Classifications

• • 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
• • 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
  • 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
  • A61K47/62—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 a protein, peptide or polyamino acid
  • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • 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
  • A61P5/00—Drugs for disorders of the endocrine system

Definitions

• the present invention relates to unit dosage forms comprising a CNP conjugate or pharmaceutically acceptable salt thereof.
• Achondroplasia is a genetic disorder which occurs due to an autosomal dominant mutation in the fibroblast-growth-factor-receptor 3 (FGFR3) gene, that causes an abnormality of cartilage formation and results in dwarfism.
• C-type Natriuretic Peptide is a hormone that binds and activates the peptide receptor B (NPR-B) resulting in the inhibition of FGFR3 downstream signaling. This in turn triggers endochondral growth and skeletal overgrowth, as observed in both mice and humans overexpressing CNP.
• CNP-53 possesses biological activity but is typically processed by an unknown mechanism to the biologically active 22 amino acids form in circulation, i.e. CNP-22.
• the bioactivity of CNP is tightly regulated and its clearance from the plasma is very rapid.
• CNP CNP-derived neuropeptidase
• Native CNP has a half-life of only 2 to 3 minutes in humans, and renal clearance and degradation by neutral endopeptidase (NEP) makes it difficult to maintain an efficacious therapeutic drug exposure.
• Vosoritide is a daily CNP analog, with increased NEP resistance, and an associated half-life of about 21.0 ( ⁇ 4.7) to 27.9 ( ⁇ 9.9) minutes after subcutaneous administration (VOXZOGOTM Prescribing Information, Reference ID: 4891169, November 2021).
• Vosoritide is rapidly absorbed after administration and reaches a peak concentration (C m ax) of about 4.71 ( ⁇ 2.32) to 7.18 ( ⁇ 9.65) ng/mL after approximately 15 minutes after administration of a 15 pg/kg subcutaneous dose (VOXZOGOTM Prescribing Information, Reference ID: 4891169, November 2021).
• Cyclic guanosine monophosphate (cGMP) is a marker of NPR-B receptor engagement, the pharmacological receptor for CNP. cGMP can be measured both in blood and urine and it is a biomarker of systemic CNP pharmacological activity.
• a unit dosage form comprising 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.
• 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 ZnCCh 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.
• CNP also includes all CNP variants, analogs, orthologs, homologs, derivatives and fragments thereof.
• the 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 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.
• 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.
• a CNP polypeptide may be, for example: (i) one in which at least one of the amino acid residues is substituted with a conserved or non-conserved amino acid residue, in certain embodiments, a conserved amino acid residue, and such substituted amino acid residue may or may not be one encoded by the genetic code; and/or (ii) one in which at least one of the amino acid residues includes a substituent group; and/or (iii) one in which the CNP polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (for example, polyethylene glycol); and/or (iv) one in which additional amino acids are fused to the CNP polypeptide, such as an IgG Fc fusion region peptide or leader or secretory sequence or a sequence which is employed for purification of the above form of the polypeptide or a preprotein sequence.
• CNP polypeptide fragment refers to any peptide comprising a continuous span of a part of the amino acid sequence of a CNP polypeptide.
• a CNP polypeptide fragment comprises at least 6, such as at least 8, at least 10 or at least 17 consecutive amino acids of a CNP polypeptide.
• a CNP polypeptide fragment may additionally be described as sub-genuses of CNP polypeptides comprising at least 6 amino acids, wherein “at least 6” is defined as any integer between 6 and the integer representing the C-terminal amino acid of a CNP polypeptide.
• CNP polypeptide fragment as individual species are all CNP polypeptide fragments, at least 6 amino acids in length, as described above, that may be particularly specified by a N-terminal and C-terminal position. That is, every combination of a N-terminal and C-terminal position that a fragment at least 6 contiguous amino acid residues in length could occupy, on any given amino acid sequence of a CNP polypeptide.
• CNP includes the above-described variants, analogs, orthologs, homologs, derivatives and fragments of CNP, all references to specific positions within a reference sequence also include the equivalent positions in the variants, analogs, orthologs, homologs, derivatives and fragments of a CNP moiety, even if not explicitly mentioned.
• Naturally occurring 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:4 (M-CNP-53):
• SEQ ID NO: 10 (CNP-50):
• SEQ ID NO: 18 (CNP-44 Al 5-22):
• SEQ ID NO:44 (CNP-30): KYKGANKKGLSKGCFGLKLDRIGSMSGLGC;
• 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:57 (M-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:68 (R-CNP-22 K4R):
• 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:83 (fibronectin fragment-CNP-22 K4R):
• SEQ ID NO:84 (zinc finger fragment-CNP-22 K4R):
• SEQ ID NO:90 (BNP fragment-CNP-17-BNP fragment):
• Xi, X2, X3, X4, X5 and Xf> 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, X4, X5 and Xr> is selected from the group consisting of R, P, S and Q; in certain embodiments, Xi, X2, X3, X4, X5 and Xe are selected from the group consisting of K and R, with the provision that at least one of Xi, X2, X3, X4, X5 and Xe is R;
• 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.
• CNP also includes poly( amino acid) conjugates which have a sequence as described above, but have a backbone that comprises both amide and non-amide linkages, such as ester linkages, like for example depsipeptides.
• Depsipeptides are chains of amino acid residues in which the backbone comprises both amide (peptide) and ester bonds.
• side chain refers either to the moiety attached to the alpha-carbon of an amino acid moiety, if the amino acid moiety is connected through amine bonds such as in polypeptides, or to any carbon atom-comprising moiety attached to the backbone of a poly( amino acid) conjugate, such as for example in the case of depsipeptides.
• the term “CNP” refers to polypeptides having a backbone formed through amide (peptide) bonds.
• ring moiety refers to the stretch of consecutive amino acid residues of the CNP drug or moiety that is located between two cysteine residues that form an intramolecular disulfide bridge or between homologous amino acid residues which are connected through a chemical linker.
• the ring moiety is located between two cysteine residues that form an intramolecular disulfide bridge.
• These two cysteines correspond to the cysteines at position 22 and position 38 in the sequence of CNP-38 (SEQ ID NO:24). Accordingly, amino acids 23 to 37 are located in said ring moiety, if the CNP drug or moiety has the sequence of CNP-38.
• sequence of the ring moiety of wild-type CNP is FGLKLDRIGSMSGLG (SEQ ID NO:96).
• CNP includes the above-described variants, analogs, orthologs, homologs, derivatives and fragments of CNP
• ring moiety also includes the corresponding variants, analogs, orthologs, homologs, derivatives and fragments of the sequence of SEQ ID NO:96. Accordingly, all references to specific positions within a reference sequence also include the equivalent positions in variants, analogs, orthologs, homologs, derivatives and fragments of a CNP moiety, even if not explicitly mentioned.
• CM 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. When two moieties of a molecule are linked by the C1-4 alkyl, then examples for such CM alkyl groups are -CH2-, -CH2-CH2-,
• CM alkyl may be interrupted by one or more moieties as defined below.
• Ci-6 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-6 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.
• examples for such Ci-6 alkyl groups are -CH2-, -CH2-CH2-, -CH(CH 3 )-, -CH
• 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.
• C1-20 alkyl or “C1-50 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 C1-10, C1-20 or Ci-50 carbon may optionally be replaced by a substituent as defined above.
• a C1-10, Ci -20 alkyl or C1-50 alkyl 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 straight-chain 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.
• a C2-6 alkynyl may be interrupted by one or more moieties as defined below.
• the term “C2-10 alkynyl”, “C2-20 alkynyl” and “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.
• 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 norbomane or norbomene.
• 8- to 30-membered carbopolycyclyl 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 carbopolycyclyl 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, benzo furan, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, 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 heterobi cyclyl or 8- to 11 -membered heterobicycle carbon may be replaced by a substituent as defined below.
• 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 in 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 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 ⁇ O)-”.
• a moiety: can be attached to two moieties or can interrupt a moiety either 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-50 alkyl C2-50 alkenyl, C2-50 alkynyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11 -membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl, and tetralinyl; 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-50 alkyl C2-50 alkenyl, C2-50 alkynyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11 -membered heterobicyclyl, phenyl, naphthyl, indenyl, indanyl, and tetralinyl; and
• -R and -R a are independently of each other selected from the group consisting of -H, 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.
• the conjugates of the present invention are prodrugs.
• the term “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.
• a drug moiety such as a CNP moiety
• 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.
• 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.
• 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.
