.
  • Infigratinib is a FGFR selective tyrosine kinase inhibitor which has been approved for the treatment of certain cancers (Truseltiq), and is in clinical development for the increasing height in children with achondroplasia (Savariray an et al. , Ther Adv Musculoskelet Dis 2022 Mar 21 ; 14).
  • TYRA-300 is an oral, potent FGFR 3-selective tyrosine kinase inhibitor that has activity in the presence of mutations including the FGFR3 V555 mutation, and which has selectivity for FGFR3 over FGF1 and other FGFR isoforms.
  • TYRA-300 was developed by Tyra Biosciences.
  • FGFR3 signals through several intracellular pathways, including signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) and constitutive activation of FGFR3 is associated with the achondroplasia phenotype. FGFR3 activation is associated with increased phosphorylation of the STAT and MAPK pathways.
  • the MAPK pathway can be regulated by C-type natriuretic peptide (CNP).
  • NPR-B natriuretic-peptide receptor B
  • PDEs cyclic nucleotide phosphodiesterases
  • GICs cGMP -regulated ion channels
  • cGKI and cGKII cGMP-dependent protein kinases
  • An example of an FGFR3 inhibitor that acts downstream of FGFR3 includes molecules that activate the NPR-B receptor, as activation of this receptor inhibits FGFR3 downstream signaling by inhibiting the pathway of mitogen-activated protein kinase (MAPK).
  • MAPK mitogen-activated protein kinase
  • Vosoritide is a C-type natriuretic peptide (CNP) variant which has been approved for the treatment of achondroplasia in pediatric patients whose bones are still growing, and works directly on the growth plates of bones to promote new bone growth (https://www.ema.europa.eu/en/medicines/human/EPAR/voxzogo).
  • CNP C-type natriuretic peptide
  • CNP is a potent regulator of growth plate chondrogenesis, and CNP binding to the natriuretic peptide binding receptor-2 (NPR-B) on the chondrocyte cell surface induces intracellular synthesis of cyclic guanosine monophosphate (cGMP) and activating cGMP-dependent signal transduction (Potter et al., Handb Exp Pharmacol. 2009 ; (191): 341-366).
  • CNP is indicated in cardiac remodeling and acute myocardial infarction, relaxation of smooth muscle and treatment of hypertension (Nakagawa and Saito, Biology 2022, 11, 1017).
  • C-type natriuretic peptide is a pivotal regulator of metabolic homeostasis.
  • CNP exerts these metabolic regulatory actions by inhibiting sympathetic thermogenic programming via Gi-coupled natriuretic peptide receptor (NPR)-C and reducing peroxisome proliferator-activated receptor-y coactivator- 1 a expression, while concomitantly driving adipogenesis via NPR-B/protein kinase-G.
  • NPR Gi-coupled natriuretic peptide receptor
  • FGFR3 inhibitor which acts on the pathway downstream of FGFR3 itself is the molecule Meclizine which attenuates the MAPK signalling pathway at the level of ERK phosphorylation (see e.g. Kitoh et al 2020 . PLoS ONE 15(4): e0229639. https://doi.org/10.1371/joumal.pone.0229639 ).
  • achondroplasia Treatment of achondroplasia has been focused on promoting endochondrial bone growth and therapeutics have been selected for their ability to improve annualized growth/height velocity of achondroplasia in children.
  • the inventors of the present invention have surprisingly found that treatment of children with achondroplasia with a CNP drug, TransCon CNP, resulted in an improvement of physical function, as well as a reduction of achondroplasia disease related adverse events. Based on the studies reported below, these improvements in physical function are believed to result from improvements in muscular function, independent of bone growth. Children on placebo showed deteriorated physical performance and a much higher incidence of achondroplasia disease related adverse events.
  • the binding of CNP to the NPR-B receptor may contribute to the mechanism of action and as such NPR-B receptor agonists are also contemplated for this use.
  • the binding of CNP to the NPR-C receptor may contribute to the mechanism of action and as such NPR-C receptor agonists are also contemplated for this use.
  • the invention provides for a method of improving muscle function in a subject suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of an inhibitor of FGFR3 signaling to said subject.
  • the invention provides for a method of improving muscle function in a subject suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of an NPR-B agonist to said subject.
  • the invention provides for a method of improving muscle function in a subject suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of an an NPR-C agonist to said subject.
  • the invention provides for a method of improving muscle function in a subject suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of an inhibitor of FGFR3 signaling, an NPR-B agonist or an NPR-C agonist to said subject.
  • the invention provides for a method of improving muscle function in a subject suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of a C-type natriuretic peptide (CNP) to said subject.
  • CNP C-type natriuretic peptide
  • the NPR-B agonist or CNP is vosoritide (SEQ ID NO:30).
  • the invention provides for a method of improving muscle function in a subject suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of a C-type natriuretic peptide (CNP) to said subject, wherein the CNP is administered as a CNP conjugate and/or as a prodrug of CNP; or a pharmaceutically acceptable salt thereof.
  • CNP C-type natriuretic peptide
  • the invention provides for a method of improving muscle function in a subject suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of a C-type natriuretic peptide (CNP) to said subject, wherein the CNP is administered in as a CNP conjugate and/or as a prodrug of CNP; or a pharmaceutically acceptable salt thereof; wherein said method comprises administering successive doses of a therapeutically effective amount of the CNP conjugate and/or prodrug of CNP to the subject, wherein the sustained exposure of free CNP in the blood plasma of the patient between successive doses of the therapeutically effective amount of the CNP conjugate and/or prodrug of CNP is at least about 1 pmol/L.
  • CNP C-type natriuretic peptide
  • the successive doses are administered, for example daily or weekly or biweekly, or monthly. In certain embodiments time interval between successive doses is at least about 24 hours, such as at least about one week.
  • the CNP conjugate or prodrug of CNP is a compound of formula (Ilf ’), formula (Ilf), compound (1), or a pharmaceutically acceptable salt thereof.
  • the invention provides for a method of improving muscle function in a subject suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of a C-type natriuretic peptide (CNP) to said subject, wherein the CNP is administered in as a CNP conjugate and/or as a prodrug of CNP; or a pharmaceutically acceptable salt thereof, wherein the CNP conjugate or prodrug of CNP is a compound of formula (Ilf ’), formula (Ilf), compound (1 ), or a pharmaceutically acceptable salt thereof.
  • CNP C-type natriuretic peptide
  • the subject is a human subject. In certain embodiments, the subject is a human subject less than 18 years of age. In certain embodiments, the subject is a human subject at least 18 years of age. In certain embodiments, the subject has closed bone epiphysis.
  • the invention provides for a method of improving muscle function in a subject suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of a C-type natriuretic peptide (CNP) to said subject, wherein said method comprises an infusion, such as a i.v. or s.c.
  • CNP C-type natriuretic peptide
  • the sustained exposure of CNP (free CNP) in the blood plasma of the patient over a period of at least about 1 hour of at least Ipmol/L results in a sustained exposure of CNP (free CNP) in the blood plasma of the patient over a period of at least about 1 hour of at least Ipmol/L.
  • the invention provides for a method of improving muscle function in a subject suffering from a disease or condition in which muscle function is impaired, the method comprising administering a therapeutically effective amount of an inhibitor of FGFR3 signaling to said subject, wherein the inhibitor of FGFR3 signaling (a FGFR3 antagonist) is an FGFR3 tyrosine kinase inhibitor, such as a FGFR3 tyrosine kinase inhibitor is selected from the group consisting of infigratinib, pemigatinib, futibatinib, erdafitinib and TYRA-300.
  • the invention provides for a method (such as a therapeutic method) for improving muscle function in a subject.
  • the invention provides for a method (such as a therapeutic method) for improving skeletal muscle function in a subject.
  • the invention provides for a method (such as a therapeutic method) for improving muscle strength and/or improving muscle stamina in a subject (e.g. skeletal muscle strength and/or skeletal muscle stamina).
  • a method for improving muscle strength and/or improving muscle stamina in a subject (e.g. skeletal muscle strength and/or skeletal muscle stamina).
  • the invention provides for a method (such as a therapeutic method) for improving muscle tonicity in a subject (e.g. skeletal muscle tonicity).
  • the method comprises administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-C agonist or an effective amount of an NPR-B agonist to said subject.
  • the method comprises administering an effective amount of an NPR-B / NPR-C agonist (e.g a CNP).
  • the subject may be suffering from a disease or a disorder which causes an impairment of muscle function (e.g. muscle strength, stamina and/or tonicity).
  • a disease or a disorder which causes an impairment of muscle function e.g. muscle strength, stamina and/or tonicity.
  • the disease or a disorder may be one which causes an impairment of skeletal muscle function.
  • the inhibitors of FGFR3 signalling or NPR-B agonists or NPR-C agonists, or CNP may be used in combination with a growth hormone, such as human growth hormone.
  • the invention provides an inhibitor of FGFR3 signalling or NPR-B agonists or an NPR-C agonist for use in a method of improving muscle function in a subject, optionally where the subject is suffering from a disease or a disorder which causes an impairment in muscle function.
  • the invention provides an inhibitor of FGFR3 signalling or NPR-B agonists or an NPR-C agonist for use in a method of improving skeletal muscle function in a subject, optionally wherein the subject is suffering from a disease or a disorder which causes an impairment in skeletal muscle function.
  • the subject has a chondroplasia disease, such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia.
  • a chondroplasia disease such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia.
  • the subject is preferably a human subject.
  • the subject may be less than 18 years of age or at least 18 years of age.
  • the subject may have closed bone epiphysis.
  • the inhibitor of FGFR3 signalling is an FGFR3 antagonist or an NPR-B agonist.
  • NPR-C agonists may be used in the methods or uses of the invention.
  • FGFR3 antagonists may include a fibroblast growth factor receptor (FGFR) 3 tyrosine kinase inhibitor, an anti- FGFR3 antibody, an anti-FGFR3 antisense oligonucleotide or an anti-FGFR3 siRNA.
  • FGFR fibroblast growth factor receptor
  • a suitable NPR-B agonist is a C-type natriuretic peptide, or conjugate or prodrug thereof.
  • a suitable NPR-C agonist is a C-type natriuretic peptide, or conjugate or prodrug thereof.
  • F GFR3 antagonists include fibroblast growth factor receptor (F GFR) 3 tyrosine kinase inhibitor, such as infigratinib, pemigatinib, futibatinib, erdafitinib or TYRA-300.
  • F GFR fibroblast growth factor receptor
  • WO2022147246A1 discloses such FGFR3 antagonists, which is hereby incorporated by reference in its entirety.
  • the invention provides a method of improving muscle function (e.g. skeletal muscle function) in a subject suffering from a disease or condition in which muscle function (e.g skeletal muscle function) is impaired, said method comprising administering a therapeutically effective amount of a CNP.
  • muscle function e.g. skeletal muscle function
  • the invention provides a method of improving muscle function (e.g skeletal muscle function) in a subject suffering from a disease or condition in which muscle function (e.g skeletal muscle function) is impaired, said method comprising administering a therapeutically effective amount of vosoritide.
  • the CNP comprises or consists of SEQ ID NO: 24. In certain embodiments, the CNP comprises or consists of a peptide selected from the group consisting of SEQ ID NO:30, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO: 100, SEQ ID NO:101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105 and SEQ ID NO:90.
  • the CNP is a CNP conjugate or pharmaceutically acceptable salt thereof, comprising a CNP selected from the group consisting of SEQ ID NO:30, SEQ ID NO:98, SEQ ID NO:99, SEQ ID N0: 100, SEQ ID NO:101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104 or SEQ ID NO: 105 and SEQ ID NO:90.
  • the improvement in muscle function can be for example, a) increased muscle (e.g. skeletal muscle) strength, b) increased muscle (e.g. skeletal muscle) tone, c) increased muscle (e.g. skeletal muscle) stamina, d) increased muscle (e.g. skeletal muscle) mass, e) decreased muscle (e.g. skeletal muscle) fatigue, f) increased cardiovascular endurance, g) increased cardiovascular fitness, h) decreased exercise intolerance, i) increased exercise capacity, j) decreased exercise induced fatigue, or k) increased hypertonia.
  • the administration of the effective amount of the inhibitor of FGFR3 signalling, or the effective amount of the NPR-B agonist, or the effective amount of the NPR-C agonist may give rise to increased muscle (e.g. skeletal muscle) mass and/or skeletal muscle/fat ratio in the subject.
  • the administration of the effective amount of the inhibitor of FGFR3 signalling, or the effective amount of the NPR-B agonist, or the effective amount of the NPR-C agonist may give rise to treatment or prevention of musculoskeletal pain in the subject, an improvement in posture or a reduction in an abnormal curvature of the spine, an improvement in kyphosis, lordosis, spinal stenosis or scoliosis, improvement in sleep apnea, obstructive sleep apnea, otitis media, or a reduction in obesity.
  • These improvements may arise as a result of the improvement(s) in muscle function (e.g. skeletal muscle function).
  • the treatment, prevention or improvement in any condition referred to above is preferably by improvement of muscle function (e.g. skeletal muscle function).
  • the CNP is administered as a prodrug.
  • the CNP prodrug provides a sustained exposure of active CNP peptide after administration to the subject.
  • the prodrug is optionally a compound of formula (Ilf ’) or formula (Ilf) or compound (1), or a pharmaceutically acceptable salt thereof.
  • the subject may have been treated with the inhibitor of FGFR3 signalling, or NPR-B agonist (e.g. CNP) or NPR-C agonist before the age of 18.
  • NPR-B agonist e.g. CNP
  • NPR-C agonist e.g. CNP
  • the invention therefore provides for a therapeutic treatment which is initiated before the age of 18 years and is continued into beyond 18 years of age.
  • Administration of the the inhibitor of FGFR3 signalling, or NPR-B agonist, or NPR-C agonist may give rise to one or more of improvement in muscle function, selected from the group conistsiting of: a) increased skeletal muscle strength, b) increased skeletal muscle tone, c) increased skeletal muscle stamina, d) increased skeletal muscle mass, e) decreased skeletal muscle fatigue, f) increased cardiovascular endurance, g) increased cardiovascular fitness, h) decreased exercise intolerance, i) increased exercise capacity, or j) decreased exercise induced fatigue, and k) decreased hypotonia.
  • the method can alternatively be described as a method of increasing skeletal muscle strength, in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method can also be described as a method of increasing skeletal muscle tone in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method can also be described as a method of increasing skeletal muscle stamina in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method can also be described as a method of increasing skeletal muscle mass in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method can also be described as a method of decreasing skeletal muscle fatigue in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method can also be described as a method of increasing cardiovascular endurance in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method can also be described as a method of increasing cardiovascular fitness in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method can also be described as a method of decreasing exercise intolerance in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method can also be described as a method of increasing exercise capacity in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method can also be described as a method of decreasing exercise induced fatigue in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method can also be described as a method of decreasing hypotonia in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • Administration of the inhibitor of F GFR3 signalling or an effective amount of an NPR-B agonist, or NPR-C agonist may give rise to an increase in the skeletal muscle / fat ratio of the subject and the method may alternatively be framed as a method of increasing the skeletal muscle / fat ratio in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • Administration of the inhibitor of F GFR3 signalling or an effective amount of an NPR-B agonist, or NPR-C agonist may give rise to a decrease in hypotonia in the subject and the method can therefore be framed as a method of decreasing hypotonia in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method thus may be described as a method of treating hypotonia in the subject.
  • Administration of the inhibitor of F GFR3 signalling or an effective amount of an NPR-B agonist, or NPR-C agonist may give rise to a decrease in musculoskeletal pain in the subject and the method can therefore be framed as a method of treating, preventing or reducing decreasing musculoskeletal pain in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method of also gives rise to an improvement in posture, an improvement in an abnormal curvature of the spine and the method can therefore be framed as a method of improving posture or for treatment of an abnormal curvature of the spine in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method may give rise to an improvement in kyphosis, lordosis or scoliosis and as such can be defined as a method of treating one or more of these conditions in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the method may give rise to an improvement in sleep apnea, snoring, obstructive sleep apnea, otitis media and as such can be defined as a method of treating one or more of these conditions in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • a reduction in the frequency of occurrence, incidence and/or severity of the sleep apnea, snoring, obstructive sleep apnea, otitis media may result.
  • the method may give rise to a reduction in obesity and as such can be defined as a method of reducing obesity in a subject (optionally wherein the subject is suffering from a disease or condition in which muscle e.g. skeletal muscle function is impaired), the method comprising administering an effective amount of an inhibitor of FGFR3 signalling or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the present invention also provides for a method for treating kyphosis in a patient in need of said treatment, said method comprising administering an effective amount of CNP, CNP conjugate or pharmaceutically acceptable salt thereof or unit dosage form to the patient thereby treating kyphosis.
  • the patient has been diagnosed with a bone dysplasia or bone disorder, such as a disorder selected from the group consisting of achondroplasia, hypochondroplasia, short stature, Noonan syndrome and SHOX deficiency.
  • a bone dysplasia or bone disorder such as a disorder selected from the group consisting of achondroplasia, hypochondroplasia, short stature, Noonan syndrome and SHOX deficiency.
  • the present invention also provides for a method for treating foramen magnum stenosis in a patient in need of said treatment, said method comprising administering an effective amount of CNP, CNP conjugate or pharmaceutically acceptable salt thereof or unit dosage form to the patient thereby treating foramen magnum stenosis.
  • the patient has achondroplsia.
  • the present invention also provides for a method for treating otitis media or ear infection in a patient or for reducing incidence of ear infection in a patient in need of said treatment, said method comprising administering a therapeutically effective amount of a CNP, CNP conjugate or pharmaceutically acceptable salt thereof or unit dosage form to the patient thereby treating otitis media, or ear infection or reducing incidence of ear infection.
  • the patient has achondroplsia.
  • the present invention also provides for a method for treating sleep apnea syndrome in a patient in need to said treatment, said method comprising administering a therapeutically effective amount of a CNP, CNP conjugate or pharmaceutically acceptable salt thereof or unit dosage form to the patient.
  • the treatment may reduce the incidence of sleep apnea or reduce the severity of sleep apnea.
  • the patient has achondroplsia.
  • the present invention also provides for a method for reducing the frequency of achondroplasia related adverse events in a patient diagnosed with achondroplasia, said method comprising administering a therapeutically effective amount of a CNP, CNP conjugate or pharmaceutically acceptable salt thereof or unit dosage form, wherein optionally the patient may be a pediatric patient, and/or a patient with open bone epiphysis
  • the subject may have a chondrodysplasia disease, such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia.
  • a chondrodysplasia disease such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia.
  • the subject may have achondroplasia. In some embodiments the subject does not have achondroplsia.
  • the subject may have achondroplasia wherein the subject is a human subject of at least 18 years of age, or a human subject whose bone epiphesis have closed.
  • the invention also provides an inhibitor of FGFR3 signalling, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist for use in that method and use of an inhibitor of FGFR3 signalling, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist in the manufacture of a medicament for use in that method.
  • the CNP is in the form of a unit dosage forms comprising a CNP conjugate or pharmaceutically acceptable salt thereof.
  • the unit dosage form of CNP comprises a therapeutically effective amount of a CNP conjugate or pharmaceutically acceptable salt thereof in which a CNP moiety is reversibly conjugated to a polymeric moiety.
  • Figure 1 Percentage survival of Fgfr3 Y367C/+ pups over study period, comparing groups treated with Compound (1) at 5.6 mg/kg/day (solid line). Compound (1) at 1 .2 mg/kg/every third day (dashed line) or Vehicle alone (dotted line).
  • Figure 2 The change in pedicular width after 52 weeks on treatment (cohorts 3 and 4), as compared to placebo, as detailed in Example 14. The data illustrates a trend for increased pedicular width on treatment as compared to placebo.
  • Figure 3 The change in mean hand length after 52 weeks on treatment (Cohorts 3 and 4) as compared to placebo, as detailed in Example 15. The results indicate a clear trend for dose dependent increase in the hand length on treatment.
  • the term “about” in combination with a numerical value is used to indicate a range ranging from and including the numerical value plus and minus no more than 10% of said numerical value, in certain embodiments, no more than 8% of said numerical value, in certain embodiments, no more than 5% of said numerical value and in certain embodiments, no more than 2% of said numerical value.
  • the phrase “about 200” is used to mean a range ranging from and including 200 +/- 10%, i.e. ranging from and including 180 to 220; in certain embodiments, 200 +/- 8%, i.e. ranging from and including 184 to 216; in certain embodiments, ranging from and including 200 +/-5%, i.e.
  • antimicrobial refers to a chemical substance, such as a chemical substance that kills or inhibits the growth of microorganisms, such as bacteria, fungi, yeasts, protozoans, molds and/or destroys viruses.
  • buffer or “buffering agent” refers to a chemical compound that maintains the pH in a desired range.
  • Physiologically tolerated buffers are, for example, sodium phosphate, succinate, histidine, bicarbonate, citrate, acetate, sulfate, nitrate, chloride and pyruvate.
  • Antacids such as Mg(OH)2 or ZnCO; may be also used.
  • CNP refers to all CNP polypeptides, in certain embodiments from mammalian species, such as from human and mammalian species, in particular from human and murine species, as well as their variants, analogs, orthologs, homologs and derivatives and fragments thereof, that are characterized by regulating the growth, proliferation and differentiation of cartilaginous growth plate chondrocytes.
  • the human prepro-CNP which comprises 126 amino acids is further cleaved to yield CNP-53 and CNP-22.
  • CNP also includes all CNP variants, analogs, orthologs, homologs, derivatives and fragments thereof.
  • CNP variants, analogs, orthologs, homologs, derivatives and fragments thereof as disclosed in WO 2009/067639 A2 and WO 2010/135541 A2 are herewith incorporated by reference.
  • CNP peptides and pharmaceutical compositions comprising CNP peptides are disclosed in W02009/067639, W02010/135541, WO2017/020034, WO2017/100400, WO2021055497, WO2021/030411, WO2023/283657, WO2022/115563 which are all incorporated by reference herein.
  • Exemplary CNP peptides are provided herein, and include vosoritide.
  • C1.4 alkyl alone or in combination means a straight-chain or branched alkyl moiety having 1 to 4 carbon atoms. If present at the end of a molecule, examples of straight-chain or branched C1.4 alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • C1.4 alkyl groups are -CH2-, -CH2-CH2-, -CEI(CEI 3 )-, -CH2-CH2-CH2-, -CH(C2H 5 )-, -C(CH 3 )2-.
  • Each hydrogen of a C1.4 alkyl carbon may optionally be replaced by a substituent as defined above.
  • a C1.4 alkyl may be interrupted by one or more moieties as defined below.
  • Ci-e alkyl alone or in combination means a straight-chain or branched alkyl moiety having 1 to 6 carbon atoms. If present at the end of a molecule, examples of straight-chain and branched Ci-e alkyl groups are 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.
  • Ci-e alkyl groups When two moieties of a molecule are linked by the Ci-e alkyl group, then examples for such Ci-6 alkyl groups are -CH 2 -, -CH2-CH2-, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -,
  • Ci-6 carbon may optionally be replaced by a substituent as defined above.