• 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 -.
• 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 C1-50 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-, -C(O)-, -C(O)NH-, -C(O)N(CI- 4 alkyl)-, -O-C(O)-, -S(O)-, -S(O) 2 -, 4- to 7-membered heterocyclyl, phenyl and naphthyl.
• 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”.
• such 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 , -C(O)N(R xl R xla ), -S(O) 2 N(R xl R xla ), -S(O)N(R xl R xla ), -S(O) 2 R xl , -S(O)R xl , -N(R xl )S(O) 2 N(R xla R xlb ), -SR xl , -N(R xl R xla ), -NO 2 , -OC(O)R xl , -N(R xl )C(O)R xla , -N(R xl )S(O) 2 R xla , -N(R
• -R xl , -R xla , -R xlb are independently of each other selected from the group consisting of -H, -T°, Ci-50 alkyl, C 2 .so alkenyl, and C 2 -so alkynyl; wherein -T°, C1-50 alkyl, C 2 -so alkenyl, and C 2 .so alkynyl are optionally substituted with one or more -R x2 , which are the same or different and wherein C1-50 alkyl, C 2 -50 alkenyl, and C 2 -50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T°-, -C(O)O-, -O-, -C(O)-, -C(O)N(R x3 )-, -S(O) 2 N(R x3 )-, -S(O)N(R X3 )
• 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 , -C(O)N(R xl R xla ), -S(O) 2 N(R xl R xla ), -S(O)N(R xl R xla ), -S(O) 2 R xl , -S(O)R xl ,
• Ci-io alkyl, C 2 -io alkenyl, and C2-10 alkynyl are optionally substituted with one or more -R x2 , which are the same or different and wherein Ci-io alkyl, C 2 -io alkenyl, and C 2 -io 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 -, -S(O) 2 -, -S(O)
• 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 , -C(O)N(R xl R xla ), -S(O) 2 N(R xl R xla ), -S(O)N(R xl R xla ), -S(O) 2 R xl , -S(O)R xl ,
• Ci-6 alkyl, C 2 -6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more -R x2 , which are the same or different and wherein Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T 0 -, -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 -, -S(O)-, -N(R x3 )S(O)S(O)S(O)
• 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.
• the term “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 unit dose comprised within the unit dosage form of the present invention depends on the patient's actual body weight.
• 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.
• 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.
• 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 patient is an adult. In certain embodiments, the patient is a pediatric patient. In certain embodiments, the patient is an infant. In certain embodiments, 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.
• the patient's body weight is about 30 kg. In certain embodiment, the patient's body weight is about 40 kg. In certain embodiment, the patient's body weight is about 50 kg. In certain embodiment, the patient's body weight is about 60 kg. In certain embodiment, the patient's body weight is about 70 kg. In certain embodiment, the patient's body weight is about 80 kg.
• 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.
• 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 dualchamber 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. In certain embodiments, the preservative is benzylalcohol. In certain embodiments, 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.
• the preservative is thimerosal. In certain embodiments, the preservative is sorbic acid. In certain embodiments, 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-ethoxyethanol. 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, butylhydroxytoluene, butylhydroxyanisol, tocopherol, propylgallate, ascorbic acid, ethylenediaminetetraacetic acid (EDTA), poly(ethylenimine), vitamin E and mixtures thereof.
• the preservative is methionine.
• the preservative is butylhydroxytoluene.
• the preservative is butylhydroxyanisol.
• the preservative is tocopherol.
• the preservative is propylgallate.
• the preservative is ethylenediaminetetraacetic acid.
• the preservative is poly(ethylenimine).
• 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. In certain embodiments, 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. In certain embodiments, 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 maybe 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 15 pl.
• the patient is an infant and the volume of the unit dose is about 20 pl. In certain embodiments, 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 pg 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. In certain embodiments, 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
• 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. In certain embodiments, 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.
• 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. In certain embodiments, 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: CNP conjugate 8.2 - 44.4 % (w/w) succinic acid 0.9 - 1.2 % (w/w) trehalose dihydrate 53.7 - 89.1 % (w/w) Tris 1.0 - 1.5 % (w/w).
• 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. In certain embodiments, 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. In certain embodiments, 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.
• 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.
• no treatment emergent anti-CNP antibodies were detected upon treatment with the conjugate of the present invention.
• 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.
• 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): la), 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, 11, 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. In certain embodiments, 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 NOTO, 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 NOTO.
• -D of formula (la) or (lb) has the sequence of SEQ ID NOTO, 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.
• 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;
• -X- is -C(R 4 R 4a )-; -N(R 4 )-; -O-; -C(R 4 R 4a )-C(R 5 R 5a )-;
• X 1 is C; or S(O);
• -X 2 - is -C(R 8 R 8a )-; or -C(R 8 R 8a )-C(R 9 R 9a )-;
• -R 3 , -R 3a are independently selected from the group consisting of -H; and Ci-6 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 n 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 -R’/-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 C3-10 cycloalkyl; or 3- to 10-membered heterocyclyl; optionally, one or more of the pairs -Rfr-R 4 , -RV
• 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; 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.
• such 3- to 10-membered heterocycle formed by -R 3 /-R 3a together with the nitrogen atom to which they are attached has the following structure: wherein the dashed line indicates attachment to the rest of -L 1 -; the ring comprises 3 to 10 atoms comprising at least one nitrogen; and 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-6 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. In certain embodiments, -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.
• at least one of -R 8 and -R 8a of formula (Ila) is -H.
• 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 (Uh) is not replaced by -L 2 -Z or a substituent.
• -L 1 - of formula (lib) is substituted with one moiety -L 2 -Z. In certain embodiments, 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 (Uh) 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 (Uh’) 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 (Uh’) 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 (Uh’) 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 optional further substituents of -L 1 - of formula (II), (Ila), (Uh), (Uh’), (lie), (Ilc-a), (Ilc-b), (Ilc-i), (Ilc-ii), (Ilc-iii), (Ilc-iv), (IIc-v) are in certain embodiments as described above.
• 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;
• each -R 10 , -R 10a , -R 10b is independently selected from the group consisting of -H, -T, Ci- 20 alkyl, C2-20 alkenyl, and C2-20 alkynyl; wherein -T, C1-20 alkyl, C2-20 alkenyl, and C2-20 alkynyl are optionally substituted with one or more -R 11 , which are the same or different and wherein C1-20 alkyl, C2-20 alkenyl, and C2-20
• each T is independently of each other selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11 -membered heterobi cyclyl; wherein each T is independently optionally substituted with one or more -R 11 , which are the same or different; each -R 11 is independently of each other selected from halogen, -CN, oxo (
• Ci-6 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-6 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 -R'/-R l a , -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 -Rfr-R 2 ,
• 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.
• a moiety -L 1 - is of formula (IV): wherein the dashed line indicates attachment to -D which is a CNP moiety and wherein attachment is through a functional group of -D selected from the group consisting of -OH, -SH and -NH2; m is O or l; at least one or both of -R 1 and -R 2 is/are independently of each other selected from the group consisting of -CN, -NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, -C(O)R 3 , -S(O)R 3 , -S(O) 2 R 3 , and -SR 4 , one and only one of -R 1 and -R 2 is selected from the group consisting of
• -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 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 some 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.
• moiety -L 1 - is of formula (V): wherein the dashed line indicates attachment to -D which is a CNP moiety and wherein attachment is through an amine functional group of -D;
• -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-C& 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 cyclohetero alkyl; wherein -L 1 - is substituted with -L 2 -Z and wherein -L 1 - is optionally further substituted; wherein
• -Z is a water-soluble polymeric.
• -L 1 - of formula (V) is substituted with one moiety -L 2 -Z.
• 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 carboncarbon 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, indenyl, 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 -D;
• R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, 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-6 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.
• -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, alkoxyalkyl, aryl, “alkaryl” and “aralkyl” mean 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-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, Ci-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy, and C1-6 heteroalkoxy;
• Ar is a moiety which when included in formula (VII) forms a multisubstituted 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; wherein
• -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 -methoxythiophone; 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
• -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
• -L 2 - is a single chemical bond or a spacer; and is a water-soluble polymeric moiety.
• the optional further substituents of -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 maybe 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.
• -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) 2 N(R y1 )-, -S(O)N(R y1 )-, -S(O) 2 -, -S(O)-, -N(R yl )S(O) 2 N(R yla )-, -S-, -N(R y1 )-, -OC(OR yl )(R yla )-, -N(R yl )C(O)N(R yla )-, -OC(O)N(R y1 )-, Ci-50 alkyl, C 2 -so alkenyl, and C2-50 alkynyl; wherein
• -R yl and -R yla are independently of each other selected from the group consisting of -H, -T, Ci-50 alkyl, C 2 .so alkenyl, and C 2 -so alkynyl; wherein -T, C1-50 alkyl, C 2 .so alkenyl, and C 2 -so alkynyl are optionally substituted with one or more -R y2 , which are the same or different, and wherein C1-50 alkyl, C 2 -50 alkenyl, and C 2 -50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, -C(O)O-, -O-, -C(O)-, -C(O)N(R y4 )-, -S(O) 2 N(R y4 )-, -S(O)N(R y4 )-, -S(O) 2 -,
• -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, Ci-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl; wherein -T, C1-10 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 C1-10 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
• -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 )-, -S(O) 2 -, -S(O)-, -N(R yl )S(O) 2 N(R yla )-, -S-, -N(R y1 )-, -OC(OR yl )(R yla )-, -N(R yl )C(O)N(R yla )-, -OC(O)N(R y1 )-, C1.50 alkyl, C 2.5 o alkenyl, and C 2.5 o alkynyl; wherein
• -R yl and -R yla are independently selected from the group consisting of -H, -T, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl; 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 carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; each -R y2 is independently selected from the group consisting of halogen, and Ci-6 alkyl; and each -R y3 , -R y3a , -R y4 , -R y4a , -R y5 , -R y5a and -R y5b is independently of each other selected
• -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 carbopolycyclyl, and 8- to 30-membered heteropolycycl
• -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 -L 1 -; the unmarked dashed line indicates attachment to -Z;
• -R 1 is selected from the group consisting of -H, Ci-6 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. In certain embodiments, -R 1 of formula (i) is selected from the group consisting of -H, methyl, ethyl and propyl. In certain embodiments, -R 1 of formula (i) is selected from the group consisting of -H and methyl. In certain embodiments, -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 -L 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),
• -L 2 - is selected from the group consisting of wherein the dashed line marked with the asterisk indicates attachment to -L 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 -L 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 -L'-L 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 -L’-L 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 -L’-L 2 - is of formula (Ild-ii ’):
• the moiety -L’-L 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.
• -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.
• -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. In certain embodiments, -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(
• -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 2011123813 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 2021/055497 Al which is herewith incorporated by reference. Accordingly, in certain embodiments, -Z of formula (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). In certain embodiments, -Z is of formula (w) and -L 1 - is of formula (V).
• -Z-L 2 -L’- 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); 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-L 2 -L'- 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 -NH2 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:
• PGQEHPQARRYRGAQRRGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO:98); PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO:30); PGQEHPNARRYRGANRRGLSRGCFGLKLDRIGSMSGLGC (SEQ ID NO:99); and PGQEHPQARKYKGAQKKGLSKGCFGLKLDRIGSMSGLGC (SEQ ID NO: 100).
• CNP is selected from the group consisting of:
• AC-PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC-NH 2 SEQ ID NO: 102
• Ac-PGQEHPNARRYRGANRRGLSRGCFGLKLDRIGSMSGLGC SEQ ID NO: 103
• -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 In certain embodiments, -Z comprises an amide bond.
• -Z of formula (la) or (lb) comprises a moiety of formula (a): (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 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)-, -N(R
• 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-6 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 Ci-io alkyl, C2-10 alkenyl and C2-10 alkynyl, which C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more chemical groups selected from the group consisting of -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O) 2 N(R 4 )-, -S(O)N(R 4 )-, -S(O) 2 -, -S(O)-, -N(R 4 )S(O) 2 N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-, -N(R 4 )C(O)N(R 4a )-, and -OC(O)
• -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 C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl, which C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more chemical groups selected from the group consisting of -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O) 2 N(R 4 )-, -S(O)N(R 4 )-, -S(O) 2 -, -S(O)-, -N(R 4 )S(O) 2 N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-, -N(R 4 )C(O)N(R 4a )-, and -OC(O)N
• -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 C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more chemical groups selected from the group consisting of -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O) 2 N(R 4 )-, -S(O)N(R 4 )-,-S(O) 2 -, -S(O)-, -N(R 4 )S(O) 2 N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-, -N(R 4 )C(O)N(R 4a )-, and -OC(O)N
• -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 C 1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl, which C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl are optionally interrupted by one or more chemical groups selected from the group consisting of -C(O)O-, -O-, -C(O)-, -C(O)N(R 4 )-, -S(O) 2 N(R 4 )-, -S(O)N(R 4 )-,-S(O) 2 -, -S(O)-, -N(R 4 )S(O) 2 N(R 4a )-, -S-, -N(R 4 )-, -OC(OR 4 )(R 4a )-, -N(R 4 )C(O)N(R 4a )-, and -OC(O)N(
• -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- oxazolines),
• -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 PEG-based moiety.
• -P a , -P a and -P a of formula (a) independently comprise a PEG-based moiety comprising at least 20% PEG, in certain embodiments at least 30% PEG, in certain embodiments at least 40% PEG, in certain embodiments at least 50% PEG, in certain embodiments at least 60% PEG, in certain embodiments at least 70% PEG, in certain embodiments at least 80% PEG and in certain embodiments at least 90% PEG.
• -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
• BP a , -S a -, -S a -, -S a -, -S 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.
• -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): wherein the dashed line indicates attachment to -L 2 -;
• -S g -, -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 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-,
• 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 carbopolycycly
• 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-6 alkyl, wherein Ci-6 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, C 2 .6 alkenyl and C 2 -6 alkynyl, which are optionally substituted with one or more -R 1 , which is the same or different, wherein
• -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-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 C 1-6 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-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.
• -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).
• -S g -, -S g - and -S g - of formula (g-i) are as defined for formula (g).
• -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 -L 2 -; and each -Z c is a moiety wherein each cl is an integer independently ranging from about 200 to 250.
• the moiety of formula (h) is substituted with one or more substituents.
• both cl of formula (h) are the same.
• both cl of formula (h) are about 225.
• the moiety -Z is of formula (h-i): wherein the dashed line indicates attachment to -L 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. In certain embodiments, -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.
• -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.
• 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 15, if the CNP has the sequence of SEQ ID NO:24. In certain embodiments, 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 16, 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 20, if the CNP has the sequence of SEQ ID NO:24.
• said lysine side chain is 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 26, if the CNP has the sequence of SEQ ID NO:24.
• the CNP conjugate is of formula (Ilf), wherein cl is about 225, -D is a CNP moiety having the sequence of SEQ ID NO:20 and is attached to -L 1 - through the amine functional group provided by the side chain of the lysine at position 30.
• the CNP conjugate is of formula (Ilf), wherein cl is about 225, -D is a CNP moiety having the sequence of SEQ ID NO:21 and is attached to -L 1 - through the amine functional group provided by the side chain of the lysine at position 29.
• the CNP conjugate is of formula (Ilf), wherein cl is about 225, -D is a CNP moiety having the sequence of SEQ ID NO:22 and is attached to -L 1 - through the amine functional group provided by the side chain of the lysine at position 28.
• the CNP conjugate is of formula (Ilf), wherein cl is about 225, -D is a CNP moiety having the sequence of SEQ ID NO:23 and is attached to -L 1 - through the amine functional group provided by the side chain of the lysine at position 27.
• the CNP conjugate is of formula (Ilf), wherein cl is about 225, -D is a CNP moiety having the sequence of SEQ ID NO:30 and is attached to -L 1 - through the amine functional group provided by the side chain of the lysine at position 27.
• positions of the cysteines and lysines mentioned above vary depending on the lengths of the CNP moiety and that the person skilled in the art will have no difficulty identifying the corresponding cysteines and lysines in longer or shorter versions of the CNP moiety and also understands that for example some lysines may not be present in shorter CNP moieties. It is further understood that as a result of for example site-directed mutagenesis there might be more lysine residues in the non-ring forming part and/or ring forming part of the CNP moiety.
• the CNP conjugate is of formula (Ilf), wherein cl is about 225, -D is a CNP moiety having the sequence of SEQ ID NO:24 and is attached to -L 1 - through the amine functional group provided by the side chain of the lysine at position 26.
• the CNP conjugate is of formula (Ilf ’):
• each cl is an integer independently ranging from 200 to 250.
• each cl of formula (Ilf ’) is about 225.