  • a Ci-6 alkyl may be interrupted by one or more moieties as defined below.
  • Ci-io alkyl means an alkyl chain having 1 to 10, 1 to 20 or 1 to 50 carbon atoms, respectively, wherein each hydrogen atom of the Cnio, C1.20 or C1.50 carbon may optionally be replaced by a substituent as defined above.
  • a Ci-io, C1.20 alkyl or C1.50 alkyl may be interrupted by one or more moieties as defined below.
  • Each hydrogen atom of a C2- e alkenyl moiety may optionally be replaced by a substituent as defined above.
  • a C2-6 alkenyl may be interrupted by one or more moieties as defined below.
  • C2-10 alkenyl C2-20 alkenyl or “C2-50 alkenyl” alone or in combination means a straightchain or branched hydrocarbon moiety comprising at least one carbon-carbon double bond having 2 to 10, 2 to 20 or 2 to 50 carbon atoms.
  • Each hydrogen atom of a C2-10 alkenyl, C2-20 alkenyl or C2-50 alkenyl group may optionally be replaced by a substituent as defined above.
  • a C2-10 alkenyl, C2-20 alkenyl or C2-50 alkenyl may be interrupted by one or more moieties as defined below.
  • -C C-.
  • Each hydrogen atom of a C2-6 alkynyl group may optionally be replaced by a substituent as defined above.
  • one or more double bond(s) may occur.
  • a C2-6 alkynyl may be interrupted by one or more moieties as defined below.
  • C2-10 alkynyl C2-20 alkynyl
  • C2-50 alkynyl alone or in combination means a straight-chain or branched hydrocarbon moiety comprising at least one carbon-carbon triple bond having 2 to 10, 2 to 20 or 2 to 50 carbon atoms, respectively.
  • Each hydrogen atom of a C2-10 alkynyl, C2-20 alkynyl or C2- 50 alkynyl group may optionally be replaced by a substituent as defined above.
  • one or more double bond(s) may occur.
  • a C2-10 alkynyl, C2-20 alkynyl or C2-50 alkynyl may be interrupted by one or more moieties as defined below.
  • a C1.4 alkyl, Ci-6 alkyl, Cmo alkyl, C1.20 alkyl, C1.50 alkyl, C2-6 alkenyl, C2-10 alkenyl, C2-20 alkenyl, C2-50 alkenyl, C2-6 alkynyl, C2-10 alkynyl, C2-20 alkenyl or C2-50 alkynyl may optionally be interrupted by one or more moieties which are in certain embodiments, selected from the group consisting of wherein dashed lines indicate attachment to the remainder of the moiety or reagent; and
  • -R and -R a are independently of each other selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • C3-10 cycloalkyl means a cyclic alkyl chain having 3 to 10 carbon atoms, which may be saturated or unsaturated, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl.
  • Each hydrogen atom of a C3-10 cycloalkyl carbon may be replaced by a substituent as defined above.
  • the term “C3-10 cycloalkyl” also includes bridged bicycles like norbornane or norbomene.
  • the term “8- to 30-membered carbopoly cyclyl” or “8- to 30-membered carbopolycycle” means a cyclic moiety of two or more rings with 8 to 30 ring atoms, where two neighboring rings share at least one ring atom and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated).
  • an 8- to 30-membered carbopoly cyclyl means a cyclic moiety of two, three, four or five rings, in certain embodiments of two, three or four rings.
  • 3- to 10-membered heterocycles include but are not limited to aziridine, oxirane, thiirane, azirine, oxirene, thiirene, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetra
  • Examples for an 8- to 11- membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydro quinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine and pteridine.
  • 8- to 11 -membered heterobicycle also includes spiro structures of two rings like l,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo [3.2.1] octane.
  • Each hydrogen atom of an 8- to 11 -membered heterobicyclyl or 8- to 11 -membered heterobicycle carbon may be replaced by a substituent as defined below.
  • CNP polypeptide variant refers to a polypeptide from the same species that differs from a reference CNP polypeptide. Generally, differences are limited so that the amino acid sequence of the reference and the variant are closely similar overall and, in many regions, identical. In certain embodiments, CNP polypeptide variants are at least 70%, 80%, 90%, or 95% identical to a reference CNP polypeptide. By a polypeptide having an amino acid sequence at least, for example, 95% “identical” to a query amino acid sequence, it is intended that the amino acid sequence of the subject polypeptide is identical to the query sequence except that the subject polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence.
  • CNP polypeptide variants may be naturally occurring variants, such as naturally occurring allelic variants encoded by one of several alternate forms of a CNP occupying a given locus on a chromosome or an organism, or isoforms encoded by naturally occurring splice variants originating from a single primary transcript.
  • a CNP polypeptide variant may be a variant that is not known to occur naturally and that can be made by mutagenesis techniques known in the art. It is known in the art that one or more amino acids may be deleted from the N-terminus or C-terminus of a bioactive peptide or protein without substantial loss of biological function. Such N- and/or C- terminal deletions are also encompassed by the term CNP polypeptide variant.
  • dose refers to the predetermined amount of the drug, such as CNP, administered at one time to produce a certain degree of biological response in a patient.
  • the dose of a drug is governed by its inherent potency and in this case, it is a therapeutic dose or therapeutic unit dose.
  • the term “dosage form” refers to the physical form that comprises the active pharmaceutical ingredient in combination with selected additional ingredients or excipients and which is intended to be delivered to sites of action within the body by various routes of drug administration. It also refers to the physical form in which a precise mixture of active pharmaceutical ingredients and excipients are presented to help administration and delivery to the sites of action, achieve rapid onset of action and improve bioavailability.
  • the term “unit dosage form” refers to a dosage form configured for a single administration to a patient.
  • a unit dosage form can be a single vial or the container containing an amount of drug suitable for a single administration.
  • Dosage regimen is the combination of dose, and frequency with which a drug is administered.
  • Dosage regimen can also include a route of administration (e.g., subcutaneous) and/or duration of administration (e.g., until a patient reaches 18 years old or ephiphyseal closure).
  • Administration of a dosage regimen may maintain a steady-state serum concentration of CNP, in which peaks, troughs and area under the curve over a defined interval remain with defined margins of fluctuation and/or the ratio of peaks to troughs does not exceed a defined threshold.
  • drug refers to a substance used in the treatment, cure, prevention, or diagnosis of a disease or used to otherwise enhance physical or mental well-being. If a drug, such as CNP, is conjugated to another moiety, the moiety of the resulting product that originated from the drug is referred to as “drug moiety”.
  • excipient refers to compounds administered together with the drug or drug conjugate, for example, buffering agents, isotonicity modifiers, preservatives, stabilizers, anti-adsorption agents, oxidation protection agents, or other auxiliary agents. However, in some cases, one excipient may have dual or triple functions.
  • excipient may also refer to a diluent, adjuvant, or vehicle with which the drug or drug conjugate, is administered.
  • Such pharmaceutical excipient can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including, but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Water is a preferred excipient when the pharmaceutical formulation is administered orally.
  • Saline and aqueous dextrose are preferred excipients when the pharmaceutical formulation is administered intravenously or subcutaneously.
  • Saline solutions and aqueous dextrose and glycerol solutions are in certain embodiments, employed as liquid excipients for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, mannitol, trehalose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the pharmaceutical formulation can also contain minor amounts of wetting or emulsifying agents, pH buffering agents, like, for example, acetate, succinate, Tris (tris(hydroxymethyl)aminomethane), carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-l -piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), or can contain detergents, like Tween®, poloxamers, poloxamines, CHAPS, Igepal®, or amino acids like, for example, glycine, lysine, or histidine.
  • pH buffering agents like, for example, acetate, succinate, Tris (tris(hydroxymethyl)aminomethane), carbonate, phosphate, HEPES (4-(2-hydroxyethyl)-l -piperazineethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid)
  • detergents like
  • These pharmaceutical formulations can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the pharmaceutical formulation can be formulated as a suppository, with traditional binders and excipients such as triglycerides.
  • Oral formulation can include standard excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • Such formulations will contain a therapeutically effective amount of the drug or drug moiety, together with a suitable amount of excipient so as to provide the form for proper administration to the patient.
  • the formulation should suit the mode of administration.
  • formulation refers to a formulation containing one or more CNP conjugates and one or more excipients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients of the composition, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical formulations of the present invention encompass any formulation or composition made by admixing one or more CNP conjugates and a pharmaceutically acceptable excipient such as a buffering agent and bulking agent.
  • free form of a drug refers to the drug in its unmodified, pharmacologically fully active form, e.g. after being released from the CNP conjugate or pharmaceutically acceptable salt thereof.
  • the term “functional group” means a group of atoms which can react with other groups of atoms.
  • halogen means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.
  • the term “interrupted” means that a moiety is inserted m between two carbon atoms or - if the insertion is at one of the moiety’s ends - between a carbon or heteroatom and a hydrogen atom, in certain embodiments between a carbon and a hydrogen atom.
  • isotonicity agent refers to a compound that minimizes pain, irritation and tissue damage that can result from cell damage due to osmotic pressure differences between the injected solution and plasma.
  • the term “moiety” means a part of a molecule, which lacks one or more atom(s) compared to the corresponding reagent. If, for example, a reagent of the formula “H-X-H” reacts with another reagent and becomes part of the reaction product, the corresponding moiety of the reaction product has the structure “H-X-” or “-X-”, whereas each indicates attachment to another moiety. Accordingly, a drug moiety, such as a CNP moiety, is released from a conjugate as a drug, such as CNP.
  • sequence or chemical structure of a group of atoms is provided which group of atoms is attached to two moieties or is interrupting a moiety, said sequence or chemical structure can be attached to the two moieties in either orientation, unless explicitly stated otherwise.
  • a moiety “-C(O)N(R 1 )-” can be attached to two moieties or interrupting a moiety either as “-C(O)N(R 1 )-” or as “-N(R 1 )C(O)-”.
  • a moiety: can be attached to two moieties or can interrupt a moiety either as: or as
  • the unit dosage form comprises also their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the CNP moieties comprising one or more acidic groups can be present and used, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids, and other salts or amines known to the person skilled in the art.
  • CNP moieties comprising one or more basic groups i.e.
  • acids which can be protonated, can be present and can be used in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the pharmaceutical formulations according to the present invention also include, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • inner salts or betaines zwitterions
  • the respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these conjugates with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the unit dosage form according to the present invention also includes all salts of the CNP conjugates which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • the term “patient” refers to a subject amenable to treatment or prophylaxis according to the invention, particularly a human subject.
  • the term “pharmaceutically acceptable” means a substance that does not cause harm when administered to a patient and preferably means approved by a regulatory agency, such as the EMA (Europe) and/or the FDA (US) and/or any other national regulatory agency for use in animals, preferably for use in humans.
  • a regulatory agency such as the EMA (Europe) and/or the FDA (US) and/or any other national regulatory agency for use in animals, preferably for use in humans.
  • physiological conditions refers to an aqueous buffer at pH 7.4 and 37 °C.
  • polypeptide refers to a chain of at least 2 and up to and including 50 amino acid monomer moieties linked by peptide (amide) linkages. Only for CNP drugs and CNP moieties also the sequences having more than 50 amino acids will be referred to as “polypeptide” for simplification.
  • the term “preservative” refers to a chemical substance that has antimicrobial effects and prevents chemical degradation.
  • protein refers to a chain of more than 50 amino acid monomer moieties linked by peptide linkages, in which preferably no more than 12000 amino acid monomers are linked by peptide linkages, such as no more than 10000 amino acid monomer moieties, no more than 8000 amino acid monomer moieties, no more than 5000 amino acid monomer moieties or no more than 2000 amino acid monomer moieties.
  • polymer means a molecule comprising repeating structural units, i.e. the monomers, connected by chemical bonds in a linear, circular, branched, crosslinked or dendrimeric way or a combination thereof, which may be of synthetic or biological origin or a combination of both. It is understood that a polymer may also comprise one or more other chemical groups and/or moieties, such as, for example, one or more functional groups. In certain embodiments, a soluble polymer has a molecular weight of at least 0.5 kDa, e.g.
  • the polymer has a molecular weight of at most 1000 kDa, such as at most 750 kDa, such as at most 500 kDa, such as at most 300 kDa, such as at most 200 kDa, such as at most 100 kDa.
  • a protein or a polypeptide is a polymer in which the amino acids are the repeating structural units, even though the side chains of each amino acid may be different.
  • polymeric or “polymeric moiety” means a reagent or a moiety comprising one or more polymers or polymer moieties.
  • a polymeric reagent or moiety may optionally also comprise one or more other moiety/moieties, which are in certain embodiments selected from the group consisting of:
  • Ci-5o alkyl C2-50 alkenyl, C2-50 alkynyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11- membered heterob icy clyl, phenyl, naphthyl, indenyl, indanyl, and LeLralmy I: and
  • -R and -R a are independently of each other selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • the molecular weight ranges, molecular weights, ranges of numbers of monomers in a polymer and numbers of monomers in a polymer as used herein refer to the number average molecular weight and number average of monomers, i.e. to the arithmetic mean of the molecular weight of the polymer or polymeric moiety and the arithmetic mean of the number of monomers of the polymer or polymeric moiety.
  • any integer given for “x” therefore corresponds to the arithmetic mean number of monomers.
  • Any range of integers given for “x” provides the range of integers in which the arithmetic mean numbers of monomers lies.
  • An integer for “x” given as “about x” means that the arithmetic mean numbers of monomers lies in a range of integers of x +/- 10%, in certain embodiments lies in a range of integers x +/- 8%, in certain embodiments lies in a range of integers x +/- 5% and in certain embodiments lies in a range of integers x +/- 2%.
  • a PEG-based moiety or reagent in relation to a moiety or reagent means that said moiety or reagent comprises PEG.
  • a PEG-based moiety or reagent comprises at least 10% (w/w) PEG, such as at least 20% (w/w) PEG, such as at least 30% (w/w) PEG, such as at least 40% (w/w) PEG, such as at least 50% (w/w), such as at least 60% (w/w) PEG, such as at least 70% (w/w) PEG, such as at least 80% (w/w) PEG, such as at least 90% (w/w) PEG, such as at least 95% (w/w) PEG.
  • the remaining weight percentage of the PEG-based moiety or reagent are other moieties selected from the following moieties and linkages:
  • Ci-5o alkyl C2-50 alkenyl, C2-50 alkynyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11- membered heterob icy clyl, phenyl, naphthyl, indenyl, indanyl, and LeLralmy I: and
  • -R and -R a are independently of each other selected from the group consisting of -El, methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • PEG-based comprising at least X% PEG in relation to a moiety or reagent means that said moiety or reagent comprises at least X% (w/w) ethylene glycol units (-CH2CH2O-), wherein the ethylene glycol units may be arranged blockwise, alternating or may be randomly distributed within the moiety or reagent and in certain embodiments, all ethylene glycol units of said moiety or reagent are present in one block; the remaining weight percentage of the PEG-based moiety or reagent are other moieties in certain embodiments selected from the following moieties and linkages:
  • -R and -R a are independently of each other selected from the group consisting of -H, methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • hyaluronic acid-based comprising at least X% hyaluronic acid is used accordingly.
  • prodrug refers to a drug moiety, such as a CNP moiety, reversibly and covalently conjugated to a polymeric moiety, such as -Z, through a reversible linker moiety.
  • a prodrug releases the reversibly and covalently bound drug moiety in the form of its corresponding drug.
  • a prodrug is a conjugate comprising a drug moiety, such as a CNP moiety, which is covalently and reversibly conjugated to a polymeric moiety via a reversible linker moiety, which covalent and reversible conjugation of the polymeric moiety to the reversible linker moiety is either direct or through a spacer.
  • prodrugs or conjugates release the formerly conjugated drug moiety in the form of a free drug.
  • the term “random coil” refers to a peptide or protein adopting/having/forming, in certain embodiments having, a conformation which substantially lacks a defined secondary and tertiary structure as determined by circular dichroism spectroscopy performed in aqueous buffer at ambient temperature, and pH 7.4.
  • the ambient temperature is about 20 °C, i.e. between 18 °C and 22 °C, while in certain embodiments the ambient temperature is 20 °C.
  • reversible linkage is a linkage that is cleavable, in the absence of enzymes under physiological conditions (aqueous buffer at pH 7.4, 37°C) with a half-life ranging from one hour to six months, such as from one hour to four months, such as from one hour to three months, from one hour to two months or from one hour to one month.
  • a stable linkage is a linkage having a half-life under physiological conditions (aqueous buffer at pH 7.4, 37°C) of more than six months.
  • the term “reagent” means a chemical compound which comprises at least one functional group for reaction with the functional group of another chemical compound or drug. It is understood that a drug comprising a functional group (such as a primary or secondary amine or hydroxyl functional group) is also a reagent.
  • the term “reversible linker moiety” is a moiety which is covalently conjugated to a drug moiety, such as a CNP moiety, through a reversible linkage and is also covalently conjugated to a polymeric moiety, such as -Z, wherein the covalent conjugation to said polymeric moiety is either direct or through a spacer moiety, such as -L 2 -. In certain embodiments, the linkage between -Z and -L 2 - is a stable linkage.
  • a conjugate comprising a reversible linker moiety can be referred to as a reversible conjugate.
  • spacer refers to a moiety suitable for connecting two moieties. Suitable spacers may be selected from the group consisting of C1.50 alkyl, C2-50 alkenyl or C2-50 alkynyl, which Ci. 50 alkyl, C2-50 alkenyl or C2-50 alkynyl is optionally interrupted by one or more groups selected from -NH-, -N(CI-4 alkyl)-, -O-, -S-,
  • substituted means that one or more -H atom(s) of a molecule or moiety are replaced by a different atom or a group of atoms, which are referred to as “substituent”.
  • -R xl , -R xla , -R xlb are independently of each other selected from the group consisting of -H, -T°, C1.50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T°, C1.50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -R x2 , which are the same or different and wherein C1.50 alkyl, C2-50 alkenyl, and C2-50 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 x3 )-, -S(O) 2 N(R X3 )-, -S(O)N(R X3 )-; -S(O) 2 -,
  • Ci-e alkyl is optionally substituted with one or more halogen, which are the same or different; each -R x3 , -R x3a , -R x4 , -R x4a , -R x4b is independently selected from the group consisting of -H and Ci-e alkyl; wherein Ci-e alkyl is optionally substituted with one or more halogen, which are the same or different.
  • the one or more substituents are independently of each other selected from the group consisting of halogen, -CN, -COOR xl , -OR xl , -C(O)R xl ,
  • each -R xl , -R xla , -R xlb , -R x3 , -R x3a is independently selected from the group consisting of -H, halogen, Ci-6 alkyl, C 2 -6 alkenyl, and C 2 .e alkynyl; each T° is independently selected from the group consisting of phenyl, naphthyl, indeny 1, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11 -membered heterobicyclyl; wherein each T° is independently optionally substituted with one
  • Ci-e alkyl is optionally substituted with one or more halogen, which are the same or different; each -R x4 , -R x4a , -R x4b is independently selected from the group consisting of -H, halogen, Ci-6 alkyl, C 2 .e alkenyl, and C 2 -6 alkynyl.
  • the one or more substituents are independently of each other selected from the group consisting of halogen, -CN, -COOR xl , -OR xl , -C(O)R xl ,
  • each -R xl , -R xla , -R xlb , -R x2 , -R x3 , -R x3a is independently selected from the group consisting of -H, halogen, Ci-e alkyl, C2-6 alkenyl, and C2-6 alkynyl; each T° is independently selected from the group consisting of phenyl, naphthyl, indeny 1, indanyl, tetralinyl, cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11 -membered heterobicyclyl; wherein each T° is independently optionally substituted with one or more
  • a maximum of 6 -H atoms of an optionally substituted molecule are independently replaced by a substituent, e. g. 5 -H atoms are independently replaced by a substituent, 4 -H atoms are independently replaced by a substituent, 3 -H atoms are independently replaced by a substituent, 2 -H atoms are independently replaced by a substituent, or 1 -H atom is replaced by a substituent.
  • therapeutically effective amount means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician. Within the scope of this invention, therapeutically effective amount relates to dosages that aim to achieve therapeutic effect for an extended period of time, i.e. for at least one day, such as for two days, such as for three days, such as for four days, such as for five days, such as for six days, such as for one week or such as for two weeks.
  • traceless linker means a reversible linker which upon cleavage releases the drug in its free form.
  • water-soluble with reference to a polymeric moiety means that when such polymeric moiety is part of the CNP conjugate, at least 1 g of the CNP conjugate comprising such water-soluble polymeric moiety can be dissolved in one liter of water at 20°C to form a homogeneous solution.
  • the amino acid sequences of CNP polypeptides can be varied without significant effect on the structure or function of the peptide.
  • Such mutants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art so as to have little effect on activity.
  • guidance concerning how to make phenotypically silent amino acid substitutions is provided in Bowie et al. (1990), Science 247: 1306-1310, which is hereby incorporated by reference in its entirety, wherein the authors indicate that there are two main approaches for studying the tolerance of the amino acid sequence to change.
  • CNP analog refers to CNP of different and unrelated organisms which perform the same functions in each organism, but which did not originate from an ancestral structure that the organisms’ ancestors had in common. Instead, analogous CNPs arose separately and then later evolved to perform the same or similar functions.
  • analogous CNP polypeptides are polypeptides with quite different amino acid sequences that perform the same biological activity, namely regulating the growth, proliferation and differentiation of cartilaginous growth plate chondrocytes.
  • CNP ortholog refers to CNP within two different species which sequences are related to each other via a common homologous CNP in an ancestral species, but which have evolved to become different from each other.
  • CNP homolog refers to CNP of different organisms which perform the same functions in each organism, and which originate from an ancestral structure that the organisms’ ancestors had in common.
  • homologous CNP polypeptides are polypeptides with quite similar amino acid sequences that perform the same biological activity, namely regulating the growth, proliferation and differentiation of cartilaginous growth plate chondrocytes.
  • CNP polypeptide homologs may be defined as polypeptides exhibiting at least 40%, 50%, 60%, 70%, 80%, 90% or 95% identity to a reference CNP polypeptide.
  • the invention relates to a method of improving muscle function, such as skeletal muscle function, in a subject suffering from a disease or condition in which muscle function is impaired, the method comprising administering an effective amount of an inhibitor of FGFR3 signalling, or an effective amount of an NPR-B agonist, or an effective amount of an NPR-C agonist to said subject.
  • the FGFR3 signalling pathway is well understood and involves the MAPK and the STET pathways.
  • the receptor is activated by ligand (e.g. FGF1, FGF2 or FGF9) binding and receptor dimerization which brings tyrosine kinase domains of each member of the receptor dimer pair into close proximity, allowing them to cross-phosphorylate each other on tyrosines in their activation loops.
  • ligand e.g. FGF1, FGF2 or FGF9
  • receptor dimerization which brings tyrosine kinase domains of each member of the receptor dimer pair into close proximity, allowing them to cross-phosphorylate each other on tyrosines in their activation loops.
  • This activates the kinases, which then bind adaptor proteins and phosphorylate cytoplasmic substrates, triggering downstream signalling cascades that control cell growth and differentiation.