• the unit dosage form of the present invention comprises a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf): wherein the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of a CNP moiety of SEQ ID NO:24 by forming an amide bond; 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, and wherein the unit dose is about 50 pg CNP /kg.
• the unit dosage form of the present invention comprises a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf):
• the unit dosage form of the present invention comprises a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf):
• the unit dosage form of the present invention comprises a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf ’): wherein the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; 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, and wherein the unit dose is 50 pg CNP/kg.
• the unit dosage form of the present invention comprises a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf ’):
• the unit dosage form of the present invention comprises a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf ’): wherein the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; 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, and wherein the unit dose is 100 pg CNP/kg.
• a further aspect of the present invention is a method of treating, reducing risk or delaying in a human patient a disease treatable by CNP, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose from about 6 pg CNP/kg to at least about 150 pg CNP/kg.
• the present invention is a method of treating, reducing risk or delaying in a human patient a disease treatable by CNP, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose from about 6 pg CNP/kg to at least about 100 pg CNP/kg.
• the present invention relates to a unit dosage form for use in the treatment of a disease treatable by CNP.
• said disease treatable by CNP is selected from the group consisting of bone-related disorders such as skeletal dysplasias; cancer; autoimmune diseases; fibrotic diseases; inflammatory diseases; central nervous system diseases such as neurodegenerative diseases; infectious diseases; lung diseases; heart and vascular diseases; metabolic diseases and ophthalmic diseases.
• said disease treatable by CNP is selected from the group consisting of achondroplasia, hypochondroplasia, short stature, dwarfism, osteochondrodysplasias, thanatophoric dysplasia, osteogenesis imperfecta, achondrogenesis, chondrodysplasia punctata, homozygous achondroplasia, camptomelic dysplasia, congenital lethal hypophosphatasia, perinatal lethal type of osteogenesis imperfecta, short-rib polydactyly syndromes, rhizomelic type of chondrodysplasia punctata, Jansen-type metaphyseal dysplasia, spondyloepiphyseal dysplasia congenita, atelosteogenesis, diastrophic dysplasia, congenital short femur, Langer- type mesomelic dysplasia, Nievergelt-type mesomelic dysplasia, Robinow syndrome, Reinhard
• said disease treatable by CNP is selected from the group consisting of achondroplasia such as homozygous achondroplasia, hypochondroplasia, short stature, dwarfism, osteochondrodysplasias, thanatophoric dysplasia, osteogenesis imperfecta, achondrogenesis, chondrodysplasia punctata, camptomelic dysplasia, congenital lethal hypophosphatasia, perinatal lethal type of osteogenesis imperfecta, short-rib polydactyly syndromes, rhizomelic type of chondrodysplasia punctata, Jansen-type metaphyseal dysplasia, spondyloepiphyseal dysplasia congenita, atelosteogenesis, diastrophic dysplasia, congenital short femur, Langer-type mesomelic dysplasia, Nievergelt-type mesomelic dysplasia, Robinow syndrome, Rein
• said disease treatable by CNP is one or more cardiovascular diseases selected from the group consisting of arrhythmia such as cardiac or sinus arrhythmia; atrial fibrillation; atrial flutter; bradycardia; Brugada syndrome; premature cardiac complexes; commotio cordis; heart block; long QT syndrome; parasystole; pre-excitation syndrome; tachycardia; ventricular fibrillation; ventricular flutter; cardiac conduction system disease; low cardiac output; cardiomegaly; dilated cardiomyopathy; hypertrophy such as left ventricular hypertrophy or right ventricular hyperthrophy; cardiomyopathy such as alcoholic, dilated, hypertrophic, restrictive, diabetic or Chagas cardiomyopathy; arrhythmogenic right ventricular dysplasia; endocardial fibroelastosis; endomyocardial fibrosis; glycogen storage disease type lib; Kearns-Sayre syndrome; myocardial reperfusion injury; myocarditis;
• said disease treatable by CNP is selected from the group consisting of ischemic heart disease such as myocardial infarction; congestive heart failure; arrhythmia and atherosclerosis.
• said disease treatable by CNP is one or more central nervous system diseases selected from the group consisting of brain ischemia such as ischemic hypoxia; brain infarction; transient ischemic attack; vertebrobasilar insufficiency; cerebrovascular disorders; stroke; intracranial hemorrhages; comeal neovascularization; comeal transplantation; gragft- versus-host disease; graft rejection; glaucoma such as angle-closure, neovascular, open-angle or low tension glaucoma; ischemic optic neuropathy; central serous chorioretinopathy; retinopathy such as diabetic or hypertensive retinopathy; retinal degeneration; macular degeneration; geographic atrophy; macular edema; Stargardt disease; vitelliform macular dystrophy; wet macular degeneration; retinoschisis; retinal detachment; retinal perforations; retinal haemorrhage; retinal neovascularization
• said disease treatable by CNP is selected from the group consisting of hypophosphatasia, hypochondroplasia, Muenke syndrome, hypertension, osteogenesis imperfecta and achondroplasia.
• said disease treatable by CNP is selected from the group consisting of achondroplasia, hypochondroplasia, short stature, Noonan syndrome or SHOX deficiency.
• said disease treatable by CNP is hypophosphatasia. In certain embodiments, said disease treatable by CNP is hypochondroplasia. In certain embodiments, said disease treatable by CNP is Muenke syndrome. In certain embodiments, said disease treatable by CNP is hypertension. In certain embodiments, said disease treatable by CNP is osteogenesis imperfecta. In certain embodiments, said disease treatable by CNP is achondroplasia.
• the present invention relates to a unit dosage form for use in the treatment of skeletal dysplasia, such as achondroplasia, the unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of at least 24 nmol CNP/kg and is administered to a human patient, wherein said administration results in an annualized growth velocity (AGV) of about 5.4 cm/year, such as of about 5.42 cm/year.
• AAV annualized growth velocity
• the present invention relates to a unit dosage form for use in the treatment of skeletal dysplasia, such as achondroplasia, the unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of about 24 nmol CNP/kg and is administered to a human patient, wherein said administration results in an annualized growth velocity (AGV) of 5.42 cm/year.
• AAV annualized growth velocity
• the present invention relates to a unit dosage form for use in the treatment of skeletal dysplasia, such as achondroplasia, the unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of about 100 pg CNP/kg and is administered to a human patient, wherein said administration results in an annualized growth velocity (AGV) of about 5.4 cm/year, such as of about 5.42 cm/year.
• AAV annualized growth velocity
• the present invention relates to a unit dosage form for use in the treatment of skeletal dysplasia, such as achondroplasia, the unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 100 pg CNP/kg and is administered to a human patient, wherein said administration results in an annualized growth velocity (AGV) of 5.42 cm/year.
• AAV annualized growth velocity
• the present invention relates to a unit dosage form for use in the treatment of skeletal dysplasia, such as achondroplasia, the unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg and is administered to a human patient aged 2 to 10 years, wherein said administration results in an annualized growth velocity (AGV) of 5.42 cm/year.
• AAV annualized growth velocity
• the present invention relates to a unit dosage form for use in the treatment of skeletal dysplasia, such as achondroplasia, the unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg and is administered to a human patient aged 2 to 5 years, wherein said administration results in an annualized growth velocity (AGV) of about 5.95 cm/year.
• AAV annualized growth velocity
• the present invention relates to a unit dosage form for use in the treatment of skeletal dysplasia, such as achondroplasia, the unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg and is administered to a human patient aged 2 to 5 years, wherein said administration results in an annualized growth velocity (AGV) of 5.95 cm/year.
• AAV annualized growth velocity
• the present invention relates to a unit dosage form for use in the treatment of skeletal dysplasia, such as achondroplasia, the unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose ranging from 12.3 nmol CNP/kg to 36.9 nmol CNP/kg, wherein said unit dosage form is administered to a human patient with open epiphysis and said treatment reduces the incidence of achondroplasia-related adverse events in the human patient.
• the present invention relates to a unit dosage form for use in the treatment of skeletal dysplasia, such as achondroplasia, the unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 24.6 nmol CNP/kg, wherein said unit dosage form is administered to a human patient with open epiphysis and said treatment reduces the incidence of achondroplasia-related adverse events in the human patient.
• the present invention relates to a unit dosage form for use in the treatment of skeletal dysplasia, such as achondroplasia, the unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 100 pg CNP/kg, wherein said unit dosage form is administered to a human patient with open epiphysis and said treatment reduces the incidence of achondroplasia-related adverse events in the human patient.
• the present invention relates to a unit dosage form for use in the treatment of skeletal dysplasia, such as achondroplasia, the unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg, wherein said unit dosage form is administered to a human patient with open epiphysis and said treatment reduces the incidence of achondroplasia-related adverse events in the human patient.
• the present invention relates to a unit dosage form for use in the treatment of skeletal dysplasia, such as achondroplasia, the unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 24.6 nmol CNP/kg, wherein said unit dosage form is administered weekly to a human patient with open epiphysis via subcutaneous injection and wherein each administration is associated with a frequency of injection site reaction of less than 3%, such as less than 2%, such as less than 1% or absence of injection site reaction.
• the present invention relates to a unit dosage form for use in the treatment of skeletal dysplasia, such as achondroplasia, the unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg, wherein said unit dosage form is administered weekly to a human patient with open epiphysis via subcutaneous injection and wherein each administration is associated with a frequency of injection site reaction of less than 3%, such as less than 2%, such as less than 1% or absence of injection site reaction.
• a further aspect of the present invention is a method of treating achondroplasia in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose from about 6 pg CNP/kg to at least about 150 pg CNP/kg.
• the unit dose is about 50 pg CNP/kg to about 150 pg CNP/kg, about 75 pg CNP/kg to about 125 pg CNP/kg, about 90 pg CNP/kg to about 110 pg CNP/kg or about 100 ug CNP/kg or 100 ug/CNP/kg.
• Such dosages are preferably administered weekly.
• Such dosages are preferably administered by weekly subcutaneous injection.
• a preferred compound in such methods is a compound of formula (Ilf) or (Ilf ’) with dosages referring to the mass of the CNP 1-38 moiety of said compound.
• a preferred regimen is a compound of formula (Ilf) or (Ilf ’) administered subcutaneously weekly at unit doses of about 100 ug CNP/kg of the CNP1-38 moiety of the compound of formula (Ilf) or (Ilf ’). Dosages of other compounds can be adjusted for equimolar delivery of the CNP moiety of the relevant compound as for the CNP moiety of a compound of formula (Ilf) or (Ilf ’) within a tolerance of +/- 20% or +/-10%.
• Dosages regiments of other compounds or the compound of formula (Ilf) or (Ilf ’) can be adjusted to deliver the same area under the curve +/- 20% or +/- 10% on a molar basis of CNP moiety, as a compound of formula (Ilf) or (Ilf ’) administered weekly subcutaneously.
• the same regimens can be used in treating other disease treatable with CNP disclosed herein.
• the present invention is a method of treating achondroplasia in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 6 pg CNP /kg, 20 pg CNP /kg, 50 pg CNP/kg, 75 pg CNP /kg, 100 pg CNP/kg or 125 pg CNP/kg.
• the present invention is a method of treating achondroplasia in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 50 pg CNP/kg to 100 pg CNP/kg.
• the present invention is a method of treating achondroplasia in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 50 pg CNP/kg.
• the present invention is a method of treating achondroplasia in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 100 pg CNP/kg.
• the present invention is a method of treating achondroplasia in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 50 pg CNP/kg to 100 pg CNP/kg, wherein the CNP conjugate is a compound of formula (Ilf ’): wherein the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; the dashed line marked with the asterisk indicates attachment to -Z having the structure and wherein each cl is an integer independently ranging from 200 to 250.
• the present invention is a method of treating achondroplasia in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 50 pg CNP/kg, wherein the CNP conjugate is a compound of formula (Ilf ’): wherein the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; the dashed line marked with the asterisk indicates attachment to -Z having the structure and wherein each cl is an integer independently ranging from 200 to 250.
• the present invention is a method of treating achondroplasia in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 100 pg CNP/kg, wherein the CNP conjugate is a compound of formula (Ilf ’):
• the present invention is a method of treating achondroplasia in a human patient, the method comprising the step of administering a unit dosage comprising a unit dose of 24.6 nmol CNP/kg, wherein the unit dosage comprises a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’), wherein the age of the patient ranges from 2 to 10 years old and said administration results in an annualized growth velocity of about 5.42 cm/year.
• the present invention is a method of treating achondroplasia in a human patient, the method comprising the step of administering a unit dosage comprising a unit dose of 100 pg CNP/kg, wherein the unit dosage comprises a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’), wherein the age of the patient ranges from 2 to 10 years old and said administration results in an annualized growth velocity of about 5.42 cm/year.
• the present invention is a method of treating achondroplasia in a human patient, the method comprising the step of administering a unit dosage comprising a unit dose of 100 pg CNP/kg, wherein the unit dosage comprises a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’), wherein the age of the patient ranges from 2 to 10 years old and said administration results in an annualized growth velocity of 5.42 cm/year.
• the present invention is a method of treating achondroplasia in a human patient, the method comprising the step of administering a unit dosage comprising a unit dose of 100 pg CNP/kg, wherein the unit dosage comprises a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’), wherein the age of the patient ranges from 2 to 5 years old and said administration results in an annualized growth velocity of about 5.95 cm/year.
• the present invention is a method of treating achondroplasia in a human patient, the method comprising the step of administering a unit dosage comprising a unit dose of 100 pg CNP/kg, wherein the unit dosage comprises a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’), wherein the age of the patient ranges from 2 to 5 years old and said administration results in an annualized growth velocity of 5.95 cm/year.
• Unit doses may be administered once or multiple times. For multiple administrations, the interval is preferably weekly, but can be twice a week, biweekly, or monthly among others. In certain embodiments, one unit dose is administered weekly via one subcutaneous injection. In certain embodiments, one unit dose is administered monthly via one subcutaneous injection. In certain embodiments, for patient groups weighing 55 kg or above, one unit dose may be split and administered via two simultaneous or successive injections.
• the CNP conjugate or pharmaceutically acceptable salt thereof may be administered for at least six months, a year, five years, ten years, until a patient is 18 years old, until patient's epiphyseal closure or indefinitely. In certain embodiments, the CNP conjugate or pharmaceutically acceptable salt thereof may be administered until a patient is 18 years old. In certain embodiments, the CNP conjugate or pharmaceutically acceptable salt thereof may be administered until a patient's ephiphysis is closed.
• Treatment may start antenatally, at birth or on diagnosis of a deficit or risk relating to CNP.
• a unit dose is determined for a particular drug, such as as a reversible CNP conjugate of formula (Ilf) or (Ilf ’)
• the unit dose can be used as a guide for other reversible CNP conjugates, such that the unit dose of other reversible conjugates is the same by moles of CNP as that for CNP of formula (Ilf) or (Ilf ’).
• Such guidance is particularly useful when the other conjugate releases a CNP moiety with a release half-life within plus or minus 20% of that of the conjugate of CNP of formula (Ilf) or (Ilf ’).
• an otherwise similar reversible conjugate of CNP- 53 can be administered by multiplying the dose for CNP-38 by the ratio of molecular weights of CNP-53/CNP-38.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose from about 6 pg CNP/kg to at least about 150 pg CNP/kg.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 6 pg CNP/kg, 20 pg CNP/kg, 50 pg CNP/kg, 75 pg CNP/kg, 100 pg CNP/kg or 125 pg CNP/kg.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 50 pg CNP /kg to 100 pg CNP /kg.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 50 pg CNP /kg.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 100 pg CNP /kg.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose ranging from about 12.3 nmol CNP /kg to about 36.9 nmol CNP/kg for a period of at least 52 weeks, said administration resulting in an annualized growth velocity (AGV) of about 5.4 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of at least 24 nmol CNP/kg for a period of at least 52 weeks, said administration resulting in an annualized growth velocity (AGV) of about 5.4 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of about 24.6 nmol CNP/kg for a period of at least 52 weeks, said administration resulting in an annualized growth velocity (AGV) of about 5.42 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 24.6 nmol CNP/kg for a period of at least 52 weeks, said administration resulting in an annualized growth velocity (AGV) of about 5.42 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 24.6 nmol CNP/kg for a period of at least 52 weeks to until the patient's ephiphysis is closed, said patient being 2 to 10 years of age, said administration resulting in an annualized growth velocity (AGV) of 5.42 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 24.6 nmol CNP/kg for a period of at least 52 weeks to until the patient's ephiphysis is closed, said patient being 2 to 5 years of age, said administration resulting in an annualized growth velocity (AGV) of about 5.95 cm/year, such as of 5.95 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 24.6 nmol CNP/kg for a period of at least 104 weeks, said administration resulting in an annualized growth velocity (AGV) of about 5.42 cm/year.