  • Certain pathological states are associated with constitutive FGFR3 activation, and in these states receptor dimerization and
  • Inhibition of F GFR3 signalling can occur by reducing or preventing the activity of the signalling cascade at any point in the cascade.
  • FGFR3 antagonists may bind to the receptor itself to reduce or prevent binding of the activating ligand and such molecules may be defined as direct FGFR3 antagonists.
  • Examples include anti FGFR3 antibodies, e.g. FGFR3 monoclonal antibodies, Suitable examples are disclosed in W02022/040560 which discloses anti-FGFR3 monoclonal antibodies and their use in treatment of achondroplasia and is hereby incorporated by reference in its entirety.
  • Vofatamab (B-701) is a monoclonal antibody specific for fibroblast growth factor receptor 3 in clinical development.
  • Inhibitors of F GFR3 signalling may also act to prevent F GFR3 signalling by preventing or reducing ligand binding to FGFR3.
  • Decoy molecules for the FGFR3 ligand have been developed for this purpose, By providing an alternative molecule to which the ligand can bind, signalling through the FGFR3 moelcule is reduced or inhibited.
  • FGFR3 soluble decoys/sFGFR3 polypeptide are disclosed in WO16110786, WO2022/106976 and W02018/007597, which are all hereby incorporated by reference in their entirety.
  • Recifercept is a FGFR3 soluble decoy in clinical development for treatment of achondroplsia in children (Goncalves et al., PLoS One. 2020; 15(12): e0244368).
  • Inhibitors of FGFR3 signalling may also act to reduce or prevent FGFR3 signalling, by acting on (e.g. binding to or otherwise preventing the activity of) the intracellular portion of the FGFR3 molecule itself, for example by preventing or reducing phosphorylation of the FGFR3 molecule.
  • Tyrosine kinase inhibitors e.g. infigratinib or TYR 300, such as FGFR3 selective tyrosine kinase inhibitors can be used for this purpose.
  • WO 2022/187443 discloses FGFR3 selective FGFR3 inhibitors (tyrosine kinase inhibitors) for use in treatment of achondroplasia and other disorders and is hereby incorporated by reference in its entirety.
  • LY3866288, also referred to as LOXO- 435 is a FGFR3 inhibitor in clinical development.
  • inhibitors of FGFR3 signalling may perform this function by acting on (e.g. binding to or otherwise preventing the activity of) molecules that are downstream of the receptor in one or more of its signalling pathways.
  • Such inhibitors of the FGFR3 signalling pathway may act to reduce or prevent the activity of the MAPK signalling pathway or the STAT signalling pathway downstream from FGFR3.
  • targets for inhibitors of FGFR3 signalling in the MAPK pathway are the proteins ras, raf, mek and erk.
  • CNP acts in this way as an inhibitor of the FGFR3 signalling pathway; activation of the CNP receptor NPR-B gives rise to cGMP production and activation of PKG which inhibits the raf kinase.
  • CNP, and other NPR-B agonists can therefore also be inhibitors of FGFR3 signalling.
  • Inhibitors of FGFR3 signalling therefore may act directly or indirectly on one or more of FGFR3 itself, ras, raf, mek and erk, or STAT.
  • FGFR3 signalling may thus act to reduce or decrease the amount of FGFR3 protein in the cell.
  • suitable strategies include antisense molecules and siRNA e.g. directed to the FGFR3 protein itself. In such cases the amount of FGFR3 in the relevant cell may be less than 90. 80. 70. 60, 50, 40, 30, 20, 10% of the amount of FGFR3 in the cell in the absence of the siRNA molecule or antisense molecule, or before the siRNA molecule or antisense molecule is administered.
  • Suitable examples of inhibitors of FGFR3 signalling therefore includes antibodies to FGFR3 (e.g. antagonistic antibodies to FGFR3) tyrosine kinase inhibitors (such as infigratinib, pemigatinib, futibatinib, erdafitinib or TYRA-300), molecules that prevent or reduce FGFR3-ligand binding, molecules that inhibit FGFR3 signalling via activation of the NPR-B receptor (e.g. C-type natriuretic peptide (CNP) and variants thereof), FGFR3 siRNAs and FGFR3 antisense oligonucleotides.
  • FGFR3 e.g. antagonistic antibodies to FGFR3
  • tyrosine kinase inhibitors such as infigratinib, pemigatinib, futibatinib, erdafitinib or TYRA-300
  • molecules that prevent or reduce FGFR3-ligand binding molecules
  • the fibroblast growth factor receptor 3 (FGFR3) antagonist is infigatinib which has the structure below, or a pharmaceutically acceptable salt thereof :
  • Infigratinib has been approved for the treatment of certain cancers, and is presently in clinicial development for the treatment of achondroplasia in children 3 - 1 1 years of age, who receive upto 0.25mg/kg Infigatinib daily in tablet form (https://clinicaltrials.gov/ct2/show/NCT04265651).
  • Infigratinib at high doses used in treatment of cancer is associated with side effects which may include muscle weakness and muscle cramps, it may therefore desirable to limit the daily dose in the context of the present invention to about 3mg/kg or below, such as about 0.25mg/kg or below.
  • inhibitors of FGFR3 signalling include pemigatinib, futibatinib, erdafitinib or TYRA-300.
  • Inhibitors of FGFR3 signalling, including TYRA-300 are disclosed in WO2023/279041 , WO2021/138392, WO2022/147246 and WO2021/138391 which are all hereby incorporated by reference in their entirety.
  • Inhibitors of FGFR3 signalling can be identified and characterized by standard methods, such as those described e.g. in WO2023/279041 WO2021/138392, WO2022/147246 and WO2021/138391.
  • C-type natriuretic peptide (CNP) drugs are used.
  • CNP C-type natriuretic peptide
  • in vivo CNP binds NPR-B to exert its effect on the FGFR3 signalling pathway and can thus also be described as a NPR- B agonist.
  • Other NPR-B agonists may also be used according to the invention, including small molecule NPR-B receptor agonists.
  • CNP drugs are molecules which include a CNP peptide as defined above.
  • the CNP drugs and CNP peptides are preferably either administered in a form in which they are NPR-B agonists as defined above, or they are administered in a form that gives rise to the production of NPR-B agonists in vivo (e.g. as a result of in vivo processing which releases a CNP peptide which is an NPR-B agonist in vivo).
  • the CNP drug may be administered in the form of a CNP peptide, or a CNP peptide conjugate or CNP prodrug.
  • the methods of the invention may also employ NPR-C ligands; CNP is an example of an NPR- C ligand.
  • Guagnana et al., J. Med. Chem. 2011, 54, 7066-7083, hereby incorporated by reference in its entirety provides a radiometric kinase assay which may be used to identify a FGFR3 tyrosine kinase inhibitor:
  • the enzymatic kinase activity measures the phosphorylation of a synthetic substrate by the purified GST-fusion FGFR3-K650E kinase domain, in the presence of radiolabeled ATP.
  • BaF3 Cell Lines Proliferation Assays and FGFR1-4 Cellular Autophosphorylation Assay which may also be used to identify FGFR3 inhibitors.
  • NPR-B Activity Assay may be used to identify NPR-B agonists
  • NPR-B assay Assay for determining whether CNP peptides, and free CNP released from CNP prodrug, and other NPR-B agonists may be identified using a NPR-B assay, such as the NPR-B assay reported in Breinholt et al., 2019 J Pharmacol Exp Ther 370:459-471 , which is hereby incorporated by reference in its entirity.
  • NIH3T3 cells The activity of CNP to elicit an intracellular cyclic guanosine monophosphate (cGMP) response may be determined in NIH3T3 cells. These cells express NPR-B on the cell surface (Abbey and Potter, 2003 Endocrinology, Volume 144, Issue 1, 1 January 2003, Pages 240-246 ), and stimulation of this receptor with CNP leads to intracellular production of the secondary messenger cGMP.
  • NIH3T3 cells are cultured in Dulbecco’s modified Eagle’s medium F-12 medium with 5% FBS and 5mM glutamine at 37°C and 5% CO2.
  • cGMP kit catalogue 62GM2PEB; Cisbio, Codolet, France.
  • CNP-38 SEQ ID NO:24 (CNP-38): LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, wherein the cysteines at position 22 and 38 are connected through a disulfide-bridge
  • PPA 2.0 software Stegmann Systems, Rodgau, Germany
  • the NPR-B agonist e.g. C-type natriuretic peptide
  • the NPR-B agonist has at least about 25% of the NPR-B activity (activity to elicit intracellular cGMP response in a NIH3T3 cell assay) of a CNP-38 reference standard, such as at least about 50%, 75%, 80%, 85%, 90%of the activity of the CNP-38 reference standardin the NPR-B activity assay as described above. It will be understood that for CNP prodrugs, the activity of the prodrug in the CNP assay will need to be assessed on the CNP released (free CNP) from the prodrug.
  • NPR-C Affinity & Agonist Assays which may be used to identify NPR-C agonists
  • NPR-C affinity assay such as the NPR-C affinity assay reported in Breinholt et al., 2019 J Pharmacol Exp Ther 370:459-471.
  • This NPR-C affinity assay uses a HEK293 cell line, stably overexpressing human NPR-C .
  • This NPR-C affinity assay which may be used to assess the relative NPR-C affinity of a CNP or another NPR-C ligand versus a CNP- 38 standard.
  • the C-type natriuretic peptide has at least about 25% of the NPR-C affinity of the CNP-38 reference standard, such as at least about 50% of the affinity of the CNP-38 reference standard, such as at least about 75% affinity to NPR-C of the CNP-38 reference standard, in the NPR-C affinity assay.
  • NPR-C agonists for example a standard to use when assessing NPR-C agonists in a NPR-C activity assay is cANP4-23.
  • Zhou and Murthery further discloses a [1251] ANP binding assay, which may be used to identify NPR-C ligands.
  • CNPs including CNP Peptides
  • Naturally occurring human CNP-22 (SEQ ID NO: 1) has the following sequence: GLSKGCFGLKLDRIGSMSGLGC, wherein the cysteines at position 6 and 22 are connected through a disulfide -bridge.
  • CNP also refers to the following peptide sequences: SEQ ID NO:2 (CNP-53):
  • SEQ ID NO: 10 (CNP-50):
  • SEQ ID NO: 18 (CNP-44 Al 5-22):
  • SEQ ID NO:28 PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;
  • SEQ ID NO:30 (PG-CNP-37) (Vosoritide peptide sequence):
  • SEQ ID NO:48 (CNP-27): GANKKGLSKGCFGLKLDRIGSMSGLGC;
  • SEQ ID NO: 50 CNP-27 K4R, K5R:
  • SEQ ID NO:51 CNP-27 K4P, K5R
  • SEQ ID NO: 54 (CNP-27 K4R, K5R, K9R):
  • SEQ ID NO:55 CNP-27 K4R, K5R, K9R, M22N:
  • SEQ ID NO:56 (P-CNP-27 K4R, K5R, K9R):
  • SEQ ID NO:58 HAA fragment-CNP-27
  • SEQ ID NO:59 HSA fragment-CNP-27 M22N
  • SEQ ID NO:60 M-HSA fragment-CNP-27:
  • SEQ ID NO:61 P-HSA fragment-CNP-27:
  • SEQ ID NO:68 RGLSRGCFGLKLDRIGSMSGLGC;
  • SEQ ID NO:69 (ER-CNP-22 4KR):
  • SEQ ID NO:72 (HRGP fragment-CNP-22):
  • SEQ ID NO:74 (IgGi(F c ) fragment-CNP-22):
  • SEQ ID NO:75 HSA fragment-CNP-22
  • SEQ ID NO:76 HSA fragment-CNP-22
  • SEQ ID NO:77 (osteocrin NPR C inhibitor fragment-CNP22): FGIPMDRIGRNPRGLSKGCFGLKLDRIGSMSGLGC;
  • SEQ ID NO:78 FGF2 heparin-binding domain fragment-CNP22:
  • SEQ ID NO:79 (IgGi(F c ) fragment-CNP-22 K4R):
  • SEQ ID NO: 80 HSA fragment-CNP-22 K4R
  • SEQ ID NO:81 (fibronectin fragment-CNP-22 K4R):
  • SEQ ID NO: 82 (fibronectin fragment-CNP-22 K4R):
  • SEQ ID NO: 88 (CNP-18): GCFGLKLDRIGSMSGLGC;
  • SEQ ID NO: 90 (BNP fragment-CNP-17-BNP fragment):
  • Xi, X2, X3 and X4 are independently of each other selected from the group consisting of K, R, P, S and Q, with the provision that at least one of Xi, X2, X3 and X4 is selected from the group consisting of R, P, S and Q: in certain embodiments, Xi, X2, X3 and X4 are selected from K and R, with the provision that at least one of Xi, X2, X3 and X4 is R;
  • X1X2 are selected from the group consisting of KR, RK, KP, PK, SS, RS, SR, QK, QR, KQ, RQ, RR and QQ.
  • conjugates of the present invention may be prodrugs.
  • the unit dose comprised within the unit dosage form of the present invention depends on the patient's actual body weight.
  • Vosoritide is approved for daily subcutanteous administration, and is dosed at or about 15ug/kg, although may be dosed higher in infants (e.g. about 30ug/kg). Vosoritide is presently available in 0.4mg, 0.56mg and 1.2mg vials, and the current recommended daily dose based on actual body weight (ABW) is as follows.
  • the unit dose ranges from 50 pg to 7000 pg of CNP. In certain embodiments, the unit dose ranges from 100 pg to 5000 pg of CNP. In certain embodiments, the unit dose ranges from 100 pg to 3000 pg of CNP. In certain embodiments, the unit dose ranges from 100 pg to 2000 pg of CNP. In certain embodiments, the unit dose ranges from 100 pg to 1000 pg of CNP. In certain embodiments, the unit dose ranges from 150 pg to 750 pg of CNP. In certain embodiments, the unit dose ranges from 150 pg to 500 pg of CNP.
  • the unit dose ranges from 150 pg to 350 pg of CNP. In certain embodiments, the unit dose is about 700 pg CNP. In certain embodiments, the unit dose is about 600 pg CNP. In certain embodiments, the unit dose is about 500 pg CNP. In certain embodiments, the unit dose is about 400 pg CNP. In certain embodiments, the unit dose is about 300 pg CNP.
  • the unit dose is about 6 pg CNP/kg. In certain embodiments, the unit dose is about 20 pg CNP/kg. In certain embodiments, the unit dose is about 50 pg CNP/kg. In certain embodiments, the unit dose is about 75 pg CNP/kg. In certain embodiments, the unit dose is about 100 pg CNP/kg. In certain embodiments, the unit dose is about 125 pg CNP/kg. In certain embodiments, the unit dose is about 150 pg CNP/kg.
  • the unit dose is 6 pg CNP/kg. In certain embodiments, the unit dose is 20 pg CNP/kg. In certain embodiments, the unit dose is 50 pg CNP/kg. In certain embodiments, the unit dose is 75 pg CNP/kg. In certain embodiments, the unit dose is 100 pg CNP/kg. In certain embodiments, the unit dose is 125 pg CNP/kg. In certain embodiments, the unit dose is 150 pg CNP/kg.
  • the unit dosage form is liquid. In certain embodiments, the unit dosage form is solid.
  • the unit dose ranges from about 12.3 nmol CNP/kg to at least about 37 nmol CNP/kg. In certain embodiments, the unit dose ranges from 12.3 nmol CNP/kg to 36.9 nmol CNP/kg. In certain embodiments, the unit dose ranges is at least 24.6 nmol CNP/kg. In certain embodiments, the unit dose ranges is about 24.6 nmol CNP/kg. In certain embodiments, the unit dose ranges is 24.6 nmol CNP/kg.
  • the unit dose ranges from about 6 pg CNP/kg to at least about 100 pg CNP/kg. In certain embodiments, the unit dose ranges from about 6 pg CNP/kg to about 150 pg CNP/kg. In certain embodiments, such as for compound of formula (Ilf ’) or formula (Ilf) or compound (1), the unit dose comprised within the unit dosage form of the present invention ranges from 6 pg CNP/kg to at least 100 pg CNP/kg. In certain embodiments, the unit dose ranges from 6 pg CNP/kg to 150 pg CNP/kg.
  • the unit dose is preferably administered weekly.
  • CNP conjugates or CNP prodrugs such as such as for compound of formula (Ilf ’) or formula (Ilf) or compound (1)
  • x pg CNP/kg refers to “x” pg of CNP, i.e. of the CNP moiety comprised within the CNP conjugate, per kilogram of patient's body weight
  • y nmol CNP/kg refers to “y” nmol of CNP, i.e. of the CNP moiety comprised within the CNP conjugate, per kilogram of patient's body weight.
  • the subject is an adult.
  • Adult humans are 18 years of age and above.
  • the subject is at least 19 years of age, such as at least 20 or 25 years of age.
  • the subject is a pediatric patient, i.e. below 18 years of age, such as below 16 years or below 14 years, or 5 years of age. In certain embodiments, the subject is an infant (e.g. less than 1 year or less than 9 or 6 months).
  • the subject is also referred to as the patient.
  • the patient's body weight ranges from about 2 kg to about 80 kg. In certain embodiments, the patient's body weight ranges from about 4 kg to about 60 kg. In certain embodiment, the patient's body weight is about 5 kg. In certain embodiment, the patient's body weight is about 9 kg. In certain embodiment, the patient's body weight is about 10 kg. In certain embodiment, the patient's body weight is about 11 kg. In certain embodiment, the patient's body weight is about 12 kg. In certain embodiment, the patient's body weight is about 15 kg. In certain embodiment, the patient's body weight is about 20 kg. In certain embodiment, the patient's body weight is about (at least about) 30 kg. In certain embodiment, the patient's body weight is about (at least about) 40 kg.
  • the patient's body weight is about (at least about) 50 kg. In certain embodiment, the patient's body weight is about (at least about) 60 kg. In certain embodiment, the patient's body weight is about (at least about) 70 kg. In certain embodiment, the patient's body weight is about (at least about) 80 kg.
  • the subject is suffering from a disease or condition in which muscle function (e.g. skeletal muscle) is impaired.
  • muscle function e.g. skeletal muscle
  • the reduction in muscle function can be assessed relative to threshold levels or by reference to an individual without the disease or condition. Loss or reduction in muscle function could arise as a result of the disease or condition acting directly on the muscle (e.g. a myopathy) or may be a disease affecting the neuromuscular junction or a disease affecting the nervous system.
  • the disease or condition in which muscle function e.g.
  • skeletal muscle is impaired may include a chondrodysplasia disease, such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia.
  • a chondrodysplasia disease such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia.
  • the subject has achondroplasia.
  • the subject has a Rasopathy.
  • the subject has a chondrodysplasia disease, such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia. In certain embodiments the subject has achondroplasia.
  • the subject does not have a chondrodysplasia disease, such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia. In certain embodiments the subject does not have achondroplasia. In certain embodiments the subject does not have a chondrodysplasia disease.
  • a chondrodysplasia disease such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia.
  • the subject does not have achondroplasia.
  • the subject does not have a chondrodysplasia disease.
  • Skeletal muscle is one of the three main types of muscle in the body, the others being cardiac muscle and smooth muscle. Skeletal muscle is muscle which is attached to the bone via tendons. Skeleetal muscle may also be referred to a striated muscle. Administering the inhibitor of FGFR3 signalling or NPR-B agonist or NPR-C agonist has been shown to give rise to an improvement in muscle function, particularly skeletal muscle function.
  • the subject has a myopathy.
  • Myopathies are a heterogeneous group of disorders primarily affecting the skeletal muscle structure, metabolism, or channel function, which typically result in muscle weakness, stiffness, cramps and spasms, and may result in or contribute to skeletal deformities, such as abnormal curvature of the spine.
  • Myopathies usually present with muscle weakness interfering in daily life activities.
  • the myopathy or impaired muscle function may be a mitochondrial myopathy, i.e. a myopathy caused by a defect in the mitochondria.
  • Myopathy may be inherited or acquired.
  • Inherited myopathies may be congenital myopathy, i.e. myopathy symptoms start at birth or early childhood.
  • the subject has a disease or condition associated with an impairment in neuromuscular function, such as a neuromuscular or a neurodegen erative disease.
  • the methods are carried out on a subject having a disease or condition associated with an impairment in neuromuscular function, such as a neuromuscular or a neurodegenerative disease.
  • the invention also provides a method of treating or preventing a disease or condition associated with an impairment in neuromuscular function, such as a neuromuscular or neurodegenerative disease, the method comprising administering a therapeutically effective amount of an inhibitor of FGFR3 signaling, an NPR-B agonist or an NPR-C agonist (e.g. an NPR-B agonist, such as a C type natriuretic peptide (such as conjugates of CNP)), to a subject who is suffering from the neuromuscular or or neurodegenerative disease.
  • the neuromuscular or neurodegenerative disease is is one in which mitochondrial dysfunction is present.
  • the said administration of the effective amount of the inhibitor of FGFR3 signaling, NPR-B agonist or NPR-C agonist (e.g. NPR-B agonist) to the subject who has a disease or condition associated with an impairment in neuromuscular function may result in improved mitochondrial function in said subject.
  • This may, for example be observed (or monitored) via improved muscle function such as improved skeletal muscle function or improved neuromuscular function; or via a slowing, delaying or reduction of disease progression, such as a reduced rate of loss or decline of muscle function, or reduced rate of loss or decline of neuromuscular function (e.g. compared to a reference, or to the subject prior to, or in the absence of the treatment).
  • the method of treatment may be initiated after diagnosis of the disease or condition associated with an impairment in neuromuscular function, and optionally prior to significant or noticeable loss in muscle or neuromuscular function.
  • Mitochondrial dysfunction may be identified by the diagnosis of a disease or disorder which is associated with mitochondrial dysfunction, via genetic testing, i.e. identification of a genetic polymorphism which is associated with or causes mitochondria dysfunction, via biochemical analysis from a biopsy of the affected tissue, or via biochemical markers in blood or urine (See for example Muraresku et al., Curr Genet Med Rep. 2018 Jun; 6(2): 62-72).
  • the disease or condition associated with an impairment in neuromuscular function may include a neuromuscular disorder /neuromuscular disease (NMDs).
  • NMDs neuromuscular disorder /neuromuscular disease
  • Suitable NMD disorders and diseases may be associated with mitochondrial impairment and dysfunction (see for example Marra et al., Biomolecules 2021, vol 11 (11); 1633.
  • the methods of the present invention may therefore be used to improve mitochondrial function, or slow the decline in mitochondrial function, in subject having a disease or condition associated with an impairment in neuromuscular function (e.g. a NMD) (e.g. compared to a reference, or to the subject prior to or in the absence of the treatment).
  • neuromuscular diseases include genetically acquired diseases, including muscular dystrophies and myopathies as well as neuromuscular diseases.
  • Neuromuscular diseases include neurodegenerative diseases and disorders associated with loss of mitochondrial function, and may for example, be selected from the group consisting of: Motor neuron disease (MND, also known as Amyotrophic Lateral Sclerosis, ALS); Parkinson’s Disease (PD), Multiple Sclerosis (MS, including progressive MS or relapsing remitting MS); Alzheimer’s Disease (AD); ataxia’s such as Friedreich’s ataxia (FRDA), and Huntington’s disease (HD).
  • MND Motor neuron disease
  • ALS Amyotrophic Lateral Sclerosis
  • PD Parkinson’s Disease
  • MS Multiple Sclerosis
  • AD Alzheimer’s Disease
  • ataxia’s such as Friedreich’s ataxia (FRDA), and Huntington’s disease (HD).
  • Parkinson’s disease is associated with mitochondrial dysfunction and the pathogenesis in PD leads to muscular weakness and fatigue (Borsche et al., J Parkinsons Dis. 2021 ;11 (l):45-60). Timmer et al., J Neurosci. 2007 Jan 17; 27(3): 459-471 indicates aberrant FGFR3/FGF-2 signaling in animal models of PD. Central and systemic CNP (amino-terminal proCNP) levels are both reduced in Parkinson's Disease, and can be restored by treatment with monoamine oxidase inhibitors (Espiner et al., J Neural Transm (Vienna). 2014 Apr: I 2 l (4j:371 -8: Woodward, Parkinsonism Relat Disord.
  • Muscle function may be routinely monitored in PD patients using physical functioning tests such as sit to stand tests and six -minute walk tests (see e.g. Clael et al, Neurosci J 2918 8507018). Suitable physical functioning tests used in monitoring of PD patients may include speech, facial expression, rising from a chair, gait, or postural stability (see e.g. Brusse et al., Physical Therapy, Volume 85, Issue 2, 1 February 2005, Pages 134-141). Recently, the FDA has approved a PD monitoring app (Rube Labs) for patient monitoring via a smart device (e.g. a phone or smart watch), which can provide all day monitoring of physical activities such as walking, as well as other PD symptoms such as tremors and dyskinesia, it is therefore envisaged that such smart device apps be used to monitor the effective treatment according to the present invention.
  • a smart device e.g. a phone or smart watch
  • Zhao et al., Cells 2002 Jul; 11(13) 2049 reports that mitochondria dysfunction is a key contributing factor in amyotrophic lateral sclerosis (ALS) and that mitochondria disfunction is associated with and involved in the pathogenesis of the disease. Zhao et al., Molecular Neurodegeneration 6, Article number: 51 (2011) reports that PGC-lalpha plays a protective role in ALS.
  • ALS amyotrophic lateral sclerosis
  • Impairment of PGC-la mediated mitochondrial biogenesis is indicated in Alzheimer’s disease pathology, and precedes mitochondrial dysfunction associated with progression of AD (Bhatia, Curr. Neuropharmacol. 2002 20(4): 675-692.
  • Physical functioning is affected in people living with dementia, such as Alzheimer’s Disease (AD), and can lead to slow reaction time, muscle weakness, poor coordination and impaired balance, and along with cognitive impairment is a major contributor to events such as falls and fractures.
  • AD Alzheimer’s Disease
  • cognitive impairment is a major contributor to events such as falls and fractures.
  • physical ability may be significantly compromised, severely limiting walking, gait and motion (see e.g. Taraldsen et al., BMC Geriatrics volume 21 , Article number: 670 (2021) which reports on the use of physical accelerometer sensors to monitor daily physical activity in dementia patients).
  • Muscle strength is the maximal ability to exert force for a short period of time. This may be assessed for example using the Oxford Scale which involves testing key muscles from the upper nd lower extremities against the examiner’s resistance and grading the patient’s strength on a 0 to 5 scale accordingly (Naqvi U. Muscle strength grading. InStatpearls [Internet] 2019 May 29. StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK436008/):
  • Commonly tested muscles include the shoulder abductors, elbow flexors, elbow extensors, wrist extensors, finger flexors, hand intrinsics, hip flexors, knee extensors, dorsiflexors, great toe extensor, and plantar flexors. These muscle groups are commonly chosen, so that important spinal nerve roots are assessed systematically eg testing the strength of the elbow flexors, elbow extensors, wrist extensors, finger flexors, and hand intrinsics allow for a methodical evaluation of the C5 to T1 nerve roots.
  • distal strength can be semiquantitatively measured with a handgrip ergometer (or with an inflated BP cuff squeezed by the patient) to record grip strength, or dynamometry, which is a more precise measurement of the force that a muscle can exert and can allow for differences in strength to be recorded over time.
  • An increase in muscle strength therefore may be observed as an increase in the Oxford score, or an increase in distal strength as assessed by a handgrip ergometer (or with an inflated BP cuff squeezed by the patient) to record grip strength, or dynamometry.
  • Muscle tone is also referred to as residual muscle tension or tonus and is the continuous and passive partial contraction of the muscles, or the muscle's resistance to passive stretch during resting state. It helps to maintain posture and declines during REM sleep. It is distinct from muscle strength. Muscle tone is regulated by the activity of the motor neurons and can be affected by various factors, including age, disease, and nerve damagehypotonia. Hypotonia refers to a decreased resting tone of the muscle and decreased resistance to passive movement. Hypotonia is rarely seen in isolation without some degree of weakness.
  • Hypotonus (low muscle tone) describes a reduced stiffness of muscle that does not effectively support upright posture against gravity or to produce adequate force during contraction; as a result, hypotonic muscles are typically more compliant than they are stiff. Hypotonia is observed for example in subjects having various conditions such as Down syndrome, Muscular dystrophy, Cerebral palsy, Prader-Willi syndrome, Myotonic dystrophy, Marfan syndrome, Tay-Sachs disease. Hypotonia is in general assessed by medical observation and an improvement in hypotonia will result in increased resting tone and resistance to passive movement, as assessed by a medical professional.
  • muscular endurance or muscle stamina
  • This is the ability of a muscle’s or group of muscles’ resistance to fatigue during repetitive muscle contractions against and external force. This is generally assessed observationally, e,g, by carrying out a repetitive exercise over a period of time, for example counting the number of push ups a patient can carry out in a given period, e.g. 60 seconds, or determining how long an individual takes to carry out a set number of repeats of an exercise.
  • An improvement in muscular endurance would manifest in an improvement in the number of repeptive exercises in the given period of time or in a reduction in the amount of time required to carry out a set number of repeats of the exercise.
  • Muscle mass is the amount of muscle in the subject’s body, including skeletal muscles, smooth muscles, and cardiac muscles.
  • Muscle mass can be measured e.g. by carrying out Dual energy X-ray absorptiometry, a CT scan, or an MRI scan.
  • Muscle mass may be increased by the methods of the invention, and an increase in muscle mass may also give rise to an increase in mscle to fat ratio (e.g skeletal muscle to fat ratio).
  • Fat mass can be measured usinsg DEXA and Bioelectric Impedance Analysis (BIA). Additionally or alternatively there may also be an increase in one or more of muscle volume, muscle density and muscle length of the subject.
  • Muscle fatigue is used to describe the decline in force produced by a muscle or group of muscles during repetitive contractions against an external force.
  • An example of a test to measure muscle fatgue is the Biering-Sorenson test which has been used to assess fatigue of the trunk extensor muscle group and which is also used as a test for back pain. The test as described by Sorenson (Biering- Sorensen F. Physical measurements as risk indicators for low-back trouble over a one-year period. Spine.
  • cardiovascular endurance is the ability of the subject’s heart and lungs to fuel their body with oxygen. This could also be defined the ability to perform moderate to high intensity exercise (at a percentage of V02max) for a prolonged period.
  • Cardiovascular endurance can be measured by standard techniques including measuring VO2 max through indirect calorimetry.
  • V02max is the maximum amount of oxygen that an individual can utilize during intense or maximal exercises and is typically measured by determining volume and gas concentrations of inspired and expired air while a person performs maximal, graded exercise on a treadmill or cycle ergometer.
  • V02max can be expressed in terms of liters of oxygen consumed per minute (1/min), or the values can be normalized for differences in body size and expressed as milliliters of oxygen consumed per kilogram of body weight per minute (ml/kg/min). An increase in cardiovascular endurance may therefore be observed as an increase in V02max (1/min), or (ml/kg/min) using this assay.
  • Cardiovascular fitness is the the body’s maximal ability to take up oxygen. This is also measured as V02max (L 02/Min). An increase in cardiovascular fitness may therefore also be observed as an increase in V02max (1/min), or (ml/kg/min) .
  • Exercise intolerance is the reduced ability of the body to perform activities that involve strenuous movement, and may result in inability or decreased ability to perform physical exercise at a normal level or duration.
  • Objective tests for exercise intolerance include moderate activity, e.g. stair climbing, walking for six minutes, a shuttle -walk test, a cardiac stress test, and the cardiopulmonary exercise test (CPET).
  • CPET cardiopulmonary exercise test
  • the goal is to see how far the person can walk, with approximately 600 meters being a reasonable outcome for an average person without exercise intolerance.
  • a decrease in exercise intolerance may therefore be observed as an increase in the distance a person can walk in the six-minute test.
  • exercise capacity is the maximum amount of physical exertion that a patient can sustain.
  • maximal exercise tests e.g. ESTs which are symptom-limited tests performed with a 12-lead ECG used to diagnose exercise-induced myocardial ischaemia, arrhythmias or an abnormal blood pressure response, or a cardiopulmonary exercise test
  • submaximal exercise tests e.g. six minute walk tests and incremental shuttle walk tests, with the appropriate test being selected depending on the subject’s physical state.
  • An increase in exercise capacity may therefore be observed as an increase in the score obtained in any of these assessments.
  • EF exercise-induced fatigue
  • any such increases or improvements that can be quantified may be an increase or improvement in the performance as determined by a score or value that is at least 1, 2, 3, 5, 10, 15, 20, 25, 30, 35% , improved (whether the actual value increases or decreases, depending on the nature of the test) relative to that value without or before administration of the FGFR3 signalling inhibitor or or NPR-B agonist or NPR-C agonist, for example after at least 1, 2, 3, 4, 5, 6, 12, 18, 24, 36 months of administration of the FGFR3 signalling inhibitor or NPR-B agonist or NPR-C agonist.
  • biochemical assays on muscle biopsy or for products of muscle metabolism released to body fluids may be used in these methods, and may give rise to quantitative outcomes.
  • an improvement in muscle function may be defined as an improvement relative to muscle function without or before administration of FGFR3 signalling inhibitor or or NPR-B agonist or NPR-C agonist.
  • a subject treated with an FGFR3 signalling inhibitor or or NPR-B agonist or NPR-C agonist may still have an overall decline in muscle function (e.g. over time), but this decline in muscle function may in these embodiments be less than the decline that would have occurred in the absence of the treatment.
  • an improvement in muscle function may be manifest as a reduction in decline of muscle function (e.g.
  • a disease or condition associated with an impairment in neuromuscular function such as a neuromuscular or a neurodegenerative disease.
  • a subject takes longer to reach a certain level of muscle function than would be expected, based on the subject’s diagnosis.
  • the progression of the disease e.g. in terms of muscle function
  • Musculo-skeletal pain is defined as acute or chronic pain that affects bones, muscles, ligaments, tendons, and even nerves.
  • the pain may comprise a number of different pain syndromes, which range from local pain to neuropathic pain.
  • Musculoskeletal pain is primarily somatic in nature. The most prevalent forms of musculoskeletal pain are chronic low back pain, neck pain.
  • Musculo skeletal pain may be pain in the musculoskeletal system including joints, ligaments, muscles, nerves, or tendons, In some embodiments the musculo-skeletal pain may be chronic pain, typically a pain that carries on for longer than 12 weeks. In some embodiments the musculo-skeletal pain may be muscle pain, such as skeletal muscle pain, such as chronic skeletal muscle pain. In some embodiments the musculo-skeletal pain may be pain associated with abnormal curvature of the spine. In some embodiments the pain may not be associated with arthritis, such as osteoarthritis. In some embodiments the musculo-skeletal pain may be myalgia.
  • the musculo-skeletal pain may be associated with or caused by muscle cramps or spasms. Musculo-skeletal pain may be diagnosed or monitored via, for example, patient reported pain (See for example Nielsen and Arendt-Nielsen, Curr Pain Headache Rep. 2003 Dec;7(6):443-51); MRI or CT scan; electromyography e.g. to measure electrical activity in nerves and muscles.
  • Poor or bad posture refers to postural dysfunction, and may be defined as when a subject’s spine is positioned in unnatural positions, in which the curves are emphasized. Complications of poor posture include back pain, spinal dysfunction, joint degeneration, rounded shoulders and a potbelly.
  • the improvements associated with posture and spine curvature after administration of the inhibitor of FGFR3 signalling, or NPR-B agonist, or NPR-C agonist, may result from the improvements in muscle function as described above.
  • Example 1 This is consistent with the osbservations in Example 1 that treatment with the test Compound (1) had an impact on survival after only 15 days of treatment which is a time frame that is consistent with effects on muscle historic survival and increased incidence of maternal infanticide has been described in mouse models with muscle weakness as a major phenotypical trait (e.g., Sullivan 2014).
  • the improvement may be in kyphosis, lordosis, or scoliosis, or in spinal stenosis, which may e.g. arise from any of the above spinal deformities.
  • Kyphosis is an exaggerated, forward rounding of the upper part of the spine.
  • Lordosis is an exaggerated inward curve of the spine.
  • Scoliosis is an abnormal lateral curvature of the spine.
  • Spinal stenosis may for example arise from any of the above spinal deformities and is a narrowing of the spinal canal in the spine.
  • the improvement in kyphosis, lordosis, spinal stenosis or scoliosis is by improving muscle function.
  • These spinal abnormalities may occur in chondrodysplasia disease and preferably the subject with kyphosis, lordosis, spinal stenosis or scoliosis has a chondrodysplasia disease, such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia.
  • Abnormal curvature of the spine may, for example, be monitored via physical examination, or an imaging method (e.g. x-ray examination, spinal radiography, CT scan or MRI scan). Signs of abnormal curvature of the spine may include, for example, uneven shoulders, head not cantered above the pelvis, one or both hips raised or unusually high, uneven waist, body lean. Curvature of the spine may for example be measured using the Cobb method.
  • the invention relates to the treatment of a spinal deformity in a subject who has a chondrodysplasia disease, such as a chondrodysplasia disease disclosed herein, such as achondroplasia.
  • a chondrodysplasia disease such as a chondrodysplasia disease disclosed herein, such as achondroplasia.
  • Spinal deformities in chondrodysplasias such as achondroplasia can lead to pain and disability.
  • Congenital narrowing of spinal canal is common in achondroplasia and is associated with neurological symptoms that worsen with age and can cause premature or sudden death, and may require corrective surgery or repeated corrective surgeries during the lifetime of the patient.
  • the spinal deformity may include an abnormal curvature of the spine which can be corrected, at least partially by the strengthening of muscles in the back, suitably via the therapeutic uses disclosed or claimed herein.
  • the spinal deformity may be an abnormal spinal pedicle morphology or spinal stenosis, which is typical in achondroplasia, which may be further compounded by an abnormal curvature of the spine.
  • the abnormal spinal pedicle morphology may be a reduction in the interpedicular distance or reduced pedicular width. Inter- pediculate narrowing and thickened pedicles are common on achondroplasia and the resulting spinal canal stenosis often requires surgical intervention, for example to correct narrowing of the foramen magnum (FM).
  • FM foramen magnum
  • the invention provides for the use of the inhibitor of F GFR3 signaling or the NPR-B agonist for use according to the invention or as according to any one of the claims, wherein said use gives rise to an increase spine height, such as increased thoracic height; increased interpedicular distance or increased pedicular width.
  • the invention provides for the use of the NPR-B agonist for use according to the invention or as according to any one of the claims, wherein said use gives rise to an increase spine height, such as increased thoracic height; increased interpedicular distance or increased pedicular width.
  • the invention provides for a method of treating a spinal pedicular deformity in a subject in need of treatment, said method comprising administering a therapeutically effective amount of an inhibitor of FGFR3 signaling, or an NPR-B agonist to said subject.
  • said method may comprise an initial step of (i) diagnosing or measuring the spinal pedicular deformity in the subject, and then (ii) administering a therapeutically effective amount of an inhibitor of FGFR3 signaling, an NPR-B agonist, to the subject.
  • the measurement step may involve one or more x-rays, such as an anteroposterior (AP) X-ray, and or a lateral x-ray. Lateral x-rays are useful to measure e.g. the pedicular width, and the AP X-ray is useful to measure e.g. the interpedicular distance. X-rays of the spine or spinal deformity taken prior to and after the administration may be used to determine the effective treatment.
  • AP anteroposterior
  • the diagnosis or measurement step may be the measurement of one or more of spine height, thoracic height; interpedicular distance and pedicular width.
  • the disgnosis measurement step may be or include the measurement of spinal pedicle morphology or spinal stenosism / spinal canal stenosis.
  • the administration gives rise to an improvement in sleep apnea, obstructive sleep apnea, or otitis media.
  • Sleep apnea is a condition in which the subject’s breathing stops and restarts many times during sleep. This can prevent the subject’s body from getting enough oxygen.
  • Obstructive sleep apnea (OSA), is a form of sleep apnea that occurs when throat muscles relax and block the flow of air into the lungs.
  • Otitis media is an infection of the middle ear that causes inflammation (redness and swelling) and a build-up of fluid behind the eardrum, and is associated with mid face hypoplasia. Otitis media can result in hearing loss.
  • the improvement in sleep apnea, obstructive sleep apnea, or otitis media is by improving muscle function.
  • These conditions may occur in chondrodysplasia disease and preferably the subject with sleep apnea, obstructive sleep apnea, or otitis media has a chondrodysplasia disease, such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia. It is believed that an improvement in muscle function will give rise to a benefit in these conditions in view of an association between sleep-disordered breathing, and upper airway (e.g. laryngeal and phalinguial) muscle weakness.
  • upper airway e.g. laryngeal and phalinguial
  • the invention relates to a method of treating obstructive sleep apnea.
  • Sleep apnea such as obstructive sleep apnea may be monitored for example via nocturnal polysomnography / using breathing monitor.
  • Otitis media is defined as an infection of the middle ear space, and is typically diagnosed and monitored via a physical exam, and several diagnostic tools are available such as a pneumatic otoscope, tympanometry, and acoustic reflectometry. Otitis media is often associated with ear pain, reduced hearing and fever, which may also be monitored.
  • the otitis media is acute otitis media, and the present invention provides effective treatment which may reduce the frequency of acute otitis media events, reduce the severity of acute otitis media, or both.
  • the invention relates to a prophylactic treatment of otitis media. The monitoring of otitis media may therefore be assessing the frequency or severity of acute otitis media events, or both.
  • the administration gives rise to a reduction in obesity.
  • subjects prior to treatment are suffering from low muscle function, this makes it harder for them to excercise and to exercise well and effectively for weight control and general physical health.
  • a reduction in obsesity can also be obtained.
  • This problem has been observed in patients having chondrodysplasia disease and obesity is noted as a major health problem in achondroplasia necessitating an early yet complex clinical management (see Saint-Laurent, C., Garde-Etayo, L. & Gouze, E. Obesity in achondroplasia patients: from evidence to medical monitoring. Orphanet J Rare Dis 14, 253 (2019). https://doi.org/10.
  • achondroplasia 1 186/s 13023-019- 1247- 6) which notes that children with achondroplasia are limited by their psychomotor development and their physical condition, and the early appearance of overweight and obesity contributes to worsen a sedentary lifestyle and/or to exclude these children from the sports practiced by children their age.
  • the reduction in obesity is by improving muscle function.
  • Obesity may occur in chondrodysplasia disease and preferably the subject with obesity has a chondrodysplasia disease, such as a disease selected from the group consisting of achondroplasia, hypochondroplasia, and thanatophoric dysplasia.
  • Obesity is defined as a body mass index (BMI) of over 30.
  • BMI body mass index
  • the subject may have a BMI of over 30 at initiation of administration, e.g. a BMI of over 30, 32, 35, 38, 40 before administration.
  • Hand deformities are a characteristic in achondroplasia, and include short finger length, trident hand deformity, and an inability to fully extend fingers.
  • the invention provides for an inhibitor of FGFR3 signaling or an NPR-B agonist, for use in promoting hand length growth or finger length growth in a human subject who is less than 18 years of age or whose bone epiphysis have not closed.
  • the invention provides for an inhibitor of FGFR3 signaling or an NPR-B agonist, for use in correcting a hand deformity in a human subject who is less than 18 years of age or whose bone epiphysis have not closed.
  • the invention provides for an inhibitor of FGFR3 signaling or an NPR-B agonist, for use according to the invention or according to any one of the claims, wherein said use increases hand length growth or finger length growth in the human subject, such as a human subject who is less than 18 years of age or whose bone epiphysis have not closed.
  • the invention provides for a method of increasing the rate of hand or finger length in a subject in need of treatment, said method comprising administering a therapeutically effective amount of an inhibitor of FGFR3 signaling, or an NPR-B agonist to said subject.
  • the method of the invention may comprise the steps of (i) assessing hand length or finger length(s) in the subject in need of treatment, and (ii) administering a therapeutically effective amount of an inhibitor of FGFR3 signaling, or an NPR-B agonist, to the subject, and (iii) optionally measuring the increase in hand length or finger length(s) after said administration.
  • the invention provides for a method of correcting hand deformity in a subject in need of treatment, said method comprising administering a therapeutically effective amount of an inhibitor of FGFR3 signaling, or an NPR-B agonist to said subject.
  • the method of the invention may comprise the steps of (i) assessing hand deformity, in the subject in need of treatment, and (ii) administering a therapeutically effective amount of an inhibitor of FGFR3 signaling, or an NPR-B agonist, to the subject, and (iii) optionally assessing the change in hand deformity in the subject after said administration.
  • the invention provides methods of improving muscle function in a subject suffering from a disease or condition in which muscle function is impaired.
  • the methods include assessing muscle function at least once in the subject suffering from a disease or condition in which muscle function is impaired, and administering a therapeutically effective amount or regimen of an inhibitor of FGFR3 signaling, an NPR-B agonist or an NPR-C agonist to the subject.
  • This may be described as a method of improving muscle function in a subject suffering from a disease or condition in which muscle function is impaired, the method comprising:
  • the assessing step can be performed before the administering step, e.g. to determine a baseline value or determination of muscle function before administration begins. This may be useful e.g. for comparison with subsequent values or determination of muscle function, which may be assessed after administration. For example, in such case, the assessing step can be performed, e.g., up to a week, a month or three months before initiating administration.
  • the assessment step before administration can be used as a comparison, e.g. to determine the effectiveness of the treatment.
  • the administering step may be initiated responsive to the assessing step.
  • the administering step will in general comprise administering the inhibitor of FGFR3 signaling, the NPR-B agonist or the NPR-C agonist a plurality of times.
  • Assessment of muscle function can also be performed at least twice, or a plurality of times.
  • it is performed once or or at least once before initiating the administering step (e.g. to determine a baseline) and once or at least once after initiating the administering step.
  • the assessing step may also be performed at least three times, once or at least once before initiating the administering step (e.g. to determine a baseline) and twice or at least twice after initiating the administering step.