• AAV annualized growth velocity
• the annualized growth velocity can be determined by either measuring the increase in a patient's height for at least 52 weeks, such as for at least 104 weeks or 156 weeks or by measuring for a fraction of one year, such as for 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months and then extrapolating the value to one full year.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the steps of:
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of at least 100 pg CNP /kg for a period of at least 52 weeks, said administration resulting in an annualized growth velocity (AGV) of about 5.42 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of about 100 pg CNP/kg for a period of at least 52 weeks, said administration resulting in an annualized growth velocity (AGV) of about 5.42 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 100 pg CNP/kg for a period of at least 52 weeks, said administration resulting in an annualized growth velocity (AGV) of 5.42 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 100 pg CNP/kg for a period of at least 52 weeks until the patient's ephiphysis is closed, said patient being 2 to 10 years of age, said administration resulting in an annualized growth velocity (AGV) of 5.42 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 100 pg CNP/kg for a period of at least 52 weeks until the patient's ephiphysis is closed, said patient being 2 to 5 years of age, said administration resulting in an annualized growth velocity (AGV) of about 5.95 cm/year, such as 5.95 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 100 pg CNP/kg for a period of at least 104 weeks, said administration resulting in an annualized growth velocity (AGV) of 5.42 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose ranging from 12.3 nmol CNP/kg to 36.9 nmol CNP/kg for a period of at least 52 weeks, wherein said CNP conjugate unit dosage form is administered weekly to a human patient with open epiphysis via subcutaneous injection and wherein each administration is associated with a frequency of injection site reaction of less than 3%, such as less than 2%, such as less than 1% or absence of injection site reaction.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 24.6 nmol CNP/kg for a period of at least 52 weeks, wherein said CNP conjugate or unit dosage form is administered weekly to a human patient with open epiphysis via subcutaneous injection and wherein each administration is associated with a frequency of injection site reaction of less than 3%, such as less than 2%, such as less than 1% or absence of injection site reaction.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 100 pg CNP/kg for a period of at least 52 weeks, wherein said CNP conjugate or unit dosage form is administered weekly to a human patient with open epiphysis via subcutaneous injection and wherein each administration is associated with a frequency of injection site reaction of less than 3%, such as less than 2%, such as less than 1% or absence of injection site reaction.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg for a period of at least 52 weeks, wherein said CNP conjugate or unit dosage form is administered weekly to a human patient with open epiphysis via subcutaneous injection and wherein each administration is associated with a frequency of injection site reaction of less than 3%, such as less than 2%, such as less than 1% or absence of injection site reaction.
• the frequency of injection site reaction is less than 3%. In certain embodiments, the frequency of injection site reaction is less than 2%. In certain embodiments, the frequency of injection site reaction is less than 1%. In certain embodiments, there are no injection site reactions.
• the present invention is a method of increasing growth velocity in a achondroplasia human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose ranging from 12.3 nmol CNP/kg to 36.9 nmol CNP/kg for a period of at least 52 weeks, wherein said CNP conjugate or unit dosage form is administered to a human patient with open epiphysis and said treatment reduces the incidence of achondroplasia-related adverse events in the human patient.
• the present invention is a method of increasing growth velocity in a achondroplasia human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 24.6 nmol CNP/kg for a period of at least 52 weeks, wherein said CNP conjugate or unit dosage form is administered to a human patient with open epiphysis and said treatment reduces the incidence of achondroplasia-related adverse events in the human patient.
• the present invention is a method of increasing growth velocity in a achondroplasia human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg for a period of at least 52 weeks, wherein said CNP conjugate or unit dosage form is administered to a human patient with open epiphysis and said treatment reduces the incidence of achondroplasia-related adverse events in the human patient.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf’) at a unit dose of 50 pg CNP/kg to 100 pg CNP/kg.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 50 pg CNP/kg.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of at least 100 pg CNP/kg for a period of at least 52 weeks, said administration resulting in an annualized growth velocity (AGV) of about 5.42 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of about 100 pg CNP/kg for a period of at least 52 weeks, said administration resulting in an annualized growth velocity (AGV) of about 5.42 cm/year.
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg for a period of at least 52 weeks, said administration resulting in an annualized growth velocity (AGV) of 5.42 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg for a period of at least 52 weeks until the patient's ephiphysis is closed, said patient being 2 to 10 years of age, said administration resulting in an annualized growth velocity (AGV) of about 5.42 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg for a period of at least 52 weeks until the patient's ephiphysis is closed, said patient being 2 to 5 years of age, said administration resulting in an annualized growth velocity (AGV) of about 5.95 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg for a period of at least 104 weeks, said administration resulting in an annualized growth velocity (AGV) of at least about 5.42 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing growth velocity in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg for a period of at least 104 weeks, said administration resulting in an annualized growth velocity (AGV) of about 5.42 cm/year.
• AAV annualized growth velocity
• the present invention is a method of increasing long bone growth in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose from about 6 pg CNP/kg to at least about 150 pg CNP/kg.
• the present invention is a method of increasing long bone growth in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 6 pg CNP/kg, 20 pg CNP/kg, 50 pg CNP/kg, 75 pg CNP/kg, 100 pg CNP/kg or 125 pg CNP/kg.
• the present invention is a method of increasing long bone growth in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 50 pg CNP /kg to 100 pg CNP /kg.
• the present invention is a method of increasing long bone growth in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 50 pg CNP /kg.
• the present invention is a method of increasing long bone growth in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 100 pg CNP /kg.
• the present invention is a method of increasing long bone growth in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf’) at a unit dose of 50 pg CNP /kg to 100 pg CNP/kg.
• the present invention is a method of increasing long bone growth in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 50 pg CNP/kg.
• the present invention is a method of increasing long bone growth in a human patient, the method comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) at a unit dose of 100 pg CNP/kg.
• administration of the unit dose takes place by subcutaneous injection with a syringe, needle, pen injector or auto-injector. In certain embodiments, administration of the unit dose takes place by subcutaneous injection with a syringe. In certain embodiments, administration of the unit dose takes place by subcutaneous injection with a pen injector. In certain embodiments, administration of the unit dose takes place by subcutaneous injection with an auto-injector.
• the present methods can be used for treating or effecting prophylaxis of a patient having or at risk of (e.g., genetic risk) of a disease treatable with CNP. The present methods can also be used for treating a population of patients having or at risk of such a disease.
• Such a population can include at least 10, 100 or 1000 patients or may represent all patients at a particular institution.
• clinical trials can be useful for determining doses and dosage regimens de novo, the present methods can also be performed not in the course of a clinical trial.
• the regimen used results in a statistically significant improvement (p ⁇ 0.05) in at least one sign or symptom of patients (e.g., annualized growth velocity or A height SDS) in such a population relative to a contemporary or historical control population receiving placebo.
• Improvement in a sign or symptom of a disease treatable by CNP can also be monitored in an individual patient compared with baseline measurement(s) before treatment or comparison with mean values from a historical control population.
• improvement in a sign or symptom of an individual patient can be deemed significant if beyond the mean and one or two standard deviations of the mean value in such a control population in a direction indicating improvement.
• clinical trials can be useful for determining doses and dosage regimens de novo, the present methods can also be performed not in the course of a clinical trial.
• Treating refers to curing, reducing or inhibit further deterioration of at least one sign or symptom of a disease or stabilizing at least one sign or symptom of disease. Treating can be determined by comparing sign(s) and symptom(s) in an individual patient before (baseline) and after receiving treatment or by comparing a population of treated patients to a control population as in a clinical trial or trial with an animal model.
• Prophylaxis refers to preventing, reducing risk or delaying onset of at least one sign or symptom of disease in a population of patients (or animal models) at risk of the disease administered a drug or CNP conjugate according to the invention compared to a control population of patients (or animal models) at risk of the disease not treated with a drug or CNP conjugate according to the invention.
• the amount is also considered prophylactically effective if an individual treated patient achieves an outcome more favorable than the mean outcome in a control population of comparable patients not treated by methods of the invention.
• the present invention is a kit of parts comprising the unit dosage form of the present invention in a vial, a syringe prefilled with a reconstitution solution, a needle for transferring the reconstitution solution from the syringe into the vial, an administration syringe and an injection needle.
• the reconstitution solution is a sterile liquid, such as sterile water.
• a vial adapter could be used instead of the needle for transferring the reconstitution solution from the syringe into the vial and for transferring the reconstituted unit dosage form from the vial to the administration syringe.
• the vial adaptor is a one-piece moulded plastic part with a plastic spike or needle for penetration.