  • Assessment of muscle function before initiating administration can also be used, optionally in combination with other signs or symptoms of a subject, to diagnose a subject as suffering from a disease or condition in which muscle function is impaired.
  • the methods referred to herein may thus additionally comprise diagnosing the subject as suffering from an impairment of muscle function and/or from a disease or condition in which muscle function is impaired.
  • Administration can begin responsive to the assessment step and/or to diagnosis of the disease or condition in the subject.
  • Administration can also begin in response to assessment of impaired muscle function relative to reference values, e.g. which may be obtained by assessment carried out on normal or control subjects (e.g. subjects known not to be suffering from a disease or condition in which muscle function is impaired).
  • An assessing step can additionally or alternatively be performed after initiating the administration, e.g., between successive doses of drug.
  • the assessing step performed after initiating the administration can be performed once or a plurality of times.
  • the assessing step may be performed at least 4, 5, 6, 7, 8, 9, 10 times, e..g weekly, monthly, annually, e.g. at regular intervals.
  • the assessing step may be performed for the duration of the treatment.
  • Assessment of muscle function can include any of a) skeletal muscle strength, b) skeletal muscle tone c) skeletal muscle stamina, d) skeletal muscle mass, e) skeletal muscle fatigue, f) cardiovascular endurance, g) cardiovascular fitness, h) exercise intolerance, i) exercise capacity, j) exercise induced fatigue, k) hypotonia, 1) skeletal muscle mass and/or muscle/fat ratio (such as skeletal muscle/fat ratio), m) musculo-skeletal pain, n) posture or curvature of the spine, optionally kyphosis, lordosis, spinal stenosis or scoliosis o) sleep apnea, obstructive sleep apnea, or otitis media, p) obesity.
  • assessments include those described elsewhere herein. Examples include measures of muscle weight, muscle length, muscle density, muscle size and/or volume.
  • the assessments may including subject imaging, observing subject performance.
  • the assessments may be with or without quantitative metrics in physical testing, such as for muscle fatigue and cardiovascular testing or by biochemical assays on muscle biopsy or for products of muscle metabolism released to body fluids.
  • the assessment may comprise imaging, e.g. at least one imaging step (such as X-ray examination, spinal radiography, CT scan or MRI scan).
  • imaging e.g. at least one imaging step (such as X-ray examination, spinal radiography, CT scan or MRI scan).
  • the assessment may comprise determining a performance metric of the subject, which may for example be a measurement or an observation of the subject’s ability to carry out certain tasks, e.g. with reference to physical functioning tests such as those described elsewhere herein (e.g. to determine muscle fatigue and endurance levels such as sit to stand tests and six-minute walk tests).
  • a composite index may be generated.
  • a composite index is generated for at least 2, 3, 4, 5, 6, 7 (or 1 -6, 2-5, 3-4) of any assessments carried out, e.g. for at least 2, 3, 4, 5, 6, 7 (or 1-6, 2-5, 3-4) of the assessments a) to p) set out above. If a composite index is generated, this may form the basis of any comparisons referred to elsewhere herein.
  • An improvement in muscle function can be any improvement in muscle function as defined elsewhere herein.
  • an assessing step is performed at least once before initiating the administering step e.g. to determine a baseline value or determination for muscle function and once, twice or more times after initiating administration , e.g. to allow determination of changes of muscle function responsive to administration.
  • Comparison of values of muscle function before and after administration can indicate increased muscle function, unchanged muscle function or decreased muscle function.
  • Increased muscle function following and responsive to initiation of administration may be one indicator of a positive response to treatment, i.e., that the treatment is successful.
  • an increase in muscle function or progressive increases with further dosing, or an increase in muscle function when muscle function was declining in the subject before treatment or shows decline in historical control subjects are indicators of a positive response to treatment.
  • a finding of unchanged muscle function or decreased muscle function may indicate a positive response to treatment or may indicate a need for a change in the treatment protocol (e.g., to increase dosage and/or frequency thereof), and this will depend on the particular condition and expected outcome. For example, if muscle function was impaired but stable in a subject before initiating administration of drug, unchanged or decreased muscle function after administration of drug may be a negative indicator of response to treatment. But if muscle function was impaired and declining in a subject before initiating administration of drug, then unchanged muscle function following and response to administration of drug may indicate a positive response to treatment. Likewise, even decreased muscle function following initiating administration of drug is less than expected based on a decline in the subject before initiating administration or in untreated historical control subjects can indicate a positive response to treatment.
  • a change in the treatment protocol e.g., to increase dosage and/or frequency thereof
  • Decreased muscle function beyond any expectations based on a decline in the subject before initiating administration of drug or in untreated historical control subjects may indicate a negative response to drug administration.
  • the expectations may depend on comparison with control value(s) determined in the same subject before initiating drug administration, reference subjects or normal and/or control subjects.
  • Assessment of changes in muscle function in response to administration can be used to guide treatment decisions whether to continue administration of the drug, modify the regimen of the drug (e.g., change dosage or frequency) or discontinue administration of the drug. For example, if the assessment provides an indication of a positive response to administration, the same treatment can continue to be administered, e.g. under the same regimen. Variation of the dosage and/or frequency up or down can also be considered depending on the magnitude of the response and any side effects the subject is experiencing. For example, an increased dose and/or frequency can be administered for an increased response or decreased dose and/or frequency to reduce any side effects.
  • the assessment indicates a negative response to treatment (or no positive response to treatment) and the subject is tolerating the administered drug without unacceptable side effects, then a higher dose or frequency of the same drug can be administered to attempt to elicit a positive treatment response. If the assessment continues to indicate a negative response to treatment (or no positive response to treatment) or the subject cannot tolerate a higher dose or frequency due to side effects, then administration of the drug can be discontinued.
  • An assessment step may follow any method of treatment referred to herein.
  • the invention provides the method according to any one of Items 34 - 114.
  • Methods relating to treating or preventing a disease or condition associated with an impairment in neuromuscular function, such as a neurodegenerative disease in a subject may likewise incorporate assessment steps relating to determination of muscle (e.g. skeletal muscle function, e.g as referred to above).
  • assessment steps relating to determination of mitochondrial dysfunction, neuromuscular function e.g. to establish whether the treatment gives rise to a slowing, or delaying or reduction of disease progression, such as a reduced rate of loss or decline of muscle function, or reduced rate of loss or decline of neuromuscular function.
  • the growth hormone is or comprises somatropin, or is a somatropin conjugate such as a PEGylated somatropin, or a fatty acid growth hormone conjugate.
  • the growth hormone is a conjugate of growth hormone such as a conjugate of human growth hormone.
  • the conjugate moiety may, for example comprise a PEG moiety, a fatty acid moiety, a serum albumin binding moiety, an antibody moiety, or an antibody fragment moiety.
  • the growth hormone is a long-acting growth hormone, such as a growth hormone for weekly administration.
  • long-acting growth hormone may be administered weekly or less frequently than weekly.
  • the growth hormone may be a controlled-release hGH.
  • Long acting human growth hormone and controlled-release hGH are disclosed in WO 2018/060314 Al, which is hereby incorporated by reference in its entirety.
  • the growth hormone is lonapegsomatropin (lonapegsomatropin-tcgd).
  • the growth hormone conjugate such as human growth hormone conjugate, long acting human growth hormone or controlled-release hGH, such as lonapegsomatropin, is administered to a subject in a dose ranging from about 0.021 mg/kg/week to about 0.7 mg/kg/week such as at or about 0.21 mg/kg/week (mg/kg refers to the mass of growth hormone polypeptide without the conjugate moiety administered per week).
  • the growth hormone is selected from the group consisting of somapacitan or somapacitan- beco (marketed as SOGROYA® Novo Nordisk), somatrogon (marketed as NGENLA TM by (Pfizer/OPKO), eftansomatropin alfa (also known as eftansomatropin), efpegsomatropin, albusomatropin, somavaratan, ibutamoren, and lonapegsomatropin-tcgd.
  • somapacitan or somapacitan- beco marketed as SOGROYA® Novo Nordisk
  • somatrogon marketed as NGENLA TM by (Pfizer/OPKO
  • eftansomatropin alfa also known as eftansomatropin
  • efpegsomatropin albusomatropin
  • somavaratan ibutamoren
  • Exemplary Administration Protocol for CNP Drugs such as drugs comprising CNP Conjugate, such as CNP of formula (Ilf ’) or formula (Ilf) or compound (1).
  • a further aspect of the present invention is a method of reconstituting the solid unit dosage form of the present invention wherein the method comprises the step of
  • Reconstitution may take place in the container in which the solid unit dosage form is provided, such as in a vial; syringe such as a dual-chamber syringe; ampoule; cartridge, such as a dual-chamber cartridge; or the solid unit dosage form may be transferred to a different container where is then reconstituted.
  • the container in which the reconstitution of the solid unit dosage form takes place is a vial.
  • the container in which the reconstitution of the solid unit dosage form takes place is a syringe.
  • the container in which the reconstitution of the solid unit dosage form takes place is a dual-chamber syringe.
  • the container in which the reconstitution of the solid unit dosage form takes place is a cartridge.
  • the container in which the reconstitution of the solid unit dosage form takes place is a dual-chamber cartridge.
  • the solid unit dosage form according to the present invention is provided in a first chamber of the dual-chamber syringe and the reconstitution solution is provided in a second chamber of the dual-chamber syringe.
  • the reconstitution solution is a sterile liquid, such as water or buffer, which may comprise further additives, such as preservatives and/or antimicrobials.
  • the reconstituted solution comprises one or more preservative and/or antimicrobial and/or antioxidant.
  • the reconstituted solution comprises one or more preservative.
  • the preservative may be selected from the group consisting of m-cresol, benzoic acid, phenol, methylparaben, ethylparaben, propylparaben, butylparaben, potassium sorbate, chlorobutanol, benzyl alcohol, phenylmercuric nitrate, thimerosal, sorbic acid, potassium sorbate, chlorocresol, benzalkonium chloride, 2-ethoxyethanol, chlorhexidine, chlorobutanol, phenylethyl alcohol, phenylmercuric acetate and mixtures thereof.
  • the preservative is m-cresol.
  • the preservative is benzylalcohol.
  • the preservative is benzoic acid. In certain embodiments, the preservative is phenol. In certain embodiments, the preservative is methylparaben. In certain embodiments, the preservative is ethylparaben. In certain embodiments, the preservative is propylparaben. In certain embodiments, the preservative is butylparaben. In certain embodiments, the preservative is potassium sorbate. In certain embodiments, the preservative is benzyl alcohol. In certain embodiments, the preservative is phenylmercuric nitrate. In certain embodiments, the preservative is thimerosal. In certain embodiments, the preservative is sorbic acid.
  • the preservative is potassium sorbate. In certain embodiments, the preservative is chlorocresol. In certain embodiments, the preservative is benzalkonium chloride. In certain embodiments, the preservative is 2- ethoxy ethanol. In certain embodiments, the preservative is chlorhexidine. In certain embodiments, the preservative is chlorbutanol. In certain embodiments, the preservative is phenylethyl alcohol. In certain embodiments, the preservative is phenylmercuric acetate.
  • the preservative has a concentration ranging from 1 to 10 mg/ml. In certain embodiments, the preservative has a concentration ranging from 1 .5 to 3.5 mg/ml. In certain embodiments, the preservative has a concentration ranging from 2 to 3 mg/ml.
  • the antioxidant may be selected from the group consisting of methionine, butylhydroxy toluene, butylhydroxy anisol, tocopherol, propylgallate, ascorbic acid, ethylenediaminetetraacetic acid (EDTA), poly(ethylenimine), vitamin E and mixtures thereof.
  • the preservative is methionine. In certain embodiments, the preservative is butylhydroxytoluene. In certain embodiments, the preservative is butylhydroxy anisol. In certain embodiments, the preservative is tocopherol. In certain embodiments, the preservative is propylgallate. In certain embodiments, the preservative is ethylenediaminetetraacetic acid. In certain embodiments, the preservative is poly(ethylenimine). In certain embodiments, the preservative is vitamin E.
  • the term “methionine” is intended to encompass both D-methionine and L -methionine, and mixtures thereof.
  • the term “methionine” refers to L-methionine.
  • the term “methionine” refers to D-methionine.
  • the term “methionine” refers to a mixture of D-methionine or L-methionine.
  • the term “methionine” refers to L-methionine hydrochloride salt.
  • EDTA is intended to encompass all EDTA forms that are known in the art such as EDTA salts, including EDTA metal salts, such as EDTA disodium salt, EDTA dipotassium salt, EDTA calcium salt, EDTA dimagnesium salt or mixtures thereof.
  • EDTA refers to EDTA disodium salt.
  • EDTA refers to EDTA dicalcium salt.
  • EDTA refers to EDTA anhydrous.
  • the molar ratio of antioxidant to CNP moiety is from about 0.1 : 1 to about 100: 1 .
  • the molar ratio of antioxidant to CNP moiety is from about 0.1 : 1 to about 70: 1. In certain embodiments, the molar ratio of antioxidant to CNP moiety is from about 0.1 : 1 to about 15: 1. In certain embodiments, the molar ratio of antioxidant to CNP moiety is from about 1 : 1 to about 10: 1. In certain embodiments, the molar ratio of antioxidant to CNP moiety is from about 3 : 1 to about 7: 1.
  • the reconstituted solution does not comprise an antimicrobial. In certain embodiments, the reconstituted solution comprises one or more excipient.
  • the reconstitution solution is sterile water. In certain embodiments, the reconstitution solution is sterile water comprising 0.7-1. 1 % benzylalcohol. In certain embodiments, the reconstitution solution is sterile water comprising 0.9 % benzylalcohol.
  • the reconstituted solution comprises a pH -modifying agent.
  • pH-modifying agent refers to a chemical compound that is used to modify the pH of the reconstitution solution.
  • the pH-modifying agent may be an acid or acidic salt thereof.
  • the acid may be selected from the group consisting of acetic acid, citric acid, succinic acid, hydrochloric acid, phosphoric acid, carbonic acid, nitric acid and mixtures thereof.
  • the pH-modifying agent may be a base or basic salt thereof.
  • the base may be selected from the group consisting of Tris (tris(hydroxymethyl)aminomethane), sodium hydroxide, potassium hydroxide, lysine and mixtures thereof.
  • the volume of the reconstitution solution ranges from about 0.1 ml to about 4 ml. In certain embodiments, the volume of the reconstitution solution is about 1 ml, such as about 2 ml, such as about 3 ml or such as about 4 ml.
  • the volume of the reconstitution solution is about 0.79 ml. In certain embodiments, the volume of the reconstitution solution is 0.79 ml. In certain embodiments, the volume of the reconstitution solution is about 1 ml. In certain embodiments, the volume of the reconstitution solution is 1 ml. In certain embodiments, the volume of the reconstitution solution is about 1.1 ml. In certain embodiments, the volume of the reconstitution solution is 1.1 ml. In certain embodiments, the volume of the reconstitution solution is about 1.25 ml. In certain embodiments, the volume of the reconstitution solution is 1.25 ml
  • the volume of the unit dose or injection volume is based on the patient's actual body weight and the concentration of the reconstituted solution.
  • the concentration of CNP within the reconstituted solution is not more than 7 mg/ml. In certain embodiments, the concentration of CNP within the reconstituted solution is not less than 0.5 mg/ml. In certain embodiments, the concentration of CNP within the reconstituted solution is 0.75 mg/ml. In certain embodiments, the concentration of CNP within the reconstituted solution is 1 mg/ml. In certain embodiments, the concentration of CNP within the reconstituted solution is 2.2 mg/ml. In certain embodiments, the concentration of CNP within the reconstituted solution is 3.6 mg/ml.
  • the concentration of CNP within the reconstituted solution is 4.6 mg/ml. In certain embodiments, the concentration of CNP within the reconstituted solution is 5 mg/ml. In certain embodiments, the concentration of CNP within the reconstituted solution is 5.5 mg/ml.
  • a unit dose has a volume of not more than 4 ml. In certain embodiments, the volume of the unit dose ranges from about 0.01 ml to about 1. 1 ml. In certain embodiments, the volume of the unit dose ranges from 0.01 ml to 0.75 ml. In certain embodiments, the volume of the unit dose ranges from 0.01 ml to 0.50 ml.
  • the volume of the unit dose is about 0.03 ml. In certain embodiments, the volume of the unit dose is about 0.05 ml. In certain embodiments, the volume of the unit dose is about 0.1 ml. In certain embodiments, the volume of the unit dose is about 0.2 ml. In certain embodiments, the volume of the unit dose is about 0.25 ml. In certain embodiments, the volume of the unit dose is about 0.3 ml. In certain embodiments, the volume of the unit dose is about 0.35 ml. In certain embodiments, the volume of the unit dose is about 0.4 ml. In certain embodiments, the volume of the unit dose is about 0.5 ml. In certain embodiments, the volume of the unit dose is about 0.6 ml. In certain embodiments, the volume of the unit dose is about 0.75 ml. In certain embodiments, the volume of the unit dose is about 1 ml.
  • the patient is an infant and the volume of the unit dose ranges from about 10 pl to 100 pl. In certain embodiments, the patient is an infant and the volume of the unit dose ranges from about 10 pl to 50 pl. In certain embodiments, the patient is an infant and the volume of the unit dose ranges from about 10 pl to 30 pl.
  • the patient is an infant and the volume of the unit dose is about 10 pl. In certain embodiments, the patient is an infant and the volume of the unit dose is about 15 pl. In certain embodiments, the patient is an infant and the volume of the unit dose is about 20 pl.
  • the patient is an infant and the volume of the unit dose is 10 pl. In certain embodiments, the patient is an infant and the volume of the unit dose is 15 pl. In certain embodiments, the patient is an infant and the volume of the unit dose is 20 pl.
  • the patient is an infant, the unit dose is 20 pg CNP/kg and the volume of the unit dose is about 10 pl. In certain embodiments, the patient is an infant, the unit dose is 20 pg CNP/kg and the volume of the unit dose is about 15 pl. In certain embodiments, the patient is an infant, the unit dose is 20 pg CNP/kg and the volume of the unit dose is about 20 pl.
  • the unit dose is 6 pg CNP/kg and the volume of the unit dose is 0.06 ml. In certain embodiments, the unit dose is 20 pg CNP/kg and the volume of the unit dose 0.3 ml. In certain embodiments, the unit dose is 50 pg CNP/kg and the volume of the unit dose is 0.2 ml. In certain embodiments, the unit dose is 75 jig CNP/kg and the volume of the unit dose is 0.4 ml. In certain embodiments, the unit dose is 100 pg CNP/kg and the volume of the unit dose is 0.5 ml. In certain embodiments, the unit dose is 150 pg CNP/kg and the volume of the unit dose is 0.5 ml.
  • the pH of the liquid unit dosage form is from about pH 4 to about pH 6. In certain embodiments, the pH of the liquid unit dosage form is from about pH 4.5 to about pH 5.5. In certain embodiments, the pH of the liquid unit dosage form is about 5. In certain embodiments, the pH of the liquid unit dosage form is 5.
  • the unit dosage form of the present invention further comprises a buffering agent, an isotonicity agent and a pH-modifying agent.
  • the buffering agent has a concentration ranging from 1 .3 to 57.6 mM in the unit dosage form. In certain embodiments, the buffering agent has a concentration ranging from 1.7 to 33 mM in the unit dosage form. In certain embodiments, the buffering agent has a concentration ranging from 5. 1 to 20.3 mM in the unit dosage form. In certain embodiments, the buffering agent has a concentration of about 10 mM in the unit dosage form.
  • Exemplary buffering agents may be selected from the group consisting of succinic acid, citric acid, lactic acid, acetic acid, glutamic acid, fumaric acid, aspartic acid, glutaric acid, phosphoric acid, histidine, gluconic acid, tartaric acid, malic acid and mixtures thereof. It is clear to the person skilled in the art that the corresponding conjugate bases or salts of the buffering agents such as succinate, citrate, lactate, acetate, glutamate, fumarate, aspartate, glutarate, phosphate, gluconate, tartrate, malate and mixtures thereof, respectively , may also be included.
  • the buffering agent is succinic acid. In certain embodiments, the buffering agent is citric acid. In certain embodiments, the buffering agent is lactic acid. In certain embodiments, the buffering agent is acetic acid. In certain embodiments, the buffering agent is glutamic acid. In certain embodiments, the buffering agent is fumaric acid. In certain embodiments, the buffering agent is aspartic acid. In certain embodiments, the buffering agent is glutaric acid. In certain embodiments, the buffering agent is phosphoric acid. In certain embodiments, the buffering agent is histidine. In certain embodiments, the buffering agent is gluconic acid. In certain embodiments, the buffering agent is tartaric acid. In certain embodiments, the buffering agent is malic acid.
  • the isotonicity agent may be selected from the group consisting of trehalose, mannitol, sucrose, raffinose, gelatin, lactose, dibasic calcium phosphate, sorbitol, xylitol, glycine, histidine, hydroxyethylstarch, dextrose, dextran, Ficoll®, propylene glycol and mixtures thereof.
  • the isotonicity agent may be selected from the group consisting of trehalose, mannitol, sucrose, raffinose, gelatin, lactose, dibasic calcium phosphate, sorbitol, xylitol, glycine, histidine, hydroxyethylstarch, dextrose, dextran, propylene glycol and mixtures thereof.
  • the isotonicity agent is selected from the group consisting of trehalose, sucrose and glycine.
  • the isotonicity agent is a non-reducing sugar such as trehalose or sucrose.
  • the isotonicity agent is trehalose.
  • trehalose is intended to encompass all salts and hydration states of trehalose, such as trehalose anhydrous or trehalose dihydrate.
  • trehalose refers to trehalose anhydrous.
  • trehalose refers to trehalose dihydrate.
  • the unit dosage form comprises succinic acid and trehalose.
  • the unit dosage form comprises CNP conjugate 0.9 - 82.1 mg/ml succinic acid 1.3 - 57.6 mM trehalose dihydrate 67 - 1 11 .6 mg/ml, and has a pH ranging from pH 4.0 to pH 6.0.
  • the unit dosage form comprises:
  • the unit dosage form comprises:
  • the unit dosage form comprises about 8.2 mg/ml CNP conjugate, about 10 mM succinic acid, about 89 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of about 5.
  • the unit dosage form comprises 8.2 mg/ml CNP conjugate, 10 mM succinic acid, 89 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of 5.
  • the unit dosage form comprises about 11 mg/ml CNP conjugate, about 10 mM succinic acid, about 88.5 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of about 5. In certain embodiments, the unit dosage form comprises 11 mg/ml CNP conjugate, 10 mM succinic acid, 88.5 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of 5.
  • the unit dosage form comprises about 24.2 mg/ml CNP conjugate, about 10 mM succinic acid, about 85 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of about 5.
  • the unit dosage form comprises 24.2 mg/ml CNP conjugate, 10 mM succinic acid, 85 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of 5.
  • the unit dosage form comprises about 39.6 mg/ml CNP conjugate, about 10 mM succinic acid, about 80 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of about 5.
  • the unit dosage form comprises 39.6 mg/ml CNP conjugate, 10 mM succinic acid, 80 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of 5.
  • the unit dosage form comprises about 50.5 mg/ml CNP conjugate, about 10 mM succinic acid, about 77 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of about 5.
  • the unit dosage form comprises 50.5 mg/ml CNP conjugate, 10 mM succinic acid, 77 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of 5.
  • the unit dosage form comprises about 54.9 mg/ml CNP conjugate, about 10 mM succinic acid, about 75 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of about 5.
  • the unit dosage form comprises 54.9 mg/ml CNP conjugate, 10 mM succinic acid, 75 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of about 5.
  • the unit dosage form comprises about 60.4 mg/ml CNP conjugate, about 10 mM succinic acid, about 73 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of about 5.
  • the unit dosage form comprises 60.4 mg/ml CNP conjugate, 10 mM succinic acid, 73 mg/ml trehalose dihydrate and optionally Tris and/or hydrochloric acid and has a pH of 5.
  • the unit dosage form comprises based on the total weight of the solid unit dosage form:
  • the unit dosage form comprises, based on the total weight of the solid unit dosage form, about 8.2 % (w/w) CNP conjugate, about 1.2 % (w/w) succinic acid, about 89.1 % (w/w) trehalose dihydrate and about 1.5 % (w/w) Tris.
  • the unit dosage form comprises, based on the total weight of the solid unit dosage form, 8.2 % (w/w) CNP conjugate, 1.2 % (w/w) succinic acid, 89.1 % (w/w) trehalose dihydrate and 1.5 % (w/w) Tris.
  • the unit dosage form comprises, based on the total weight of the solid unit dosage form, about 10.7 % (w/w) CNP conjugate, about 1.2 % (w/w) succinic acid, about 86.8 % (w/w) trehalose dihydrate and about 1.3 % (w/w) Tris.
  • the unit dosage form comprises, based on the total weight of the solid unit dosage form, 10.7 % (w/w) CNP conjugate, 1.2 % (w/w) succinic acid, 86.8 % (w/w) trehalose dihydrate and 1.3 % (w/w) Tris.
  • the unit dosage form comprises, based on the total weight of the solid unit dosage form, about 21.6 % (w/w) CNP conjugate, about 1.1 % (w/w) succinic acid, about 76. 1 % (w/w) trehalose dihydrate and about 1.2 % (w/w) Tris.
  • the unit dosage form comprises, based on the total weight of the solid unit dosage form, 21.6 % (w/w) CNP conjugate, 1.1 % (w/w) succinic acid, 76.1 % (w/w) trehalose dihydrate and 1.2 % (w/w) Tris.
  • the unit dosage form comprises, based on the total weight of the solid unit dosage form, about 32.4 % (w/w) CNP conjugate, about 1.0 % (w/w) succinic acid, about 65.4% (w/w) trehalose dihydrate and about 1.2 % (w/w) Tris.
  • the unit dosage form comprises, based on the total weight of the solid unit dosage form, 32.4 % (w/w) CNP conjugate, 1.0 % (w/w) succinic acid, 65.4% (w/w) trehalose dihydrate and 1.2 % (w/w) Tris.
  • the unit dosage form comprises, based on the total weight of the solid unit dosage form, about 38.9 % (w/w) CNP conjugate, about 0.9 % (w/w) succinic acid, about 59.2% (w/w) trehalose dihydrate and about 1 % (w/w) Tris.
  • the unit dosage form comprises, based on the total weight of the solid unit dosage form, 38.9 % (w/w) CNP conjugate, 0.9 % (w/w) succinic acid, 59.2% (w/w) trehalose dihydrate and 1 % (w/w) Tris.
  • the unit dosage form comprises, based on the total weight of the solid unit dosage form, about 41.5 % (w/w) CNP conjugate, about 0.9 % (w/w) succinic acid, about 56.6% (w/w) trehalose dihydrate and about 1 % (w/w) Tris. In certain embodiments, the unit dosage form comprises, based on the total weight of the solid unit dosage form, 41.5 % (w/w) CNP conjugate, 0.9 % (w/w) succinic acid, 56.6% (w/w) trehalose dihydrate and 1 % (w/w) Tris.
  • the unit dosage form comprises, based on the total weight of the solid unit dosage form, about 44.4 % (w/w) CNP conjugate, about 0.9 % (w/w) succinic acid, about 53.7% (w/w) trehalose dihydrate and about 1 % (w/w) Tris.
  • the unit dosage form comprises, based on the total weight of the solid unit dosage form, 44.4 % (w/w) CNP conjugate, 0.9 % (w/w) succinic acid, 53.7% (w/w) trehalose dihydrate and 1 % (w/w) Tris.
  • the incidence of hypotension is less than 10%, preferably less than 8%, most preferably less than 5%, even more preferably is less than 3%. In certain embodiments, upon administration to a patient in need thereof of the unit dosage form of the present invention, the incidence of hypotension is less than 1%. In certain embodiments, there is no incidence of hypotension.
  • CNP conjugate such as a compound of formula (Ilf ’) or formula (Ilf) or compound.
  • no anti-CNP binding antibodies have been detected upon 1 to 9 months of repeated weekly exposure to the conjugate of the present invention.
  • no anti-CNP binding antibodies have been detected upon 52 weeks of repeated weekly exposure to the conjugate of the present invention.
  • CNP conjugate such as a compound of formula (Ilf ’) or formula (Ilf) or compound
  • the CNP moiety of the CNP conjugate has the sequence of SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO:11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25 or SEQ ID NO:30.
  • the CNP moiety has the sequence of SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24 or SEQ ID NO:25. In certain embodiments, the CNP moiety has the sequence of SEQ ID NO:20. In certain embodiments, the CNP moiety has the sequence of SEQ ID NO:21. In certain embodiments, the CNP moiety has the sequence of SEQ ID NO:22. In certain embodiments, the CNP moiety has the sequence of SEQ ID NO:23. In certain embodiments, the CNP moiety has the sequence of SEQ ID NO:24. In certain embodiments, the CNP moiety has the sequence of SEQ ID NO:25.
  • the CNP conjugate is of formula (la) or (lb): wherein
  • -D is a CNP moiety
  • -L 2 - is a single chemical bond or a spacer moiety
  • -Z is a polymeric moiety
  • x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15 and 16
  • y is an integer selected from the group consisting of 1, 2, 3, 4 and 5.
  • x of formula (la) is an integer selected from the group consisting of 1, 2, 3, 4, 6 and 8. In certain embodiments, x of formula (la) is an integer selected from the group consisting of 1, 2, 4 and 6. In certain embodiments, x of formula (la) is an integer selected from the group consisting of 1, 4 and 6 and in certain embodiments, x of formula (la) is 1.
  • y of formula (lb) is an integer selected from the group consisting of 2, 3, 4 and 5. In certain embodiments, y of formula (lb) is an integer selected from the group consisting of 2, 3 and 4. In certain embodiments, y of formula (lb) is an integer selected from the group consisting of 2 and 3. In certain embodiments, y of formula (lb) is an integer selected from the group consisting of 1, 2 and 3. In certain embodiments, y of formula (lb) is 1 . In certain embodiments, y of formula (lb) is 2.
  • -D of formula (la) or (lb) has the sequence of SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 1 1, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25 or SEQ ID NO:30.
  • -D of formula (la) or (lb) has the sequence of SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24 or SEQ ID NO:25.
  • -D of formula (la) or (lb) has the sequence of SEQ ID NO:20. In certain embodiments, -D of formula (la) or (lb) has the sequence of SEQ ID NO:21. In certain embodiments, -D of formula (la) or (lb) has the sequence of SEQ ID NO:22. In certain embodiments, -D of formula (la) or (lb) has the sequence of SEQ ID NO:23. In certain embodiments, -D of formula (la) or (lb) has the sequence of SEQ ID NO:24. In certain embodiments, -D of formula (la) or (lb) has the sequence of SEQ ID NO: 25. In certain embodiments, -D of formula (la) or (lb) has the sequence of SEQ ID NO:30, SEQ ID NO:98, SEQ ID NO:99 or SEQ ID NO 90.
  • the moiety -L 1 - of formula (la) or (lb) is either conjugated to a functional group of the side chain of an amino acid residue of -D, to the N-terminal amine functional group or to the C-terminal carboxyl functional group of -D or to a nitrogen atom in the backbone polypeptide chain of -D.
  • Attachment to either the N-terminus or C-terminus can either be direct through the corresponding amine or carboxyl functional group, respectively, or indirect wherein a spacer moiety is first conjugated to the amine or carboxyl functional group to which spacer moiety -L 1 - is conjugated.
  • the moiety -L 1 - of formula (la) or (lb) is a reversible linker from which the drug, i.e. D-H is released in its free form, i.e. -L 1 - is a traceless linker.
  • Suitable reversible linkers are known in the art, such as for example the reversible linker moieties disclosed in WO 2005/099768 A2, WO 2006/136586 A2, WO 2011/089216 Al and WO 2013/024053 Al, which are incorporated by reference herewith.
  • -L 1 - is a reversible linker as described in WO 2011/012722 Al, WO 2011/089214 Al, WO 2011/089215 Al, WO 2013/024052 Al and WO 2013/160340 Al which are incorporated by reference herewith.
  • the moiety -L 1 - can be connected to -D through any type of linkage, provided that it is reversible.
  • -L 1 - is connected to -D through a linkage selected from the group consisting of amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide and acylguanidine.
  • -L 1 - is connected to -D through a linkage selected from the group consisting of amide, ester, carbamate and acylguanidine. It is understood that these linkages may not per se be reversible, but that neighboring groups comprised in -L 1 - may render the linkage reversible.
  • the moiety -L 1 - is connected to -D through an amide linkage.
  • a moiety -L 1 - is disclosed in WO 2009/095479 A2. Accordingly, in certain embodiments, the moiety -L 1 - is of formula (II): wherein the dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond;
  • -R 1 , -R la , -R 2 , -R 2a , -R 4 , -R 4a , -R 5 , -R 5a , -R 6 , -R 8 , -R 8a , -R 9 , -R 9a are independently selected from the group consisting of -H; and Ci-6 alkyl;
  • -R 3 , -R 3a are independently selected from the group consisting of -H; and Ci-e alkyl, provided that in case one of -R 3 , -R 3a or both are other than -H they are connected to the N to which they are attached through an sp 3 -hybridized carbon atom;
  • -R 7a , -R 10 , -R 10a , -R 11 are independently of each other -H; or Ci-6 alkyl; optionally, one or more of the pairs -R la /-R 4a , -R la /-R 5a , -R la /-R 7a , -R 4a /-R 5a , -R 8a /-R 9a form a chemical bond; optionally, one or more of the pairs -RV-R la , -R 2 /-R 2a , -R 4 /-R 4a , -R 5 /-R 5a , -R 8 /-R 8a ,
  • -R 9 /-R 9a are joined together with the atom to which they are attached to form a cycloalkyl; or 3- to 10-membered heterocyclyl; optionally, one or more of the pairs -RV-R 4 , -RV-R 5 , -RV-R 6 , -RV-R 7a , -R 4 /-R 5 , -R 4 /-R 6 ,
  • -R 8 /-R 9 , -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 3- to 10-membered heterocycle;
  • A is selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterob icy clyl; and wherein -L 1 - is substituted with -L 2 -Z and wherein -L 1 - is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (II) is not replaced by -L 2 -Z or a substituent; wherein
  • -Z is a water-soluble polymeric moiety
  • -L 1 - of formula (II) is substituted with one moiety -L 2 -Z. In certain embodiments, -L 1 - of formula (II) is not further substituted.
  • R # and R ## represent a sp 3 -hydridized carbon atom.
  • Exemplary embodiments of suitable 3- to 10-membered heterocycles formed by -R 3 /-R 3a of formula (II) together with the nitrogen atom to which they are attached are the following: wherein dashed lines indicate attachment to the rest of the molecule; and
  • -R is selected from the group consisting of -H and Ci-e alkyl.
  • -L 1 - of formula (II) may optionally be further substituted.
  • any substituent may be used as far as the cleavage principle is not affected, i.e. the hydrogen marked with the asterisk in formula (II) is not replaced and the nitrogen of the moiety of formula (II) remains part of a primary, secondary or tertiary amine, i.e. -R 3 and -R 3a are independently of each other -H or are connected to -N ⁇ through a sp 3 -hybridized carbon atom.
  • -R 1 or -R la of formula (II) is substituted with -L 2 -Z.
  • -R 2 or -R 2a of formula (II) is substituted with -L 2 -Z.
  • -R 3 or -R 3a of formula (II) is substituted with -L 2 - Z.
  • -R 4 of formula (II) is substituted with -L 2 -Z.
  • -R 5 or -R 5a of formula (II) is substituted with -L 2 -Z.
  • -R 6 of formula (II) is substituted with -L 2 -Z.
  • -R 7 or -R 7a of formula (II) is substituted with -L 2 -Z.
  • -R 8 or -R 8a of formula (II) is substituted with -L 2 -Z.
  • -R 9 or -R 9a of formula (II) is substituted with -L 2 -Z.
  • -R 4 of formula (II) is substituted with -L 2 -Z.
  • -X- of formula (II) is -C(R 4 R 4a )- or -N(R 4 )-. In certain embodiments, -X- of formula (II) is -C(R 4 R 4a )-.
  • X 1 of formula (II) is C.
  • -X 2 - of formula (II) is -C(R 8 R 8a )-.
  • -R 8 and -R 8a of formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R 8 and -R 8a of formula (II) is -H. In certain embodiments, both -R 8 and -R 8a of formula (II) are -H.
  • -R 1 and -R la of formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R 1 and -R la of formula (II) is -H. In certain embodiments, both -R 1 and -R la of formula (II) are -H.
  • -R 2 and -R 2a of formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R 2 and -R 2a of formula (II) is -H. In certain embodiments, both -R 2 and -R 2a of formula (II) are H.
  • -R 3 and -R 3a of formula (II) are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In certain embodiments, at least one of -R 3 and -R 3a of formula (II) is methyl. In certain embodiments, -R 3 and -R 3a of formula (II) are both -H. In certain embodiments, -R 3 and -R 3a of formula (II) are both methyl. In certain embodiments, -R 3 of formula (II) is -H and -R 3a of formula (II) is methyl.
  • -R 4 and -R 4a of formula (II) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R 4 and -R 4a of formula (II) is -H. In certain embodiments, both -R 4 and -R 4a of formula (II) are -H.
  • the moiety -L 1 - is of formula (Ila): wherein the dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond; -R 1 , -R la , -R 2 , -R 2a , -R 3 , -R 3a , -R 4 , -R 4a and -X 2 - are used as defined in formula (II); and wherein -L 1 - is substituted with -L 2 -Z and wherein -L 1 - is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (Ila) is not replaced by -L 2 -Z or a substituent.
  • -L 1 - of formula (Ila) is substituted with one moiety -L 2 -Z. In certain embodiments, the moiety -L 1 - of formula (Ila) is not further substituted.
  • -R 1 and -R la of formula (Ila) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R 1 and -R la of formula (Ila) is -H. In certain embodiments, both -R 1 and -R la of formula (Ila) are -H.
  • -R 4 and -R 4a of formula (Ila) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R 4 and -R 4a of formula (Ila) is -H. In certain embodiments, both -R 4 and -R 4a of formula (Ila) are -H.
  • -X 2 - of formula (Ila) is -C(R 8 R 8a )-.
  • -R 8 and -R 8a of formula (Ila) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R 8 and -R 8a of formula (Ila) is -H. In certain embodiments, both -R 8 and -R 8a of formula (Ila) are -H.
  • -R 2 and -R 2a of formula (Ila) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R 2 and -R 2a of formula (Ila) is -H. In certain embodiments, both -R 2 and -R 2a of formula (Ila) are H.
  • -R 3 and -R 3a of formula (Ila) are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In certain embodiments, at least one of -R 3 and -R 3a of formula (Ila) is methyl. In certain embodiments, -R 3 and -R 3a of formula (Ila) are both -H. In certain embodiments, -R 3 and -R 3a of formula (Ila) are both methyl. In certain embodiments, -R 3 of formula (Ila) is -H and -R 3a of formula (Ila) is methyl.
  • the moiety -L 1 - is of formula (lib): wherein the dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond;
  • -R 2 , -R 2a , -R 3 , -R 3a and -X 2 - are used as defined in formula (II); and wherein -L 1 - is substituted with -L 2 -Z and wherein -L 1 - is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (lib) is not replaced by -L 2 -Z or a substituent.
  • -L 1 - of formula (lib) is substituted with one moiety -L 2 -Z.
  • the moiety -L 1 - of formula (lib) is not further substituted.
  • -X 2 - of formula (lib) is -C(R 8 R 8a )-.
  • -R 8 and -R 8a of formula (lib) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R 8 and -R 8a of formula (lib) is -H. In certain embodiments, both -R 8 and -R 8a of formula (lib) are -H.
  • -R 2 and -R 2a of formula (lib) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R 2 and -R 2a of formula (lib) is -H. In certain embodiments, both -R 2 and -R 2a of formula (lib) are H.
  • -R 3 and -R 3a of formula (lib) are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In certain embodiments, at least one of -R 3 and -R 3a of formula (lib) is methyl. In certain embodiments, -R 3 and -R 3a of formula (lib) are both -H. In certain embodiments, -R 3 and -R 3a of formula (lib) are both methyl. In certain embodiments, -R 3 of formula (lib) is -H and -R 3a of formula (lib) is methyl.
  • the moiety -L 1 - is of formula (lib’): wherein wherein the dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond; the dashed line marked with the asterisk indicates attachment to -L 2 -;
  • -R 2 , -R 2a , -R 3 , -R 3a and -X 2 - are used as defined in formula (II); and wherein -L 1 - is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (lib’) is not replaced by a substituent.
  • the moiety -L 1 - of formula (lib’) is not further substituted.
  • -X 2 - of formula (lib’) is -C(R 8 R 8a )-.
  • -R 8 and -R 8a of formula (lib’) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R 8 and -R 8a of formula (lib’) is -H. In certain embodiments, both -R 8 and -R 8a of formula (lib’) are -H. In certain embodiments, -R 2 and -R 2a of formula (lib’) are independently selected from the group consisting of -H, methyl and ethyl. In certain embodiments, at least one of -R 2 and -R 2a of formula (lib’) is -H. In certain embodiments, both -R 2 and -R 2a of formula (lib’) are H.
  • -R 3 and -R 3a of formula (lib’) are independently selected from the group consisting of -H, methyl, ethyl, propyl and butyl. In certain embodiments, at least one of -R 3 and -R 3a of formula (lib’) is methyl. In certain embodiments, -R 3 and -R 3a of formula (lib’) are both -H. In certain embodiments, -R 3 and -R 3a of formula (lib’) are both methyl. In certain embodiments, -R 3 of formula (lib’) is -H and -R 3a of formula (lib’) is methyl.
  • the moiety -L 1 - is of formula (lie): wherein the dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond; and wherein -L 1 - is substituted with -L 2 -Z and wherein -L 1 - is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (lie) is not replaced by -L 2 -Z or a substituent.
  • -L 1 - of formula (lie) is substituted with one moiety -L 2 -Z. In certain embodiments, the moiety -L 1 - of formula (lie) is not further substituted.
  • the moiety -L 1 - is selected from the group consisting of formula (Ilc-i), (Ilc-ii), (Ilc-iii), (Ilc-iv) and (IIc-v): wherein the unmarked dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond; and the dashed line marked with the asterisk indicates attachment to -L 2 -Z; and
  • the moiety -L 1 - of formula (Ilc-i), (Ilc-ii), (Ilc-iii), (Ilc-iv) and (IIc-v) is not further substituted.
  • the moiety -L 1 - is of formula (Ilc-ii): wherein the unmarked dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond; and the dashed line marked with the asterisk indicates attachment to -L 2 -Z.
  • -L 1 - of formula (Ilc-ii) is substituted with one moiety -L 2 -Z.
  • the moiety -L 1 - is of formula (III): wherein the dashed line indicates attachment to a primary or secondary amine or hydroxyl of -D which is a CNP moiety by forming an amide or ester linkage, respectively;
  • -R 1 , -R la , -R 2 , -R 2a , -R 3 and -R 3a are independently of each other selected from the group consisting
  • -R 4 , -R 5 and -R 5a are independently of each other selected from the group consisting of -H, -C(R 9 R 9a R 9b ) and -T; al and a2 are independently of each other 0 or I : each -R 6 , -R 6a , -R 7 , -R 7a , -R 8 , -R 8a , -R 8b , -R 9 , -R 9a , -R 9b are independently of each other selected from the group consisting of -H, halogen, -CN, -COOR 10 , -OR 10 , -C(O)R 10 , -C(O)N(R 10 R 10a ), -S(O) 2 N(R 10 R 10a ), -S(O)N(R 10 R 10a ),
  • 2 o alkyl, C 2.2 o alkenyl, and C 2.2 o 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 12 )-, - S(O) 2 N(R 12 )-, -S(O)N(R 12 )-, -S(O) 2 -, -S(O)-, -N(R 12 )S(O) 2 N(R 12a )-, -S-, -N(R 12 )-,
  • each -R 10 , -R 10a , -R 10b is independently selected from the group consisting of -H, -T, Ci. 2 o alkyl, C 2.2 o alkenyl, and C 2.2 o alkynyl; wherein -T, Ci. 2 o alkyl, C 2.2 o alkenyl, and C 2.2 o alkynyl are optionally substituted with one or more -R 11 , which are the same or different and wherein Ci.
  • 2 o alkyl, C 2.2 o alkenyl, and C 2.2 o 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 12 )-, -S(O) 2 N(R 12 )-, -S(O)N(R 12 )-, -S(O) 2 -, -S(O)-, -N(R 12 )S(O) 2 N(R 12a )-, -S-, -N(R 12 )-,
  • Ci-e alkyl is optionally substituted with one or more halogen, which are the same or different; each -R 12 , -R 12a , -R 13 , -R 13a , -R 13b is independently selected from the group consisting of -H, and Ci-e alkyl; wherein Ci-6 alkyl is optionally substituted with one or more halogen, which are the same or different; optionally, one or more of the pairs -RV-R la , -R 2 /-R 2a , -R 3 /-R 3a , -R 6 /-R 6a , -R 7 /-R 7a are joined together with the atom to which they are attached to form a C3-10 cycloalkyl or a 3- to 10-membered heterocyclyl; optionally, one or more of the pairs -RV-R 2 , -R
  • A is selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; C3-10 cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11 -membered heterobicyclyl; wherein -L 1 - is substituted with -L 2 -Z and wherein -L 1 - is optionally further substituted; wherein
  • -L 2 - is a single chemical bond or a spacer; and -Z is a water-soluble polymeric moiety.
  • -L 1 - of formula (III) are in certain embodiments as described above. In certain embodiments, -L 1 - of formula (III) is substituted with one moiety -L 2 -Z. In certain embodiments, -L 1 - of formula (III) is not further substituted.