• the needle for transferring the reconstitution solution into the vial is a large-bore transfer needle that ensures transfer of the reconstitution solution from the syringe into the vial comprising the unit dosage form of the present invention.
• the large inner diameter of the needle cannula ensures an increased flow, thereby decreasing the required injection force.
• said needle is a 21Gx25 mm needle.
• the injection needle should ensure a comfortable subcutaneous injection, preferably with an injection time of the reconstituted unit dosage form of below 10s.
• the injection needle should have a certain needle gauge and needle length to ensure that the drug is administered in the subcutaneous layer with limited pain.
• the needle length may range from about 3 mm to 13 mm.
• injection needles such as a 29G 8 mm needle, 30G 12 mm needle or 30G/4 mm needle meet the requirements above.
• a highly concentrated reconstituted unit dosage form such as of a unit dosage form comprising about 60.4 mg/ml CNP conjugate may be challenging due to the high viscosity of the CNP conjugate.
• the present invention is a kit of parts comprising a pen injector or autoinjector and a vial comprising the unit dosage of the present invention, said vial being in the form of a pre- filled cartridge for use in the pen injector or auto-injector.
• the present invention is a pen injector or auto-injector comprising the unit dosage form of the present invention.
• the present invention also provides for a CNP, CNP conjugate or pharmaceutically acceptable salt thereof (such as a CNP or CNP conjugate or pharmaceutically acceptable salt thereof as described herein), or unit dosage form (as described herein), which is administered to a patient to provide a sustained exposure of free plasma CNP (free CNP) at an efficacious level between administrations for use in the therapeutic methods disclosed herein.
• a CNP, CNP conjugate or pharmaceutically acceptable salt thereof or unit dosage form is administered via a dosing frequency which sustains plasma free CNP concentration at a therapeutic level between successive doses, such as a plasma free CNP concentration of at least about 1 pmol/L. It will be understood that a sustained-release may be obtained by treatment with repeat dosing of a therapeutically effective amount of a CNP conjugate or pharmaceutically acceptable salt thereof.
• the sustained exposure of free CNP is for a period of at least 6 months, such as at least 9 months, such as at least 1 year.
• the minimum free CNP concentration in plasma may gradually increase after each successive dose (which may be referred to as a run in period), until a sustained therapeutically effective exposure level is maintained, that is, trough and peak values of CNP are at a steady state as a result of administration and elimination amounts being about equal through repeated cycles of administration.
• a sustained exposure may be obtained when the minimum free CNP concentration in plasma between successive administrations, also referred to as trough concentration, remains at a level which is at least about 1 pmol/L, or at least about 1.5 pmol/L, or about at least 5 pmol/L, or about 8 pmol/L, or about 15 pmol/L.
• a sustained exposure may be obtained when the minimum free CNP concentration in plasma between successive administrations, also referred to as trough concentration, remains at a level which is at least about 1.4 pmol/L, or at least about 1.6 pmol/L, or about at least 6.5 pmol/L, or about 9.4 pmol/L, or about 19.7 pmol/L.
• a sustained exposure may be obtained when the minimum free CNP concentration in plasma between successive administrations, also referred to as trough concentration, such as at least about 1.4 pmol/L, or at least about 1.6 pmol/L, or about at least 6.5 pmol/L, or about 9.4 pmol/L, or about 19.7 pmol/L.
• trough concentration such as at least about 1.4 pmol/L, or at least about 1.6 pmol/L, or about at least 6.5 pmol/L, or about 9.4 pmol/L, or about 19.7 pmol/L.
• the minimum free CNP concentration in plasma between successive administrations remains at a level of at least about 1.8 pmol/L, or at least about 2.3 pmol/L, or about at least 8.4 pmol/L, or about 12 pmol/L, or about 25 pmol/L
• the minimum free CNP concentration in plasma between successive administrations also referred to as trough concentration
• the minimum free CNP concentration in plasma between successive administrations remains at a level of at least about 2.7 pmol/L, or at least about 2.4 pmol/L, or about at least 9.7 pmol/L, or about 14.1 pmol/L, or about 29 pmol/L.
• the CNP, CNP conjugate or pharmaceutically acceptable salt thereof or unit dosage form is administered in a regimen (route of administration, frequency and amount) to achieve plasma levels of free CNP in which at steady state, troughs range from 1.8 pmol/L to about 29 pmol/L and peaks range from about 30 pmol/L to about 100 pmol/L. In some embodiments, troughs range from about 8 pmol/L to about 29 pmol/L and peaks range from about 30 pmol/L to about 50 pmol/L. In some embodiments, troughs range from about 18 pmol/L to about 29 pmol/L and peaks range from about 30 pmol/L to about 50 pmol/L.
• the ratio of peaks to troughs is no more than 1.5:1, 2:1 or 3:1.
• administration is weekly and by a subcutaneous route.
• free CNP concentrations are measured in a patient. Levels can be measured at baseline before treatment and one or more times after treatment commences.
• 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 achondroplasia-related adverse event is selected from the group consisting of sleep apnea syndrome, ear infection, foramen magnum stenosis and kyphosis.
• the achondroplasia-related adverse event is selected from the group consisting of sleep apnea syndrome, ear infection, foramen magnum stenosis and kyphosis.
• 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 present invention also provides for a method for treating ear infection in a patient or for reducing incidence of ear infection in a patient, 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 ear infection or reducing incidence of ear infection.
• 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 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.
• the patient has been diagnosed with achondroplasia. In certain embodiments, the patient is a pediatric patient with open bone epiphysis.
• the patient is aged up to 18 years of age or is less than 18 years of age. In certain embodiments, the patient is aged up to 16 years of age or is less than 16 years of age. In certain embodiments, the patient is aged up to 14 years of age or is less than 14 years of age. In certain embodiments, the patient is aged up to 10 years of age or is less than 10 years of age. In certain embodiments, the patient is aged up to 5 years of age or is less than 5 years of age. In certain embodiments, the patient is an achondroplasia patient aged up to 2 - 5 years of age, such as 2, 3 or 4 years of age.
• the patient is an achondroplasia patient at least 6 months of age, such as at least 1 year of age or at least 2 years of age. In certain embodiments, the patient is an achondroplasia patient with open bone epiphysis. In certain embodiments, the patient is an achondroplasia patient aged up to 18 years of age or is less than 18 years of age. In certain embodiments, the patient is an achondroplasia patient aged up to 16 years of age or is less than 16 years of age. In certain embodiments, the patient is an achondroplasia patient aged up to 14 years of age or is less than 14 years of age. In certain embodiments, the patient is an achondroplasia patient aged up to 10 years of age or is less than 10 years of age.
• the patient is an achondroplasia patient aged up to 5 years of age or is less than 5 years of age. In certain embodiments, the patient is an achondroplasia patient up to 2 - 5 years of age, such as 2, 3 or 4 years of age. In certain embodiments, the patient is an achondroplasia patient at least 6 months of age, such as at least 1 year of age or at least 2 years of age.
• a unit dosage form comprising 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.
• the unit dosage form of item 1 wherein the unit dosage form comprises a unit dose.
• the unit dose ranges from 50 gg to 7000 gg of CNP.
• -D is a CNP moiety
• -L 1 - is a reversible linker 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, 11, 12, 13, 14, 15 and 16
• y is an integer selected from the group consisting of 1, 2, 3, 4 and 5.
• each cl is an integer independently ranging from 220 to 245.
• a method of treating, reducing the risk of or delaying in a human patient a disease treatable by CNP comprising the step of administering the unit dosage form of any one of claims 1 to 27.
• a method of treating achondroplasia in a human patient comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 100 pg CNP/kg, wherein the CNP conjugate is a compound of formula (Ilf ’): wherein the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; the dashed line marked with the asterisk indicates attachment to -Z having the structure and wherein each cl is an integer independently ranging from 200 to 250, wherein the unit dose is administered weekly.
• a method of increasing growth velocity in a human patient comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of
• a method of increasing long bone growth in a human patient comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’), wherein each of (Ilf) and (Ilf ’) are as defined in item 2, at a unit dose of 100 pg CNP/kg, wherein the unit dose is administered weekly.
• a method of treating a skeletal dysplasia, such as achondroplasia comprising administering a unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’), wherein each of (Ilf) and (Ilf ’) are as defined in item 2, at a unit dose of 100 pg CNP/kg, wherein said unit dosage form is administered weekly to a human patient with open epiphysis and said treatment reduces the incidence of achondroplasia-related adverse events in the human patient.