  • -R 3 is selected from the group consisting of -H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR 9 and -N(R 9 )2;
  • -R 4 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; each -R 5 is independently selected from the group consisting of -H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;
  • -R 9 is selected from the group consisting of -H and optionally substituted alkyl
  • -Y- is absent and -X- is -O- or -S-;
  • -Y- is -N(Q)CH 2 - and -X- is -O-;
  • Q is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; optionally, -R 1 and -R 2 may be joined to form a 3 to 8-membered ring; and optionally, both -R 9 together with the nitrogen to which they are attached form a heterocyclic ring; wherein -L 1 - is substituted with -L 2 -Z and wherein -L 1 - is optionally further substituted; wherein
  • -Z is a water-soluble polymeric moiety.
  • -L 1 - of formula (IV) are in certain embodiments, as described above. In certain embodiments, -L 1 - of formula (IV) is substituted with one moiety -L 2 -Z. In certain embodiments, -L 1 - of formula (IV) is not further substituted.
  • alkyl as used herein includes linear, branched or cyclic saturated hydrocarbon groups of 1 to 8 carbons, or in certain embodiments 1 to 6 or 1 to 4 carbon atoms.
  • alkoxy includes alkyl groups bonded to oxygen, including methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, and similar.
  • alkenyl includes non-aromatic unsaturated hydrocarbons with carbon-carbon double bonds.
  • alkynyl includes non-aromatic unsaturated hydrocarbons with carbon-carbon triple bonds.
  • aryl includes aromatic hydrocarbon groups of 6 to 18 carbons, in certain embodiments, 6 to 10 carbons, including groups such as phenyl, naphthyl, and anthracenyl.
  • heteroaryl includes aromatic rings comprising 3 to 15 carbons containing at least one N, O or S atom, in certain embodiments, 3 to 7 carbons containing at least one N, O or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, indolyl, indenyl, and similar.
  • alkenyl, alkynyl, aryl or heteroaryl moieties may be coupled to the remainder of the molecule through an alkylene linkage.
  • the substituent will be referred to as alkenylalkyl, alkynylalkyl, arylalkyl or heteroarylalkyl, indicating that an alkylene moiety is between the alkenyl, alkynyl, aryl or heteroaryl moiety and the molecule to which the alkenyl, alkynyl, aryl or heteroaryl is coupled.
  • halogen includes bromo, fluoro, chloro and iodo.
  • heterocyclic ring refers to a 4 to 8 membered aromatic or non-aromatic ring comprising 3 to 7 carbon atoms and at least one N, O, or S atom.
  • Examples are piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidine, and tetrahydrofuranyl, as well as the exemplary groups provided for the term “heteroaryl” above.
  • suitable substituents are selected from the group consisting of alkyl, alkenyl, alkynyl, or an additional ring, each optionally further substituted.
  • Optional substituents on any group, including the above, include halo, nitro, cyano, -OR, -SR, -NR 2 , -OCOR, -NRCOR, -COOR, -CONR 2 , -SOR, -SO 2 R, -SONR 2 , -SO 2 NR 2 , wherein each R is independently alkyl, alkenyl, alkynyl, aryl or heteroaryl, or two R groups taken together with the atoms to which they are attached form a ring.
  • -R 1 is selected from the group consisting of optionally substituted Ci-Ce linear, branched, or cyclic alkyl; optionally substituted aryl; optionally substituted heteroaryl; alkoxy; and -NR 5 2 ;
  • -R 2 is selected from the group consisting of -H; optionally substituted Ci-Ce alkyl; optionally substituted aryl; and optionally substituted heteroaryl;
  • -R 3 is selected from the group consisting of -H; optionally substituted Ci-Ce alkyl; optionally substituted aryl; and optionally substituted heteroaryl;
  • -R 4 is selected from the group consisting of -H; optionally substituted Ci-Ce alkyl; optionally substituted aryl; and optionally substituted heteroaryl; each -R 5 is independently of each other selected from the group consisting of -H; optionally substituted Ci-Ce alkyl; optionally substituted aryl; and optionally substituted heteroaryl; or when taken together two -R 5 can be cycloalkyl or cycloheteroalkyl; wherein -L 1 - is substituted with -L 2 -Z and wherein -L 1 - is optionally further substituted; wherein
  • -L 2 - is a single chemical bond or a spacer; and -Z is a water-soluble polymeric.
  • -L 1 - of formula (V) is substituted with one moiety -L 2 -Z.
  • -L 1 - of formula (V) is not further substituted.
  • Alkyl “alkenyl”, and “alkynyl” include linear, branched or cyclic hydrocarbon groups of 1-8 carbons or 1-6 carbons or 1-4 carbons wherein alkyl is a saturated hydrocarbon, alkenyl includes one or more carbon-carbon double bonds and alkynyl includes one or more carbon-carbon triple bonds. Unless otherwise specified these contain 1-6 C.
  • Aryl includes aromatic hydrocarbon groups of 6-18 carbons, in certain embodiments, 6-10 carbons, including groups such as phenyl, naphthyl, and anthracene
  • Heteroaryl includes aromatic rings comprising 3-15 carbons containing at least one N, O or S atom, in certain embodiments, 3-7 carbons containing at least one N, O or S atom, including groups such as pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiszolyl, isothiazolyl, quinolyl, indolyl, indeny 1, and similar.
  • substituted means an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group comprising one or more substituent groups in place of one or more hydrogen atoms.
  • Substituents may generally be selected from halogen including F, Cl, Br, and I; lower alkyl including linear, branched, and cyclic; lower haloalkyl including fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; OH; lower alkoxy including linear, branched, and cyclic; SH; lower alkylthio including linear, branched and cyclic; amino, alkylamino, dialkylamino, silyl including alkylsilyl, alkoxysilyl, and arylsilyl; nitro; cyano; carbonyl; carboxylic acid, carboxylic ester, carboxylic amide, aminocarbonyl; aminoacyl; carbamate; urea;
  • -L 1 - is disclosed in WO 2022/115563 Al, which is herewith incorporated by reference in its entirety. Accordingly, in certain embodiments, -L 1 - is of formula (Va): wherein the dashed line marked with the asterisk indicates the attachment to -L 2 -Z and the unmarked dashed line indicates the attachment to -D.
  • -L 1 - is of formula (Va), the dashed line marked with the asterisk indicates the attachment to -L 2 -Z and the unmarked dashed line indicates the attachment to -D, wherein -D is a CNP moiety of the following amino acid sequence:
  • a moiety -L 1 - is of formula (VI): wherein the dashed line indicates attachment to -D which is a CNP moiety and wherein attachment is through an amine functional group of -I):
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxy alkyl, aryl, alkaryl, aralkyl, halogen, nitro, -SO3H, -SO2NHR 5 , amino, ammonium, carboxyl, PO3H2, and OPO3H2;
  • R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen, alkyl, and aryl; wherein -L 1 - is substituted with -L 2 -Z and wherein -L 1 - is optionally further substituted; wherein
  • -L 2 - is a single chemical bond or a spacer; and -Z is a water-soluble polymeric moiety.
  • Suitable substituents for formulas (VI) are alkyl (such as Ci-e alkyl), alkenyl (such as C2-6 alkenyl), alkynyl (such as C2-6 alkynyl), aryl (such as phenyl), heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl (such as aromatic 4 to 7 membered heterocycle) or halogen moieties.
  • alkyl such as Ci-e alkyl
  • alkenyl such as C2-6 alkenyl
  • alkynyl such as C2-6 alkynyl
  • aryl such as phenyl
  • heteroalkyl such as heteroalkenyl, heteroalkynyl, heteroaryl (such as aromatic 4 to 7 membered heterocycle) or halogen moieties.
  • -L 1 - of formula (VI) is substituted with one moiety -L 2 -Z.
  • the optional further substituents of -L 1 - of formula (VI) are in certain embodiments as described above.
  • -L 1 - of formula (VI) is not further substituted.
  • alkyl alkoxy
  • alkoxy alkyl aryl
  • alkaryl alkyl radicals of 1-8, in certain embodiments, 1-4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl and butyl, and aryl radicals of 6-10 carbon atoms, e.g. phenyl and naphthyl.
  • halogen includes bromo, fluoro, chloro and iodo.
  • a moiety -L 1 - is of formula (VII): wherein the dashed line indicates attachment to -D which is a CNP moiety and wherein attachment is through an amine functional group of -D;
  • Li is a bifunctional linking group
  • Yi and Y2 are independently O, S or NR 7 ;
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen, Ci-6 alkyls, C3-12 branched alkyls, C3.8 cycloalkyls, Ci-e substituted alkyls, C3.8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, Ci-e heteroalkyls, substituted Ci-6 heteroalkyls, Ci-e alkoxy, phenoxy, and Ci-6 heteroalkoxy;
  • Ar is a moiety which when included in formula (VII) forms a multi substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
  • X is a chemical bond or a moiety that is actively transported into a target cell, a hydrophobic moiety, or a combination thereof, y is 0 or 1 ; wherein -L 1 - is substituted with -L 2 -Z and wherein -L 1 - is optionally further substituted;
  • -L 2 - is a single chemical bond or a spacer; and -Z is a water-soluble polymeric moiety.
  • -L 1 - of formula (VII) is substituted with one moiety -L 2 -Z.
  • the optional further substituents of -L 1 - of formula (VII) are in certain embodiments, as described above.
  • -L 1 - of formula (VII) is not further substituted.
  • alkyl shall be understood to include, e.g. straight, branched, substituted C1.12 alkyls, including alkoxy, C3.8 cycloalkyls or substituted cycloalkyls, etc.
  • substituted shall be understood to include adding or replacing one or more atoms contained within a functional group or compounds with one or more different atoms.
  • Substituted alkyls include carboxyalkyls, aminoalkyls, dialkylaminos, hydroxyalkyls and mercaptoalkyls; substituted cycloalkyls include moieties such as 4-chlorocyclohexyl; aryls include moieties such as napthyl; substituted aryls include moieties such as 3-bromo-phenyl; aralkyls include moieties such as toluyl; heteroalkyls include moieties such as ethylthiophene; substituted heteroalkyls include moieties such as 3 -methoxy thiophone; alkoxy includes moieities such as methoxy; and phenoxy includes moieties such as 3 -nitrophenoxy.
  • Halo- shall be understood to include fluoro, chloro, iodo and bromo.
  • -L 1 - comprises a substructure of formula (VIII): wherein the dashed line marked with the asterisk indicates attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond; the unmarked dashed lines indicate attachment to the remainder of -L 1 -; and wherein -L 1 - is substituted with -L 2 -Z and wherein -L 1 - is optionally further substituted; wherein
  • -L 2 - is a single chemical bond or a spacer; and -Z is a water-soluble polymeric moiety.
  • -L 1 - of formula (VIII) is substituted with one moiety -L 2 -Z.
  • the optional further substituents of -L 1 - of formula (VIII) are as described above.
  • -L 1 - of formula (VIII) is not further substituted.
  • -L 1 - comprises a substructure of formula (IX): wherein the dashed line marked with the asterisk indicates attachment to a nitrogen of -D which is a CNP moiety by forming a carbamate bond; the unmarked dashed lines indicate attachment to the remainder of -L 1 -; and wherein -L 1 - is substituted with -L 2 -Z and wherein -L 1 - is optionally further substituted; wherein
  • -Z is a water-soluble polymeric moiety.
  • -L 1 - of formula (IX) are as described above.
  • -L 1 - of formula (IX) is substituted with one moiety -L 2 -Z.
  • -L 1 - of formula (IX) is not further substituted.
  • the moiety -D may be connected to -L 1 - through any functional group of D-H and is connected to -L 1 - through an amine functional group of D-H.
  • This may be the N-terminal amine functional group or an amine functional group provided by a lysine side chain, i.e. by the lysines at position 9, 11, 15, 16, 20 and 26, if the CNP has the sequence of SEQ ID NO:24.
  • Attachment of -L 1 - to the ring of a CNP moiety significantly reduces the CNP conjugate’s affinity to NPR-B compared to attachment at the N-terminus or to the non-ring part of CNP, which reduced affinity to NPR-B in turn reduces the risk of cardiovascular side effects, such as hypotension.
  • -L 1 - is conjugated to the side chain of an amino acid residue of said ring moiety of -D or to the backbone of said ring moiety of -D. In certain embodiments, -L 1 - is covalently and reversibly conjugated to the side chain of an amino acid residue of said ring moiety of -D. If -D is a CNP moiety with the sequence of SEQ ID NO:24, -L 1 - is, in certain embodiments, conjugated to the amine functional group provided by the lysine at position 26 of the corresponding drug D-H.
  • the moiety -L 2 - is a chemical bond or a spacer moiety. In certain embodiments, -L 2 - is a chemical bond. In certain embodiments, -L 2 - is a spacer moiety.
  • the moiety -L 2 - can be attached to -L 1 - by replacing any -H present, except where explicitly excluded.
  • -L 2 - is selected from the group consisting of -T-, -C(O)O-, -O- -C(O)-, -C(O)N(R y1 )-, -S(O)2N(R y1 )-, -S(O)N(R y1 )-, -S(O) 2 -,
  • -R yl and -R yla are independently of each other selected from the group consisting of -H, -T, C1.50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein -T, C1.50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -R y2 , which are the same or different, and wherein C1.50 alkyl, C2-50 alkenyl, and C2-50 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 y4 )-,
  • Ci-e alkyl is optionally substituted with one or more halogen, which are the same or different; and each -R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b is independently selected from the group consisting of -H, and Ci-e alkyl, wherein Ci-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
  • -L 2 - is selected from the group consisting of -T-, -C(O)O-, -O- -C(O)-, -C(O)N(R y1 )-, -S(O) 2 N(R y1 )-, -S(O)N(R y1 )-,
  • -R yl and -R yla are independently of each other selected from the group consisting of -H, -T, CHO alkyl, C2-10 alkenyl, and C2-10 alkynyl; wherein -T, CHO alkyl, C2-10 alkenyl, and C2-10 alkynyl are optionally substituted with one or more -R y2 , which are the same or different, and wherein CHO alkyl, C2-10 alkenyl, and C2-10 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 y4 )-, -S(O) 2 N(R y4 )-, -S(O)N(R y4 )-, -S(O) 2 -, -S(O)-, -N(R y4
  • each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropoly cyclyl; wherein each T is independently optionally substituted with one or more -R y2 , which are the same or different;
  • Ci-e alkyl is optionally substituted with one or more halogen, which are the same or different; and each -R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b is independently of each other selected from the group consisting of -H, and Ci-6 alkyl; wherein Ci-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
  • -L 2 - is selected from the group consisting of -T-, -C(O)O-, -O- -C(O)-, -C(O)N(R y1 )-, -S(O) 2 N(R y1 )-,
  • -R yl and -R yla are independently selected from the group consisting of -H, -T, CHO alkyl, alkenyl, and alkynyl; each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopoly cyclyl, and 8- to 30-
  • -L 2 - is a C1.20 alkyl chain, which is optionally interrupted by one or more groups independently selected from -O-, -T- and -C(O)N(R y1 )-; and which C1.20 alkyl chain is optionally substituted with one or more groups independently selected from -OH, -T and -C(O)N(R y6 R y6a ); wherein -R yl , -R y6 , -R y6a are independently selected from the group consisting of H and C1.4 alkyl and wherein T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11 -membered heterobicyclyl, 8- to 30-membered carbopoly cyclyl, and 8- to 30-membered heteropol
  • -L 2 - has a molecular weight in the range of from 14 g/mol to 750 g/mol.
  • -L 2 - has a chain length of 1 to 20 atoms.
  • chain length refers to the number of atoms of -L 2 - present in the shortest connection between -L 1 - and -Z.
  • -L 2 - is of formula (i): wherein the dashed line marked with the asterisk indicates attachment to -I, 1 -: the unmarked dashed line indicates attachment to -Z;
  • -R 1 is selected from the group consisting of -H, Ci-e alkyl, C2-6 alkenyl and C2-6 alkynyl; n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18; and wherein the moiety of formula (i) is optionally further substituted.
  • -R 1 of formula (i) is selected from the group consisting of -H, methyl, ethyl, propyl, and butyl.
  • -R 1 of formula (i) is selected from the group consisting of -H, methyl, ethyl and propyl.
  • -R 1 of formula (i) is selected from the group consisting of -H and methyl.
  • -R 1 of formula (i) is methyl.
  • n of formula (i) is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In certain embodiments, n of formula (i) is selected from the group consisting of 0, 1, 2, 3, 4 and 5. In certain embodiments, n of formula (i) is selected from the group consisting of 0, 1, 2 and 3. In certain embodiments, n of formula (i) is selected from the group consisting of 0 and 1. In certain embodiments, n of formula (i) is 0.
  • -L 2 - is a moiety selected from the group consisting of: wherein the dashed line marked with the asterisk indicates attachment to -I, 1 -: the unmarked dashed line indicates attachment to -Z and wherein the moieties (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), and (xvii) are optionally further substituted.
  • -L 2 - is selected from the group consisting of wherein the dashed line marked with the asterisk indicates attachment to -I, 1 -: and the unmarked dashed line indicates attachment to -Z.
  • -L 2 - is selected from the group consisting of wherein the dashed line marked with the asterisk indicates attachment to -I, 1 -: and the unmarked dashed line indicates attachment to -Z.
  • -L 2 - is of formula (xvi): wherein the dashed line marked with the asterisk indicates attachment to -L 1 -; and the unmarked dashed line indicates attachment to -Z.
  • the moiety -I, 1 -!, 2 - is selected from the group consisting of wherein the unmarked dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond; and the dashed line marked with the asterisk indicates attachment to -Z.
  • the moiety -I, '-I, 2 - is of formula (Ild-ii): wherein the unmarked dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond; and the dashed line marked with the asterisk indicates attachment to -Z.
  • the moiety -I, '-I, 2 - is of formula (Ild-ii ’): wherein the unmarked dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond; and the dashed line marked with the asterisk indicates attachment to -Z.
  • the moiety -I, 1 -!, 2 - is selected from the group consisting of and wherein the unmarked dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond; and the dashed line marked with the asterisk indicates attachment to -Z.
  • -Z of formula (la) or (lb) has a molecular weight ranging from 5 to 200 kDa. In certain embodiments, -Z of formula (la) or (lb) has a molecular weight ranging from 8 to 100 kDa. In certain embodiments, -Z of formula (la) or (lb) has a molecular weight ranging from 10 to 80 kDa. In certain embodiments, -Z of formula (la) or (lb) has a molecular weight ranging from 12 to 60 kDa. In certain embodiments, -Z of formula (la) or (lb) has a molecular weight ranging from 15 to 40 kDa.
  • -Z of formula (la) or (lb) has a molecular weight of about 20 kDa. In certain embodiments, -Z of formula (la) or (lb) has a molecular weight of about 40 kDa.
  • the polymeric moiety -Z of formula (la) or (lb) comprises a polymer.
  • -Z of formula (la) or (lb) comprises a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly (alkyloxy) polymers, poly(amides), poly (amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly (hydro xymethacrylates),
  • -Z of formula (la) or (lb) comprises a protein.
  • Preferred proteins are selected from the group consisting of carboxyl-terminal peptide of the chorionic gonadotropin as described in US 2012/0035101 Al which are herewith incorporated by reference; albumin; XTEN sequences as described in WO 2011 123813 A2 which are herewith incorporated by reference; proline/alanine random coil sequences as described in WO 2011/144756 Al which are herewith incorporated by reference; proline/alanine/serine random coil sequences as described in WO 2008/155134 Al and WO 2013/024049 Al which are herewith incorporated by reference; and Fc-fusion proteins.
  • -Z of formula (la) or (lb) is a polysarcosine. In certain embodiments, -Z of formula (la) or (lb) comprises poly(N-methylglycine). In certain embodiments, -Z of formula (la) or (lb) comprises a random coil protein moiety. In certain embodiments, -Z of formula (la) or (lb) comprises one random coil protein moiety. In certain embodiments, -Z of formula (la) or (lb) comprises two random coil protein moieties. In certain embodiments, -Z of formula (la) or (lb) comprises three random coil protein moieties. In certain embodiments, -Z of formula (la) or (lb) comprises four random coil protein moieties.
  • -Z of formula (la) or (lb) comprises five random coil protein moieties. In certain embodiments, -Z of formula (la) or (lb) comprises six random coil protein moieties. In certain embodiments, -Z of formula (la) or (lb) comprises seven random coil protein moieties. In certain embodiments, -Z of formula (la) or (lb) comprises eight random coil protein moieties.
  • such random coil protein moiety comprises at least 25 amino acid residues and at most 2000 amino acids. In certain embodiments, such random coil protein moiety comprises at least 30 amino acid residues and at most 1500 amino acid residues. In certain embodiments, such random coil protein moiety comprises at least 50 amino acid residues and at most 500 amino acid residues.
  • -Z of formula (la) or (lb) comprises a fatty acid derivative. In certain embodiments, -Z of formula (la) or (lb) is a fatty acid derivative. In certain embodiments, -Z of formula (la) is a fatty acid derivative and x is 1.
  • -Z of formula (la) or (lb) is a fatty acid derivative as disclosed in WO 2006/097537 A2 which is herewith incorporated by reference.
  • -Z of formula (la) or (lb) comprises a fatty acid derivative as disclosed in WO
  • (la) or (lb) has the following structure (w): wherein the dashed line indicates the attachment to -L 2 - or -L 1 - in formula (la) or (lb).
  • -Z is of formula (w) and -L 1 - is of formula (V).
  • -Z-L 2 -!, 1 - is of formula (w-a): wherein the dashed line indicates the attachment to -D of formula (la) or (lb).
  • CNP has the sequence selected from the group consisting of: PGQEHPQARRYRGAQRRGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO:98); PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO:30); PGQEHPNARRYRGANRRGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO:99 j: and PGQEHPQARKYKGAQKKGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO: 100).
  • CNP has the sequence selected from the group consisting of SEQ ID NO: 98, SEQ ID NO:30, SEQ ID NO:99 and SEQ ID NO: 100, -Z is of formula (w) and -L 1 - is a reversible linker moiety.
  • CNP has the sequence selected from the group consisting of SEQ ID NO:98, SEQ ID NO:30, SEQ ID NO:99 and SEQ ID NO: 100, -Z is of formula (w) and -L 1 - is of formula (V).
  • CNP has the sequence selected from the group consisting of SEQ ID NO:98, SEQ ID NO:30, SEQ ID NO:99 and SEQ ID NO:100, -Z-I, 2 -!, 1 - is of formula (w-a).
  • Said -L 1 - may be attached to said CNP via a lysine other than the lysine within the ring structure or it may be attached to the N-terminus.
  • CNP of SEQ ID NO:98, SEQ ID NO:30, SEQ ID NO:99 and SEQ ID NO: 100 further comprises an acetyl group, such as an acetyl group at the N-terminus of the peptide.
  • CNP of SEQ ID NO:98, SEQ ID NO:30, SEQ ID NO:99 and SEQ ID NO: 100 further comprises an -OH or -NH 2 group at the C-terminus.
  • CNP of SEQ ID NO:98, SEQ ID NO:30, SEQ ID NO:99 and SEQ ID NO: 100 and -L 1 - is attached to a residue of the CNP ring moiety or at a site other than the CNP moiety.
  • -L 1 - is attached at a lysine residue, such as the lysine residue in bold in SEQ ID NO:98, SEQ ID NO:30, SEQ ID NO:99 and SEQ ID NO: 100:
  • CNP is selected from the group consisting of:
  • AC-PGQEHPNARRYRGANRRGL SRGCFGLKLDRIGSMSGLGC-NH 2 SEQ ID NO: 104
  • AC-PGQEHPQARRYRGAQRRGL SRGCFGLKLDRIGSMSGLGC-NH 2 SEQ ID NO: 105
  • -Z of formula (la) or (lb) is a hyaluronic acid-based polymer.
  • -Z of formula (la) or (lb) is a polymeric moiety as disclosed in WO 2013/024047 Al which is herewith incorporated by reference.
  • -Z of formula (la) or (lb) is a polymeric moiety as disclosed in WO 2013/024048 Al which is herewith incorporated by reference.
  • -Z of formula (la) or (lb) is a PEG-based polymer. In certain embodiments, -Z is a branched or multi-arm PEG-based polymer.
  • -Z of formula (la) or (lb) is a branched polymer. In certain embodiments, -Z of formula (la) or (lb) is a branched polymer having one, two, three, four, five or six branching points. In certain embodiments, -Z of formula (la) or (lb) is a branched polymer having one, two or three branching points. In certain embodiments, -Z of formula (la) or (lb) is a branched polymer having one branching point. In certain embodiments, -Z of formula (la) or (lb) is a branched polymer having two branching points. In certain embodiments, -Z of formula (la) or (lb) is a branched polymer having three branching points.
  • a branching point is selected from the group consisting of -N ⁇ , -CH ⁇ and >C ⁇
  • such branched moiety -Z of formula (la) or (lb) is PEG-based.
  • such branched moiety -Z of formula (la) or (lb) has a molecular weight ranging from and including 5 kDa to 500 kDa. In certain embodiments, such branched moiety -Z of formula (la) or (lb) has a molecular weight ranging from and including 10 kDa to 250 kDa. In certain embodiments, such branched moiety -Z of formula (la) or (lb) has a molecular weight ranging from and including 10 kDa to 150 kDa. In certain embodiments, such branched moiety -Z of formula (la) or (lb) has a molecular weight ranging from and including 12 kDa to 100 kDa.
  • such branched moiety -Z of formula (la) or (lb) has a molecular weight ranging from and including 15 kDa to 80 kDa. In certain embodiments, such branched moiety -Z of formula (la) or (lb) has a molecular weight ranging from and including 10 kDa to 80 kDa. In certain embodiments, the molecular weight is about 10 kDa. In certain embodiments, the molecular weight of such branched moiety -Z of formula (la) or (lb) is about 20 kDa. In certain embodiments, the molecular weight of such branched moiety -Z of formula (la) or (lb) is about 30 kDa.
  • the molecular weight of such a branched moiety -Z of formula (la) or (lb) is about 40 kDa. In certain embodiments, the molecular weight of such a branched moiety -Z of formula (la) or (lb) is about 50 kDa. In certain embodiments, the molecular weight of such a branched moiety -Z of formula (la) or (lb) is about 60 kDa. In certain embodiments, the molecular weight of such a branched moiety -Z of formula (la) or (lb) is about 70 kDa.
  • the molecular weight of such a branched moiety -Z of formula (la) or (lb) is about 80 kDa. In certain embodiments, such branched moiety -Z of formula (la) or (lb) has a molecular weight of about 40 kDa.
  • -Z comprises a moiety
  • -Z comprises an amide bond
  • -Z of formula (la) or (lb) comprises a moiety of formula (a): wherein the dashed line indicates attachment to -L 2 - or to the remainder of -Z;
  • BP a is a branching point selected from the group consisting of -N ⁇ , -CR ⁇ and >C ⁇ :
  • -R is selected from the group consisting of -H and Ci-6 alkyl; a is 0 if BP a is -N ⁇ or -CR ⁇ and a is 1 if BP a is >C ⁇ ;
  • -S a -, -S a ’-, -S a and -S a are independently of each other a chemical bond or are selected from the group consisting of C1.50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein C1.50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -R 1 , which are the same or different and wherein Ci.
  • 50 alkyl, C2-50 alkenyl, and C2-50 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 2 )-, -S(O) 2 N(R 2 )-, -S(O)N(R 2 )-, -S(O) 2 -, -S(O)-, -N(R 2 )S(O) 2 N(R 2a )-, -S-, -N(R 2 )-, -OC(OR 2 )(R 2a )-,
  • Ci-e alkyl wherein Ci-6 alkyl is optionally substituted with one or more halogen, which are the same or different; each -R 2 , -R 2a , -R 3 , -R 3a and -R 3b is independently selected from the group consisting of -H, and Ci-e alkyl, wherein Ci-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and
  • -P a , -P a and -P a are independently a polymeric moiety.
  • BP a of formula (a) is -N ⁇ In certain embodiments, BP a of formula (a) is -CR ⁇ In certain embodiments, -R is -H.
  • a of formula (a) is 0.
  • BP a of formula (a) is >C ⁇
  • -S a - of formula (a) is a chemical bond.
  • -S a - of formula (a) is selected from the group consisting of Cnio alkyl, C2-10 alkenyl and C2-10 alkynyl, which Cnio alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more chemical groups selected from the group consisting of
  • -S a - of formula (a) is selected from the group consisting of methyl, ethyl, propyl, butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)- and -C(O)N(R 4 )-.
  • -S a - of formula (a) is a chemical bond.
  • -S a - of formula (a) is selected from the group consisting of Ci-io alkyl, C2-10 alkenyl and C2-10 alkynyl, which Cnio alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more chemical groups selected from the group consisting of
  • -S a - of formula (a) is selected from the group consisting of methyl, ethyl, propyl, butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)- and -C(O)N(R 4 )-.
  • -S a of formula (a) is a chemical bond.
  • -S a of formula (a) is selected from the group consisting of CHO alkyl, C2-10 alkenyl and C2-10 alkynyl, which Cnio alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more chemical groups selected from the group consisting of
  • -S a of formula (a) is selected from the group consisting of methyl, ethyl, propyl, butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)- and -C(O)N(R 4 )-.
  • -S a of formula (a) is a chemical bond.
  • -S a of formula (a) is selected from the group consisting of Cnio alkyl, C2-10 alkenyl and C2-10 alkynyl, which Cnio alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more chemical groups selected from the group consisting of
  • -S a of formula (a) is selected from the group consisting of methyl, ethyl, propyl, butyl, which are optionally interrupted by one or more chemical groups selected from the group consisting of -O-, -C(O)- and -C(O)N(R 4 )-.
  • -P a ’, -P a ” and -P a of formula (a) independently comprise a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), poly (acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly (anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly (caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly (ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazo
  • -P a ’, -P a ” and -P a of formula (a) independently have a molecular weight ranging from and including 5 kDa to 50 kDa, in certain embodiments ranging from and including 5 kDa to 40 kDa, in certain embodiments ranging from and including 7.5 kDa to 35 kDa, in certain embodiments ranging from and 7.5 to 30 kDa, in certain embodiments ranging from and including 10 to 30 kDa.
  • -P a , -P a and -P a of formula (a) have a molecular weight of about 5 kDa. In certain embodiments, -P a ’, -P a ” and -P a ” of formula (a) have a molecular weight of about 7.5 kDa. In certain embodiments, -P a ’, -P a ” and -P a ” of formula (a) have a molecular weight of about 10 kDa. In certain embodiments, -P a ’, -P a ” and -P a ” of formula (a) have a molecular weight of about 12.5 kDa.
  • -P a ’, -P a ” and -P a ” of formula (a) have a molecular weight of about 15 kDa. In certain embodiments, -P a , -P a and -P a of formula (a) have a molecular weight of about 20 kDa.
  • -P a ’, -P a ” and -P a of formula (a) independently comprise a protein moiety, in certain embodiments a random coil protein moiety and in certain embodiments a random coil protein moiety selected from the group consisting of PA, PAS, PAG, PG and XTEN moieties.
  • -P a , -P a and -P a of formula (a) are a PA moiety. In certain embodiments, -P a , -P a and -P a of formula (a) are a PAS moiety. In certain embodiments, -P a ’, -P a ” and -P a of formula (a) are a PAG moiety. In certain embodiments, -P a ’, -P a ” and -P a ” of formula (a) are a PG moiety. In certain embodiments, -P a ’, -P a ” and -P a of formula (a) are an XTEN moiety.
  • -Z comprises one moiety of formula (a). In certain embodiments, -Z comprises two moieties of formula (a). In another embodiment, -Z comprises three moieties of formula (a). In certain embodiments, -Z comprises four moieties of formula (a). In certain embodiments, -Z comprises five moieties of formula (a). In certain embodiments, -Z comprises six moieties of formula (a).
  • -Z comprises a moiety of formula (b): wherein the dashed line indicates attachment to -L 2 - or to the remainder of -Z; bl is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8; b2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; b3 is an integer ranging from and including 150 to 1000; in certain embodiments, ranging from and including 150 to 500; and in certain embodiments, ranging from and including 200 to 460; and b4 is an integer ranging from and including 150 to 1000; in certain embodiments, ranging from and including 150 to 500; and in certain embodiments, ranging from and including 200 to 460.
  • b3 and b4 of formula (b) are the same integer. In certain embodiments, b3 and b4 of formula (b) are both an integer ranging from 200 to 250 and in certain embodiments, b3 and b4 of formula (b) are about 225. In certain embodiments, b3 and b4 of formula (b) are both an integer ranging from 400 to 500 and in certain embodiments, b3 and b4 of formula (b) are about 450.
  • bl of formula (b) is selected from the group consisting of 0, 1, 2, 3 and 4. In certain embodiments, bl of formula (b) is selected from the group consisting of 1, 2 and 3. In certain embodiments, bl of formula (b) is 2.
  • b2 of formula (b) is selected from the group consisting of 1, 2, 3, 4 and 5. In certain embodiments, b2 of formula (b) is selected from the group consisting of 2, 3 and 4. In certain embodiments, b2 of formula (b) is 3. In certain embodiments, bl of formula (b) is 2, b2 of formula (b) is 3, and b3 and b4 are both about 450. In certain embodiments, bl of formula (b) is 2, b2 of formula (b) is 3, and b3 and b4 are both about 225.
  • -Z comprises one moiety of formula (b). In certain embodiments, -Z comprises two moieties of formula (b). In certain embodiments, -Z comprises three moieties of formula (b). In certain embodiments, -Z comprises four moieties of formula (b). In certain embodiments, -Z comprises five moieties of formula (b). In certain embodiments, -Z comprises six moieties of formula (b).
  • -Z comprises a moiety of formula (c):
  • both cl and c2 of formula (c) are the same integer.
  • cl and c2 of formula (c) range from and include 200 to 250 and in certain embodiments, are about 225. In certain embodiments, cl and c2 of formula (c) range from and include 400 to 500 and in certain embodiments, cl and c2 of formula (c) are about 450.
  • the moiety -Z is a branched PEG-based polymer comprising at least 10% PEG, has one branching point and two PEG-based polymer arms and has a molecular weight of about 40 kDa. Accordingly, each of the two PEG-based polymer arms has a molecular weight of about 20 kDa.
  • the branching point is -CH ⁇ .
  • -Z comprises one moiety of formula (c). In certain embodiments, -Z comprises two moieties of formula (c). In certain embodiments, -Z comprises three moieties of formula (c). In certain embodiments, -Z comprises four moieties of formula (c). In certain embodiments, -Z comprises five moieties of formula (c). In certain embodiments, -Z comprises six moieties of formula (c).
  • the moiety -Z is of formula (d):
  • -Z b - is selected from the group consisting of C1.50 alkyl, C 2 .5o alkenyl, and C 2 .5o alkynyl; wherein C1.50 alkyl, C 2 -5o alkenyl, and C 2 .5o alkynyl are optionally substituted with one or more -R 1 , which are the same or different and wherein C1.50 alkyl, C 2 .5o alkenyl, and C 2 .5o 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 2 )-, -S(O) 2 N(R 2 )-
  • Ci. 6 alkyl is optionally substituted with one or more halogen, which are the same or different; each -R 2 , -R 2a , -R 3 , -R 3a and -R 3b is independently selected from the group consisting of -H, and Ci. e alkyl, wherein Ci-e alkyl is optionally substituted with one or more halogen, which are the same or different; and
  • BP a , -S a -, -S a ’-, -S a ”-, -S a -P a ”, -P a ”, -P a ”’ and a are used as defined for formula (a).
  • BP a , -S a -, -S a ’-, -S a ”-, -S a -P a ”, -P a ”, -P a ”’ of formula (d) are as defined above for formula (a).
  • -Z a of formula (d) is of formula (b).
  • bl, b2, b3 and b4 are as described for formula (b).
  • the moiety -Z of formula (la) or (lb) is of formula (e):
  • e wherein the dashed line indicates attachment to -I, 2 -: e is selected from the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15; and
  • -Z a is wherein bl, b2, b3 and b4 are used as defined for formula (b).
  • e of formula (e) is 1. In certain embodiments, e of formula (e) is 2. In certain embodiments, e of formula (e) is 3. In certain embodiments, e of formula (e) is 4. In certain embodiments, e of formula (e) is 5. In certain embodiments, e of formula (e) is 6. In certain embodiments, e of formula (e) is 7. In certain embodiments, e of formula (e) is 8. In certain embodiments, e of formula (e) is 9. In certain embodiments, e of formula (e) is 10. In certain embodiments, e of formula (e) is 11. In certain embodiments, e of formula (e) is 12. In certain embodiments, e of formula (e) is 13. In certain embodiments, e of formula (e) is 14. In certain embodiments, e of formula (e) is 15.
  • e of formula (e) is selected from the group consisting of 2, 3, 4, 5, 6, 7, 8 and 9. In certain embodiments, e of formula (e) is selected from 3, 4, 5 and 6. In certain embodiments, e of formula (e) is 5.
  • e of formula (e) is 5, bl of formula (e) is 2, b2 of formula (e) is 3 and b3 and b4 of formula (e) are both about 450.
  • the moiety -Z of formula (la) or (lb) is of formula (e-i) or (e-i’): (e-i),
  • -Z a is wherein bl, b2, b3 and b4 are used as defined for formula (b).
  • bl, b2, b3 and b4 of formula (e-i) and (e-i’) are as defined above for formula (b).
  • e of formula (e-i) and (e-i’) are as described for formula (e).
  • bl of formula (e-i) and (e-i’) is 2, b2 of formula (e-i) and (e-i’) is 3 and b3 and b4 of formula (e-i) and (e-i’) are both about 450.
  • -Z of formula (la) or (lb) is of formula (e-i).
  • the moiety -Z is a branched PEG-based polymer comprising at least 10% PEG, has three branching points and four PEG-based polymer arms and has a molecular weight of about 40 kDa. Accordingly, each of the four PEG-based polymer arms has a molecular weight of about 10 kDa.
  • each of the three branching points is -CH ⁇
  • the moiety -Z is of formula (f): wherein the dashed line indicates attachment to -I, 2 -:
  • BP f is a branching point selected from the group consisting of -N ⁇ , -CR ⁇ and >C ⁇ :
  • -R is selected from the group consisting of -H and Ci-6 alkyl; f is 0 if BP f is -N ⁇ or -CR ⁇ and f is 1 if BP f is >C ⁇ ;
  • -S f -, -S f -, -S f - and -S f ’ are independently either a chemical bond or are independently selected from the group consisting of C1.50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein C1.50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -R 1 , which are the same or different and wherein C1.50 alkyl, C2-50 alkenyl, and C2-50 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 2 )-, -S(O) 2 N(R 2 )-,
  • Ci. 6 alkyl is optionally substituted with one or more halogen, which are the same or different; each -R 2 , -R 2a , -R 3 , -R 3a and -R 3b is independently selected from the group consisting of -H, and Ci. e alkyl, wherein Ci-e alkyl is optionally substituted with one or more halogen, which are the same or different; and
  • BP a , -S a -, -S a ’-, -S a ”-, -S a -P a ”, -P a ”, -P a ”’ and a are used as defined for formula (a).
  • BP a , -S a -, -S a ’-, -S a ”-, -S a -P a ”, -P a ” and -P a ”’ of formula (f) are as defined above for formula (a).
  • BP f of formula (f) is -CR ⁇ and r is 0.
  • -R is -H.
  • -S f - of formula (f) is a chemical bond.
  • -Z a ”, -Z a ” and -Z a of formula (f) have the same structure. In certain embodiments, -Z a ”, -Z a ” and -Z a of formula (f) are of formula (b).
  • bl, b2, b3 and b4 are as described for formula (b).
  • -S f - of formula (f) is a chemical bond
  • BP a of formula (f) is -CR ⁇ with -R being -H.
  • -S f - of formula (f) is a chemical bond
  • -Z is of formula (g):
  • -S 8 -, -S g - and -S g ”- are independently selected from the group consisting of C1.50 alkyl, C2-50 alkenyl, and C2-50 alkynyl; wherein C1.50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more -R 1 , which are the same or different and wherein C1.50 alkyl, C2-50 alkenyl, and C2-50 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 2 )-, -S(O) 2 N(R 2 )-, -S(O)N(R 2 )-, -S(O) 2 -, -S(O)-, -S(O)-, -S(O)-,
  • Ci. 6 alkyl is optionally substituted with one or more halogen, which are the same or different; each -R 2 , -R 2a , -R 3 , -R 3a and -R 3b is independently selected from the group consisting of -H, and Ci. e alkyl, wherein Ci-e alkyl is optionally substituted with one or more halogen, which are the same or different; and
  • BP a , -S a -, -S a ’-, -S a -S a -P a ’, -P a ”, -P a ” and a are used as defined for formula (a).
  • BP a , -S a -, -S a ’-, -S a ”-, -S a ”’-, -P a ’, -P a ” and -P a ” of formula (g) are as defined above for formula (a).
  • -S g - of formula (g) is selected from the group consisting of Ci-6 alkyl, C2-6 alkenyl and C2- e alkynyl, which are optionally substituted with one or more -R 1 , which is the same or different, wherein
  • Ci-e alkyl wherein Ci-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
  • -R 3 , -R 3a and -R 3b are independently selected from -H, methyl, ethyl, propyl and butyl.
  • -S g - of formula (g) is selected from Ci-6 alkyl.
  • -S g - of formula (g) is selected from the group consisting of Ci-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, which are optionally substituted with one or more -R 1 , which is the same or different, wherein
  • Ci-e alkyl wherein Ci-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
  • -R 3 , -R 3a and -R 3b are independently selected from -H, methyl, ethyl, propyl, and butyl.
  • -S g - of formula (g) is Ci-6 alkyl.
  • -S g ”- of formula (g) is selected from the group consisting of Ci-e alkyl, C 2 .e alkenyl and C 2 -6 alkynyl, which are optionally substituted with one or more -R 1 , which is the same or different, wherein
  • Ci-e alkyl wherein Ci-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
  • -R 3 , -R 3a and -R 3b are independently selected from -H, methyl, ethyl, propyl and butyl.
  • -S g ”- of formula (g) is Ci-6 alkyl.
  • -Z a and -Z a ’ of formula (g) have the same structure. In certain embodiments, -Z a and -Z a ’ of formula (g) are of formula (b).
  • BP a , -S a -, -S a ’-, -S a ”-, -S a -P a ’, -P a ” and -P a ” of formula (g-i) are as defined above for formula (a).
  • -Z a and -Z a ‘ of formula (g-i) have the same structure.
  • -Z a and -Z a ’ of formula (g-i) are of formula (b).
  • for bl, b2, b3 and b4 are as described for formula (b).
  • -Z is of formula (h): wherein the dashed line indicates attachment to -I, 2 -: and each -Z c is a moiety wherein each cl is an integer independently ranging from about 200 to 250.
  • both cl of formula (h) are the same. In certain embodiments, both cl of formula (h) are about 225.
  • the moiety -Z is of formula (h-i) : wherein the dashed line indicates attachment to -I, 2 -: and each -Z c is a moiety each cl is an integer independently ranging from 200 to 250.
  • the moiety of formula (h-i) is substituted with one or more substituents.
  • both cl of formula (h-i) are the same.
  • both cl of formula (h-i) are about 225.
  • the CNP conjugate is of formula (Ilf): wherein the unmarked dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond; and the dashed line marked with the asterisk indicates attachment to -Z having the structure wherein each cl is an integer independently ranging from 200 to 250.
  • each cl of formula (Ilf) is about 225.
  • -D of formula (Ilf) is a CNP moiety, i.e. the conjugate of formula (Ilf) is a CNP conjugate.
  • -D of formula (Ilf) is a CNP moiety having the sequence of SEQ ID NO:24, SEQ ID NO:25 or SEQ ID NO:30.
  • -D of formula (Ilf) is a CNP moiety having the sequence of SEQ ID NO:24.
  • -D of formula (Ilf) is a CNP moiety having the sequence of SEQ ID NO:20.
  • -D of formula (Ilf) is a CNP moiety having the sequence of SEQ ID NO:21.
  • -D of formula (Ilf) is a CNP moiety having the sequence of SEQ ID NO:22. In certain embodiments, -D of formula (Ilf) is a CNP moiety having the sequence of SEQ ID NO:23. In certain embodiments, -D of formula (Ilf) is a CNP moiety having the sequence of SEQ ID NO: 30.
  • -D of formula (Ilf) is a CNP moiety which is attached to -L 1 - through the nitrogen of the N-terminal amine functional group of CNP. In certain embodiments, -D of formula (Ilf) is a CNP moiety which is attached to -L 1 - through a nitrogen provided by the amine functional group of a lysine side chain of the CNP moiety.
  • said lysine side chain is not part of the ring formed by the disulfide bridge between the cysteine residues at positions 22 and 38, if the CNP moiety is of SEQ ID NO:24.
  • the CNP moiety is connected to -L 1 - in the CNP conjugate of formula (Ilf) through the amine functional group provided by the side chain of the lysine at position 9, if the CNP has the sequence of SEQ ID NO:24.
  • the CNP moiety is connected to -L 1 - in the CNP conjugate of formula (Ilf) through the amine functional group provided by the side chain of the lysine at position 11 , if the CNP has the sequence of SEQ ID NO:24.

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Abstract

La présente invention concerne des procédés d'amélioration de la fonction musculaire chez un sujet présentant une maladie ou un état dans lequel la fonction musculaire est altérée, le procédé comprenant l'administration d'une quantité efficace d'un inhibiteur de la signalisation FGFR3, d'un agoniste de NPR-B ou d'un agoniste de NPR-C audit sujet.
PCT/EP2023/081497 2022-11-14 2023-11-10 Procédé d'amélioration de la fonction musculaire squelettique WO2024104922A1 (fr)

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PCT/EP2022/085414 WO2023110758A1 (fr) 2021-12-13 2022-12-12 Doses efficaces de conjugués cnp
EPPCT/EP2022/085414 2022-12-12
EP23162994.0 2023-03-20
EP23162994 2023-03-20
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