• a method of increasing growth velocity in an achondroplasia human patient comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’), wherein each of (Ilf) and (Ilf ’) are as defined in item 2, at a unit dose of 100 pg CNP /kg for a period of at least 52 weeks, wherein said unit dosage form is administered to a human patient with open epiphysis and said treatment reduces the incidence of achondroplasia-related adverse events in the human patient
• a CNP conjugate or pharmaceutically acceptable salt thereof for use in a method of treating achondroplasia in a human patient comprising the step of administering the CNP conjugate or pharmaceutically acceptable salt thereof at a unit dose of 100 pg CNP/kg, wherein the CNP conjugate is a compound of formula (Ilf ’): wherein the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lys
• a CNP conjugate or pharmaceutically acceptable salt thereof for use in a method of increasing growth velocity in a human patient comprising the step of administering the CNP conjugate or pharmaceutically acceptable salt thereof of (a) formula (Ilf): wherein the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; the dashed line marked with the asterisk indicates attachment to -Z having the structure and wherein each cl is an integer independently ranging from 200 to 250 or
• a CNP conjugate or pharmaceutically acceptable salt thereof for use in a method of increasing long bone growth in a human patient comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’) wherein each of (Ilf) and (Ilf ’) are as defined in item 7, at a unit dose of 100 pg CNP /kg, wherein the unit dose is administered weekly.
• a CNP conjugate or pharmaceutically acceptable salt thereof for use in a method of treating a skeletal dysplasia, such as achondroplasia comprising administering a unit dosage form comprising a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’), wherein each of (Ilf) and (Ilf ’) are as defined in item 7, at a unit dose of 100 pg CNP/kg, wherein said unit dosage form is administered weekly to a human patient with open epiphysis and said treatment reduces the incidence of achondroplasia- related adverse events in the human patient.
• a CNP conjugate or pharmaceutically acceptable salt thereof for use in a method of increasing growth velocity in a achondroplasia human patient comprising the step of administering a CNP conjugate or pharmaceutically acceptable salt thereof of formula (Ilf) or (Ilf ’), wherein each of (Ilf) and (Ilf ’) are as defined in item 7, at a unit dose of 100 pg CNP/kg for a period of at least 52 weeks, wherein said unit dosage form is administered to a human patient with open epiphysis and said treatment reduces the incidence of achondroplasia-related adverse events in the human patient.
• each cl is an integer independently ranging from 200 to 250.
• Compound (1) was synthesized as described in WO2017/118693 for conjugate Hi.
• Compound (1) can also be represented as follows:
• n ranges from about 200 to about 250, such as from 200 to 250 corresponding to about lO kDa.
• Compound (1) is a long-acting essentially inactive prodrug consisting of CNP-38 transiently bound to a carrier molecule, mPEG via a reversible linker.
• mPEG acts as an inert carrier, extending CNP-38 circulation time in the body through a shielding effect that minimizes CNP- 38 clearance and largely inactivates CNP-38 until its release.
• Compound (1) releases active CNP via auto-cleavage of the reversible linker in a controlled-manner based on physiologic pH and temperature. As such, compound (1) is designed to provide sustained exposure of active CNP over 7 days, allowing an optimal pharmacokinetic profile for use in ACH.
• the drug product formulation comprising compound (1) is a lyophilized powder in a single-use vial, i.e. compound (1) 3.9 mg CNP-38/vial. Prior to use, the lyophilized powder must be reconstituted with sterile water for injection from a prefilled syringe. After reconstitution the concentration is 3.6 mg CNP-38/ml. This solution will be administered by subcutaneous injection via syringe and needle.
• the dose level CNP /kg or CNP-38/kg refers to the amount of CNP moiety (pg) present in the dose of compound (1), per kilogram of patient's bodyweight.
• TEAEs treatment-emergent adverse events
• Most TEAEs were mild or moderate.
• AEs adverse effects
• Local tolerability findings were predominantly mild to moderate redness.
• Two AEs related to injection sites, mild injection site pain (10 pg CNP/kg) and mild injection site discomfort (75 pg CNP/kg) were reported. No clinically relevant dose-dependent trends were observed on blood pressure, heart rate, or safety laboratory test results at all investigated doses. Also, no evidence of immunogenic response was observed in any subject.
• the study enrolled a minimum of 60 male and female prepubertal children with ACH aged 2 to 10 years old. The clinical trial is listed on www.clinicaltrials.gov under the ClinicalTrials.gov Identifier: NCT04085523. The objectives of the study were as follow:
• a form of skeletal dysplasia other than ACH or known medical conditions that result in short stature or abnormal growth such as severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), hypochondroplasia, growth hormone deficiency, Turner syndrome, pseudoachondroplasia, inflammatory bowel disease, chronic renal insufficiency, active celiac disease 1 , Vitamin D deficiency 2 , untreated hypothyroidism 3 , poorly controlled diabetes mellitus (HbAlc >8.0%) or diabetic complications 4 ]
• SADDAN severe achondroplasia with developmental delay and acanthosis nigricans
• hypochondroplasia growth hormone deficiency
• Turner syndrome pseudoachondroplasia
• inflammatory bowel disease chronic renal insufficiency
• active celiac disease 1 Vitamin D deficiency 2
• untreated hypothyroidism 3 untreated hypothyroidism 3
• poorly controlled diabetes mellitus HbAlc
• Vitamin D deficiency or insufficiency treated with supplementation is allowed.
• Vitamin D deficiency is defined as 25(OH)D level ⁇ 20ng/mL ( ⁇ 49.9 nmol/L)
• insufficiency is defined as 25(OH)D level 20-30ng/mL (49.92 - 74.86 nmol/L).
• Participants with Vitamin D deficiency or insufficiency must be on Vitamin D regimen before randomization.
• Child has significant electrocardiogram abnormalities, including evidence of a previous myocardial infarction, left ventricular hypertrophy, flat T waves (particularly in the inferior leads) or more than minor non-specific ST-T wave changes or:
• This trial is a multicenter trial consisting of two treatment periods.
• a 52 week double-blind, randomized, placebo controlled, dose escalation trial evaluating up to 5 different dose levels of weekly compound (1) administered subcutaneously in prepubertal children 2 to 10 years old, inclusive, with ACH.
• Table 2 describes the baseline demographics for cohorts 1, 2 and 3, with each cohort also containing placebo subjects. Following completion of the trial and unblinding of the data, the baseline demographics for cohorts 1, 2, 3 and 4 and the placebo subjects is displayed in Table 3.
• Orthostatic heart rate (HR) and systolic/diastolic BP will also be measured at Visit 1 prior to administration of study drug when the participant is at rest for 5 minutes (preferably supine) and again after standing at 3 minutes for assessment of orthostatic hypotension.
• Orthostatic hypotension is defined as decrease in SBP of > 20 mmHg (Stewart et al., Pediatrics, 141, 1-13, 2018).
• Accompanying tachycardia is defined as change of heart rate increment of >40 bpm and absolute orthostatic HR >130 bpm (for ages 13 years and younger) (Singer et al., Journal of Pediatrics, 160, 222-226, 2012).
• Sparse PK samples are collected in all subjects (if body weight allows) prior to and at 8, 24, 48 h post the initial dose and post-dose at 1 (trough), 2 (any time during the week), 3 (any time during the week), 6 (trough), 9 (any time) and 12 (trough) months + every 3 months for the duration of the study.
• a population PK model was used to characterize the sparse PK data.
• a dose related increase in exposure was observed across the four dosing cohorts, 6 pg/kg, 20 pg/kg, 50 pg/kg and 100 pg/kg. Sustained exposure to free CNP was observed, and a half-life for free CNP of ⁇ 110 hours was estimated.
• Table 4 Predicted median free CNP C m ax for the subjects
• Table 5 Estimated half-lives for free CNP in the subjects
• CNP-38 Blood samples for determination of CNP-38 were acidified immediately after collection, using citrate acid buffer, to stabilize the prodrug in the sample thereby avoiding further liberation of CNP-38 from the prodrug.
• CNP-38 was determined in plasma (heparin) following protein precipitation and solid phase extraction and analyzed using liquid chromatography and tandem mass spectrometry detection.
• CNP-38 38 amino acid peptide
• the quantification was performed using the peak area ratios of analyte versus IS.
• the calibration curve fitting was done by 1 /concentration- weighted linear regression.
• the calibration range in non-acidified plasma was 1.38 to 138 pmol/1.

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